6 - CONTACT DERMATITIS AND DRUG ERUPTIONS Flashcards
Inflammatory reaction of the skin from exposure to a substance that causes eruptions No previous exposure necessary
Irritant contact dermatitis
Acquired sensitivity to various substances that produce inflammatory reactions only in persons who have been previously sensitized
Allergic contact dermatitis
Pain and burning more common in this type of contact dermatitis
Irritant
Alkalis penetrate and destroy deeply because they:
Dissolve keratin
Principal compounds in alkalis
Sodium Potassium Ammonium Ca hydroxide
Powerful acids are______ whereas weaker acids are _______ A. Astringent B. Corrosive
B A
What type of acid produces a brownish charring of the skin, beneath which is an ulceration that heals slowly
Sulfuric acid
This acid is used more widely than any other acid in industry
Sulfuric acid
This acid causes deep burns Tissue is stained yellow
Nitric acid
One of the strongest inorganic acids, capable of dissolving glass
Hydrofluoric acid
This acid is used in the manufacturing of pigments
Titanium hydrochloride
What to do if you come in contact with titanium hydrochloride
Wipe away Water causes burns
Acid in tear gas that can cause dermatitis
Chloroacetophenone
Petrolatum dermatitis from impure petroleum jelly or lubricating oil manifests as
Verrucous thickening of skin
What type of hypersensitivity Allergic contact dermatitis
Cell mediated Type IV
Application of substances suspected to be the cause to intact uninflamed skin usually on upper back
Patch test
Patches in patch test are removed after_____ and reevaluated after ______
48 hours Day 4 or 5
In photopatch test, a standard patch test is applied for 48h then exposed to ______ J/m2 of UVA and read after another 48 hours
5-15
Most frequent site for nail polish dermatitis
Eyelids
Earlobe dermatitis is indicative of sensitivity from ______
Nickel
Deodorant and clothing dye can cause dermatitis in the axillary area. Which part of the axilla is involved in what substance?
Deodorant-axillary vault Clothing dye- axillary fold
Most common cause of allergic contact dermatitis in florists
Peruvian lily
Difference between dermatitis and fungal infection on the foot
Toe webs involved in fungal infections
Dermatitis from metals is usually due to
Nickel and chromates
Most common cause of allergic contact dermatitis in children and adults
Nickel
Leading cause of allergic contact dermatitis associated with cosmetics
Fragrance
Chemical in hair dye that can cause dermatitis
Phenylenediamine
Hair bleaches contain ________ that can cause dermatitis
Ammonium persulfate
Chemical found in most so called natural products that is an allergen
Propolis
Most common sunscreen allergen
Oxybenzone
Least irritating antiperspirant
Aluminum chlorhydrate
Which drug induces the highest rate of allergic reactions
Clonidine
Produce sensitization of skin when applied topically, when ingested, an acute flare at site of contact dermatitis may occur
Anamnestic (recalled) eruption
Most common topical local anesthetic that can cause dermatitis
Benzocaine
Antibiotics that most commonly cause dermatitis
Neomycin Bacitracin
Wheal and flare reaction occurring when a substance is applied to the intact skin
Contact urticaria
two types of dermatitis caused by substances coming in contact with the skin
irritant dermatitis and allergic contact dermatitis
inflammatory reaction in the skin resulting from exposure to a substance that causes an eruption in most people who come in contact with it
Irritant dermatitis
an acquired sensitivity to various substances that produce inflammatory reactions only in those persons who have been previously sensitized to the allergen.
Allergic contact dermatitis
Irritant Contact Dermatitis
Many substances act as irritants that produce a nonspecific inflammatory reaction of the skin. This type of dermatitis may be induced in any person if there is contact with a sufficiently high concentration. No previous exposure is necessary, and the effect is evident within minutes, or a few hours at most. The concentration and type of toxic agent, duration of exposure, and condition of the skin at the time of exposure produce the variation in severity of the dermatitis from person to person, or from time to time in the same person. The skin may be more vulnerable because of maceration from excessive humidity or exposure to water, heat, cold, pressure, or friction. Dry skin, as opposed to wet skin, is less likely to react to contactants, although in chronic xerosis, as seen in elderly patients, increased sensitivity to irritants results. Thick skin is less reactive than thin skin. Atopic patients are predisposed to irritant hand dermatitis. Repeated exposure to some of the milder irritants may produce a hardening effect over time This process makes the skin more resistant to the irritant effects of a given substance. Symptomatically, pain and burning are more common in irritant dermatitis, contrasting with the usual itch of allergic reactions. Avoidance, substitution of nonirritating agents when possible, and protection, most often by wearing gloves or using barrier creams, are the mainstays of treatment
Irritant dermatitis is often produced by alkalis such as soaps, cement, detergents, bleaches, ammonia preparations, lye, drain pipe cleaners, and toilet bowl and oven cleansers (Fig. 6.1). Alkalis penetrate and destroy deeply because they dissolve keratin. Strong solutions are corrosive, and immediate application of a weak acid such as vinegar, lemon juice, or 0.5% hydrochloric acid solution will lessen their effects.
Fig. 6.1 Cement burns. (Courtesy Steven Binnick, MD.)
ALKALIS
The principal compounds are sodium, potassium, ammonium, and calcium hydroxides. Occupational exposure is frequent among workers in soap manufacturing. Sodium silicate (water glass) is a caustic used in soap manufacture and paper sizing and for the preservation of eggs. Alkalis in the form of soaps, bleaching agents, detergents, and most household cleansing agents figure prominently in the causes of hand eczema. Alkaline sulfides are used as depilatories. Calcium oxide (quicklime) forms slaked lime when water is added. Severe burns may be caused in plasterers.
IRRITANT DERMATITIS SECONDARY TO ACIDS
Fig. 6.2 Drip burn from acid solution.
The powerful acids are corrosive, whereas the weaker acids are astringent. Hydrochloric acid produces burns that are less deep and more liable to form blisters than injuries from sulfuric and nitric acids (Fig. 6.2). Hydrochloric acid burns are encountered in those who handle or transport the product and in plumbers and those who work in galvanizing or tin-plate factories. Sulfuric acid produces a brownish charring of the skin, beneath which is an ulceration that heals slowly. Sulfuric acid is used more widely than any other acid in industry; it is handled principally by brass and iron workers and by those who work with copper or bronze. Nitric acid is a powerful oxidizing substance that causes deep burns; the tissue is stained yellow. Such injuries are observed in those who manufacture or handle the acid or use it in the making of explosives in laboratories. At times, nitric acid or formic acid is used in assaults secondary to interpersonal conflicts, resulting in scarring most prominently of the face, with the complication of renal failure present in a small number of cases.
Hydrofluoric acid is used widely in rust remover, in the semiconductor industry, and in germicides, dyes, plastics, and glass etching. It may act insidiously at first, starting with erythema and ending with vesiculation, ulceration, and finally necrosis of the tissue. Hydrofluoric acid is one of the strongest inorganic acids, capable of dissolving glass. Hypocalcemia, hypomagnesemia, hyperkalemia, and cardiac dysrhythmias may complicate hydrofluoric acid burns. Fluorine is best neutralized with hexafluorine solution, followed by 10% calcium gluconate solution or magnesium oxide.
Oxalic acid may produce paresthesia of the fingertips, with cyanosis and gangrene. The nails become discolored yellow. Oxalic acid is best neutralized with limewater or milk of magnesia to produce precipitation Titanium hydrochloride is used in the manufacture of pigments. Application of water to the exposed part will produce severe burns. Therefore treatment consists only of wiping away the noxious substance.
Phenol (carbolic acid) is a protoplasmic poison that produces a white eschar on the surface of the skin. It can penetrate deep into the tissue. If a large surface of the skin is treated with phenol for cosmetic peeling effects, the absorbed phenol may produce glomerulonephritis and arrhythmias. Locally, temporary anesthesia may also occur. Phenol is readily neutralized with 65% ethyl or isopropyl alcohol.
Chromic acid burns, which may be seen in electroplating and dye production occupations, may result in extensive tissue necrosis and acute renal damage. Excision of affected skin down to the fascia should be accomplished rapidly, and hemodialysis to remove circulating chromium should start in the first 24 hours. Other strong acids that are irritants include acetic, trichloracetic, arsenious, chlorosulfonic, fluoroboric, hydriodic, hydrobromic, iodic, perchloric, phosphoric, salicylic, silicofluoric, sulfonic, sulfurous, tannic, and tungstic acids.
Management of acid burns
Treatment of acid burns consists of immediate rinsing with copious amounts of water and alkalization with sodium bicarbonate, calcium hydroxide (limewater), or soap solutions. Phosphorus burns should be rinsed off with water, followed by application of copper sulfate to produce a precipitate.
Airbag Dermatitis
Airbags are deployed as a safety feature on cars when rapid deceleration occurs. Activation of a sodium azide and cupric oxide propellant cartridge releases nitrogen gas, which expands the bag at speeds exceeding 160 km/hour (96 miles/hour). Talcum powder, sodium hydroxide, and sodium carbonate are released into the bag. Abrasions, thermal, friction, and chemical burns and an irritant contact dermatitis may result. Superficial erythema may respond well to topical steroids, but full-thickness burns may occur and require debridement and grafting.
Give exampes of metal salts that act as irritants
Metal salts that act as irritants include the cyanides of calcium, copper, mercury, nickel, silver, and zinc and the chlorides of calcium and zinc.
Bromine, chlorine, fluorine, and iodine are also irritants. Occupational exposure to methyl bromide may produce erythema and vesicles in the axillary and inguinal areas. Insecticides, including 2,2-dichlorovinyl dimethyl phosphate used in roach powder and fly repellents and killers, can act as irritants.
Fiberglass Dermatitis
Fiberglass dermatitis is seen after occupational or inadvertent exposure. The small spicules of glass penetrate the skin and cause severe irritation with tiny erythematous papules, scratch marks, and intense pruritus. Usually, there is no delayed hypersensitivity reaction. Wearing clothes that have been washed together with fiberglass curtains, handling air conditioner filters, or working in the manufacture of fiberglass material may produce severe folliculitis, pruritus, and eruptions that may simulate scabies or insect bites. Fiberglass is also used in thermal and acoustic installation, the wind industry, padding, vibration isolation, curtains, draperies, insulation for automobile bodies, furniture, gasoline tanks, and spacecraft. Talcum powder dusted on the flexure surfaces of the arms before exposure makes the fibers slide off the skin. A thorough washing of the skin after handling fiberglass is helpful. Patch testing to epoxy resins should be done when evaluating workers in fiberglass and reinforced-plastics operations, because an allergic contact dermatitis may be difficult to discern from fiberglass dermatitis.
irritant derm secondary to dusts
Some dusts and gases may irritate the skin in the presence of heat and moisture, such as perspiration. The dusts of lime, zinc and arsenic may produce folliculitis. Dusts from various woods, such as teak, may incite itching and dermatitis. Dusts from cinchona bark, quinine, and pyrethrum produce widespread dermatitis. Tobacco dust in cigar factories, powdered orris roo , lycopodium, and dusts of various nutshells may cause swelling of the eyelids and dermatitis of the face, neck, and upper extremities, the distribution of an airborne contact dermatitis. Dusts formed during the manufacture of high explosives may cause erythematous, vesicular, and eczematous dermatitis that may lead to generalized exfoliative dermatitis.
Irritant derm secondary to capsaicin
Hand irritation produced by capsaicin in hot peppers used in Korean and North Chinese cuisine (Hunan hand) may be severe and prolonged, sometimes necessitating stellate ganglion blockade and gabapentin Pepper spray, used by police in high concentrations and by civilians in less concentrated formulas, contains capsaicin and may produce severe burns. Cold water is not much help; capsaicin is insoluble in water. Acetic acid 5% (white vinegar) or antacids (Maalox) may completely relieve the burning, even if applied an hour or more after the contact. Application should be continued until the area can be dried without return of the discomfort.
Tear Gas Dermatitis
Fig. 6.3 Mustard gas burn
Lacrimators such as chloroacetophenone in concentrated form may cause dermatitis, with a delayed appearance about 24–72 hours after exposure. Irritation or sensitization, with erythema and severe vesiculation, may result. Treatment consists of lavage of the affected skin with sodium bicarbonate solution and instillation of boric acid solution into the eyes. Contaminated clothing should be removed.
Sulfur mustard gas, also known as yperite (dichlorodiethyl sulfide), has been used in chemical warfare. Erythema, vesicles, and bullae result from mild to moderate exposure (Fig. 6.3). Toxic epidermal necrolysis (TEN)–like appearance may follow more concentrated contact. The earliest and most frequently affected sites are areas covered by clothing and humidified by sweat, such as the groin, axillae, and genitalia.
Mace is a mixture of tear gas (chloroacetophenone) in trichloroethane and various hydrocarbons resembling kerosene. It is available in a variety of self-defense sprays. Mace is a potent irritant and may cause allergic sensitization (Fig. 6.4). Treatment consists of changing clothes, then washing with oil or milk, followed by washing with copious amounts of water
Fig. 6.4 Mace-induced reaction.
Chloracne
Workers in the manufacture of chlorinated compounds may develop chloracne, with small, straw-colored follicular plugs and papules, chiefly on the malar crescent, retroauricular areas, earlobes, neck, shoulders, and scrotum. Histologically, there is a loss of sebaceous glands and the formation of cystic structures. The synthetic waxes chloronaphthalene and chlorodiphenyl, used in the manufacture of electric insulators and in paints, varnishes, and lacquers, predispose workers engaged in the manufacture of these synthetic waxes to chloracne. Exposure to 2,6-dichlorobenzonitrile during the manufacture of a herbicide, and to 3,4,3′,4′-tetrachloroazooxybenzene, which is an unwanted intermediate byproduct in the manufacture of a pesticide, may also produce chloracne.
A contaminant in the synthesis of herbicides and hexachlorophene, 2,3,7,8-tetracholorodibenzo-p-dioxin, produces a chemical burn in the acute stage, but chloracne, hyperpigmentation, hirsutism, and skin fragility (with or without criteria for porphyria cutanea tarda) are manifestations of chronic toxicity. Gastrointestinal tract cancer and malignancies of the lymphatic and hematopoietic systems are suspected to result. Although direct contact is the usual method of exposure, inhalation, ingestion, or contact with contaminated clothing may also result in chloracne. Chloracne may persist for long periods because dioxin is stored in the liver and released slowly into the circulation. Treatment is with medications used in acne vulgaris, including isotretinoin.
Hydrocarbons that produce skin eruptions
Many hydrocarbons produce skin eruptions. Crude petroleum causes generalized itching, folliculitis, or acneiform eruptions The irritant properties of petroleum derivatives are directly proportional to their fat-solvent properties and inversely proportional to their viscosity. Oils of the naphthalene series are more irritating han those of the paraffin series. Refined fractions from petroleum are less irritating than the unrefined products, although benzene, naphtha, and carbon disulfide may cause a mild dermatitis
Lubricating and cutting oils are causes of similar cutaneous lesions. They represent a frequent cause of occupational dermatoses in machine tool operators, machinists, layout men, instrument makers, and setup men. Insoluble (neat) cutting oils are responsible for a follicular acneiform eruption on the dorsa of the hands, the forearms, face, thighs, and back of the neck. Hyperpigmentation, keratoses, and scrotal cancer have been found in those exposed to insoluble cutting oils. Soluble oils and synthetic fluids used in metalworking do not result in acne, but rather an eczematous dermatitis, usually of the dorsal forearms and hands. Approximately 50% of the time it is irritant and in the remainder it is allergic. Allergic contact dermatitis arises from various additives, such as biocides, coloring agents, and deodorizers.
Coal briquette makers develop dermatitis as a result of a tarry residue from petroleum used in their trade. Paraffin exposure leads to pustules, keratoses, and ulcerations Shale oil workers develop an erythematous, follicular eruption that eventually leads to keratoses, which may become the sites of carcinoma. It is estimated that 50% of shale oil workers have skin problems.
Impure and low-grade paraffins and mineral oils cause similar skin eruptions. Initially, the skin changes are similar to those in chloracne. Over time, a diffuse erythema with dappled pigmentation develops. Gradually, keratoses appear, and after many years, some of these are the sites of carcinoma. Melanoderma may occur from exposure to mineral oils and lower-grade petroleum from creosote, asphalt, and other tar products. Photosensitization may play a role. Creosote is a contact irritant, sensitizer, and photosensitizer. Allergy is demonstrated by patch testing with 10% creosote in oil.
Petrolatum dermatitis may appear as a verrucous thickening of the skin caused by prolonged contact with impure petroleum jelly or, occasionally, lubricating oil. A follicular-centered process may occur in which erythematous horny nodules are present, usually on the anterior and inner aspects of the thighs. There are no comedones, and the lesions are separated by apparently normal skin.
Acne corne consists of follicular keratosis and pigmentation resulting from crude petroleum, tar oils, and paraffin. The dorsal aspects of the fingers and hands, the arms, legs, face, and thorax are the areas usually involved. The lesions are follicular horny papules, often black, and are associated at first with a follicular erythema and later with a dirty brownish or purplish spotty pigmentation, which in severe cases becomes widespread and is especially marked around the genitals. This syndrome may simulate pityriasis rubra pilaris or lichen spinulosus.
Coal tar and pitch and many of their derivatives produce photosensitization and an acneiform folliculitis of the forearms, legs, face, and scrotum. Follicular keratoses (pitch warts) may
develop and later turn into carcinoma. Soot, lamp black, and the ash from peat fires produce dermatitis of a dry, scaly character, which over time forms warty outgrowths and cancer. Chimney sweep’s cancer occurs under a soot wart and is usually located on the scrotum, where soot, sebum, and dirt collect in the folds of the skin. This form of cancer has virtually disappeared.
Acquired perforating disease may occur in oil field workers who use drilling fluid containing calcium chloride. Patients develop tender, umbilicated papules of the forearms that microscopically show transepidermal elimination of calcium.
Solvents that cause dermatitis
The solvents cause approximately 10% of occupational dermatitis. When solvents are applied to the hands o cleanse them, the surface oil is dissolved, and a chronic fissured dermatitis results. Additionally, peripheral neuropathy and chemical lymphangitis may occur after the solvents are absorbed through the fissured skin. Solvent sniffers may develop an eczematous eruption around the mouth and nose; erythema and edema occur. This is a direct irritant dermatitis caused by the inhalation of the solvent placed on a handkerchief.
Trichloroethylene is a chlorinated hydrocarbon solvent and degreasing agent also used in the dry-cleaning and refrigeration industry. Inhalation may produce exfoliative erythroderma, mucous membrane erosions, eosinophilia, and hepatitis.
Allergic contact dermatitis caused by alcohol is rarely encountered with lower-aliphatic alcohols. A severe case of bullous and hemorrhagic dermatitis on the fingertips and deltoid region was caused by isopropyl alcohol. Although rare, ethyl alcohol dermatitis may also be encountered. Cetyl and stearyl alcohols may provoke contact urticaria.
Pathophysiology of allergic contact dermatitis
Allergic contact dermatitis results when an allergen comes into contact with previously sensitized skin. It is caused by a specific acquired hypersensitivity of the delayed type, also known as cell-mediated (type IV) hypersensitivity. These sensitizers do not cause demonstrable skin changes on initial contact.
Persons may be exposed to allergens for years before finally developing hypersensitivity. Genetic variability in the immunologic processes leading to sensitization and other factors, such as concentration of the allergen applied, its vehicle, timing and site of the exposure, presence of occlusion, age, gender, and race of the patient, and presence of other skin or systemic disorders, likely determine whether any given exposure will result in sensitization. Once sensitized, however, subsequent outbreaks may result from extremely slight exposure.
Childhood exposures do result in allergy, and the frequency of allergy in this age group is increasing. The most common relevant allergens in young children are nickel, cobalt, fragrance, lanolin, and neomycin. In adolescents potassium dichromate and Myroxylon pereirae become significant. Sensitivity is rarely lost over the years; older patients have similar rates of allergy as adults.
Occasionally, dermatitis may be induced when the allergen is taken internally by a patient first sensitized by topical application, as with substances such as cinnamon oil or various medications. The anamnestic response is termed systemic contact dermatitis. It may appear first at the site of the prior sensitization or past positive patch test, but may spread to a generalized morbilliform or eczematous eruption. Additional morphologic patterns include vesicular hand eczema, urticaria, erythema multiforme, vasculitis, or symmetric drug-related intertriginous and flexural exanthema (SDRIFE). Formerly called baboon syndrome, SDRIFE is a deep-red-violet eruption on the buttocks, genital area, inner thighs, and sometimes the axillae.
The most common causes of contact dermatitis in the United States are toxicodendrons (poison ivy, oak, or sumac), nickel, balsam of Peru (Myroxylon pereirae), neomycin, fragrance, formaldehyde and the formaldehyde releasing preservatives, bacitracin, and rubber compounds. Frequent positive reactions to gold and thimerosal do not often correlate with the clinical exposure history. Gold reactions, which may be prolonged, can be correlated in some cases with oral gold exposure or occupational dermatitis, but in most cases, the relevance is questionable. Thimerosal reactions are probably related to its use as a preservative in common vaccines and skin-testing material. It also serves as a marker for piroxicam photosensitivity.
Eczematous delayed-type hypersensitivity reaction, as exemplified by allergic contact dermatitis and the patch test, must be distinguished from immediate-type hypersensitivity reaction. The latter presents within minutes of exposure with urticaria and is proved with a scratch test. It should be kept in mind, however, that persons who develop contact urticaria to a substance may concomitantly have a type IV delayed-type sensitization and eczema from the same allergen.
In some patients, impetigo, pustular folliculitis, and irritation or allergic reactions from applied medications are superimposed on the original dermatitis. A particularly vexing situation is when allergy to topical corticosteroids complicates an eczema, in which case the preexisting dermatitis usually does not flare, but simply does not heal as expected. The cutaneous reaction may also provoke a hypersusceptibility to various other, previously innocuous substances, which continues the eczematous inflammatory response indefinitely.
These eruptions resolve when the cause is identified and avoided. For acute generalized allergic contact dermatitis, treatment with systemic steroidal agents is effective, beginning with 40–60 mg/ day of prednisone in a single oral dose, and tapering slowly to topical steroids. When the eruption is limited in extent and severity, local application of topical corticosteroid creams, lotions, or aerosol sprays is preferred.
used to detect hypersensitivity to a substance that is in contact with the skin so that the allergen may be determined and corrective measures taken
Patch Test.
Fig. 6.5 Positive patch test reaction.
So many allergens can cause allergic contact dermatitis that it is impossible to test a person for all of them. In addition, a good history and observation of the pattern of the dermatitis, its localization on the body, and its sta e of activity are helpful in determining the cause. The patch test is confirmatory and diagnostic, but only within the framework of the history and physical findings; it is rarely helpful if it must stand alone. Interpretation of the relevance of positive tests and the subsequent education of patients are challenging in some cases. The Contact Allergen Management Program (CAMP) provides names of alternative products that may be used by patients when an allergen is identified. This is available through the American Contact Dermatitis Society.
The patch test consists of application of substances suspected to be the cause of the dermatitis to intact uninflamed skin. Patch testing may be administered by the thin-layer rapid-use epicutaneous (TRUE) test or by individually prepared patches The TRUE test has resulted in more screening for allergic contact dermatitis than in the past, but if it does not reveal the allergen for a highly suspect dermatitis, testing with an expanded series will on average yield relevant allergens in more than half of these patients. Dermatitis originating in the workplace will almost always require individualized testing.
Test substances are applied usually to the upper back, although if only one or two are applied, the upper outer arm may be used. Each patch should be numbered to avoid confusion. The patches are removed after 48 hours (or sooner if severe itching or burning occurs at the site) and read. The patch sites need to be evaluated again at day 4 or 5 because positive reactions may not appear earlier. Some allergens may take up to day 7 to show a reaction, and the patient should be advised to return if such a delayed reaction occurs. Erythematous papules and vesicles with edema are indicative of allergy (Fig. 6.5). Occasionally, patch tests for potassium iodide, nickel, or mercury will produce pustules at the
site of the test application. Usually no erythema is produced; therefore the reaction has no clinical significance.
Strong patch test reactions may induce a state of hyperirritability (“excited skin syndrome”) in which adjacent tests that would otherwise be negative appear as weakly positive. Weakly positive tests in the presence of strong tests do not prove sensitivity. The skin and mucous membranes vary widely in the ability to react to antigens. The oral mucosa is more resistant to primary irritants and is less liable to be involved in allergic reactions. This may be because the keratin layer of the skin more readily combines with haptens to form allergens. Also, the oral mucosa is bathed in saliva, which cleanses and buffers the area and dilutes irritants. However, patch testing for various types of oral signs and symptoms, such as swelling, tingling and burning, perioral dermatitis, and the appearance of oral lichen planus, is useful in determining a cause in many cases.
Potent topical corticosteroids, ultraviolet (UV) light, prednisone, and the acquired immunodeficiency syndrome (AIDS) have been reported to interfere with the reliability of patch testing. Expert opinion regarding patch testing while on other immunosuppressants (e.g , methotrexate, azathioprine, biologics) is that these are less likely to produce unreliable testing. However, with all of these, false-negative reactions may result; the value of testing in such circumstances is that if a positive reaction occurs, a diagnosis may be made. Vitiliginous skin is less reactive than normally pigmented adjacent skin.
test that may be used to screen products used by the patient
Provocative Use Test
Products that are made to stay on the skin once applied (as opposed to shampoos or soaps) are rubbed on normal skin of the inner aspect of the forearm several times da ly for 5 days. A pink itchy patch will indicate the need to avoid the product. Further testing to its individual ingredients will help identify replacement products. This test may also confirm a positive closed patch test reaction to ingredients of the personal care product.
test used to evaluate for contact photoallergy to such substances as sulfonamides, phenothiazines, p-aminobenzoic acid, oxybenzone, 6-methyl coumarin, musk ambrette, and tetrachlorosalicylanilide
Photopatch Test
A standard patch test is applied for 48 hours; this is then exposed to 5 to 15 J/m2 of UVA and read after another 48 hours. To test for 6-methyl coumarin sensitivity, the patch is applied in the same manner but for only 30 minutes before light exposure, rather than for 48 hours. A duplicate set of nonirradiated patches is used in testing for the presence of routine delayed hypersensitivity reactions. Also, a site of normal skin is given an identical dose of UVA to test for increased sensitivity to light without prior exposure to chemicals. There is a steady increase in incidence of photoallergy to sunscreening agents and a decreasing incidence of such reactions to fragrance.
Causes of contact allergies on the head and neck
The scalp is relatively resistant to the d ment of contact allergies; however, involvement may be caused by hair dye, hair spray, shampoo, or permanent wave solutions. The surrounding glabrous skin, including the ear rims and backs of the ears, may be much more inflamed and suggestive of the cause. Persistent otitis of the ear canal may be caused by sensitivity to neomycin, an ingredient of most aural medications. The eyelids are the most frequent site for nail polish dermatitis. Volatile gases, false-eyelash adhesive, fragrances, eye medications, preservatives, mascara, rubber in sponges used to apply cosmetics, and eye shadow are also frequently implicated (Fig. 6.6). Perioral dermatitis and cheilitis may be caused by flavoring agents in dentifrices and gum, as well as fragrances, shellac, medicaments, and sunscreens in lipstick and lip balms. Perfume dermatitis may cause redness just under the ears or on the neck. Earlobe dermatitis is indicative of nickel sensitivity. Photocontact dermatitis may involve the entire face and may be sharply cut off at the collar line or extend down on to the sternum in a V shape. There is a typical clear area under the chin where there is little or no exposure to sunlight. The left cheek and left side of the neck (from sun exposure while driving) may be the first areas involved.
Fig. 6.6 Eyelid dermatitis.
Causes of contact allergies on the trunk
The trunk is an infrequent site; however, the dye or finish of clothing may cause dermatitis. The axilla may be the site of deodorant dermatitis and clothing-dye dermatitis; involvement of the axillary vault suggests the former; of the axillary folds, the latter. In women, brassieres cause dermatitis from the material itself, the elastic, or the metal snaps or underwires.
Causes of contact allergies on the arms
The wrists may be involved because of jewelry or the backs of watches and clasps, all of which may contain nickel. Wristbands made of leather are a source of chrome dermatitis.
Causes of contact allergies on the hands
Innumerable substances may cause allergic contact dermatitis of the hands, which typically occurs on the backs of the hands and spares the palms. Florists will often develop fingertip or palmar lesions. A hand dermatitis that changes from web spaces to fingertips or from palms to dorsal hands should trigger patch testing. Poison ivy and other plant dermatitides frequently occur on the hands and arms. Rubber glove sensitivity must be kept constantly in mind. Usually, irritancy is superimposed on allergic contact dermatitis of the hands, altering both the morphologic and histologic clues to the diagnosis.
Causes of contact allergies on the abdomen
The abdomen, especially the waistline may be the site of rubber dermatitis from the elastic in pants and undergarments The metallic rivets in blue jeans may lead to periumbilical dermatitis in nickel-sensitive patients, as may piercings of the umbilicus.
Causes of contact dermatitis on the groin
The groin is usually spared, but the buttocks and upper thighs may be sites of dermatitis caused by dyes. The penis is frequently involved in poison ivy dermatitis. Condom dermatitis may also occur. The perianal region may be involved from the “caine” medications in suppositories, as well as preservatives and fragrances in cleansing materials. Almost half of women with pruritus vulvae have one or more relevant allergens; often these are medicaments, fragrances, or preservatives.
Causes of contact dermatitis on the lower extremities
The shins may be the site of rubber dermatitis from elastic stockings. Feet are sites for shoe dermatitis, most often attributable to rubber sensitivity, chrome-tanned leather, dyes, or adhesives. Application of topical antibiotics to stasis ulcers frequently leads to sensitivity and allergic contact dermatitis.
Dermatitis Resulting From Plants
A large number of plants, including trees, grasses, flowers, vegetables, fruits, and weeds, are potential causes of dermatitis. Eruptions from them vary considerably in appearance but are usually vesicular and accompanied by marked edema. After previous exposure and sensitization to the active substance in the plant, the typical dermatitis results from reexposure. The onset is usually a few hours or days after contact. The characteristic linearly grouped lesions are probably produced by brushing the skin with a leaf edge or a broken twig or by carriage of the allergen under the nails. Contrary to popular belief, the contents of vesicles are not capable of producing new lesions
Toxicodendron (Poison Ivy)
Fig. 6.7 Acute poison ivy reaction.
Toxicodendron dermatitis includes dermatitis from members of the Anacardiaceae family of plants: poison ivy (T. radicans, or Rhus radicans), poison oak (T. diversilobum, R. diversaloba), poison sumac (T. vernix, R. vernix), Japanese lacquer tree, cashew nut tree (allergen in nutshell), mango (allergen in rind, leaves, or sap), Rengas tree, and Indian marking nut tree. The ginkgo (allergen in fruit pulp), spider flower or silver oak, Gluta species of trees and shrubs in Southeast Asia, Brazilian pepper tree, also known as Florida holly, and poisonwood tree contain almost identical antigens.
Toxicodendron dermatitis appears within 48 hours of exposure of a person previously sensitized to the plant. It usually begins on the backs of the fingers, interdigital spaces, wrists, and eyelids, although it may begin on the ankles or other parts that have been exposed. Marked pruritus is the first symptom; inflammation, vesicles, and bullae may then appear. The vesicles are usually grouped and often linear (Fig. 6.7). Large bullae may be present, especially on the forearms and hands. The eyelids are puffy and worse in the morning, improving as the day progresses (Fig. 6.8). Pruritus ani and involvement of the genital areas occur frequently. A black lacquer deposit may occur in which the sap of the plant has been oxidized after being bound to the stratum corneum (Fig. 6.9) Untreated Toxicodendron dermatitis usually lasts 2–3 weeks.
The fingers transfer the allergen to other parts, especially the forearms and the male prepuce, which become greatly swollen. However, once the causative oil has been washed off, there is no spreading of the allergen. Some persons are so susceptible that direct contact is not necessary, the allergen apparently being carried by objects with prior exposure to the catechol. Occasionally, eating the allergen, as occurred in a patient who ingested raw cashew
nuts in an imported pesto sauce, may result in SDRIFE (see earlier) or a systematized allergic contact dermatitis with the morphology of a generalized erythematous papular eruption.
The cause is an oleoresin known as urushiol, of which the active agent is a mixture of catechols. This and related resorcinol allergens are present in many plants and also in Philodendron species, wood from Persoonia elliptica, wheat bran, and marine brown algae.
The most striking diagnostic feature is the linearity of the lesions. It is rare to see vesicles arranged linearly except in plantinduced dermatitis. A history of exposure in the country or park to plants that have shiny leaves in groups of three, followed by the appearance of vesicular lesions within 2 days, usually establishes the diagnosis.
Eradication of plants having grouped “leaves of three” growing in frequented places is one easy preventive measure, as is recognition of the plants to avoid. An excellent resource is a pamphlet available from the American Academy of Dermatology. If the individual is exposed, washing with soap and water within 5 minutes may prevent an eruption. Protective barrier creams are available tha are somewhat beneficial. Quaternium-18 bentonite has been shown to prevent or diminish experimentally produced poison ivy dermatitis.
Innumerable attempts have been made to immunize against poison ivy dermatitis by oral administration of the allergen or subcutaneous injections of oily extracts. To date, no accepted method of immunization is available. Repeated attacks do not confer immunity, although a single severe attack may achieve this by what has been called massive-dose desensitization.
When the diagnosis is clear and the eruption severe or extensive, systemic steroidal agents are effective, beginning with 40–60 mg of prednisone in a single oral dose daily, tapered off over a 3-week period. When the eruption is limited in extent and severity, local application of topical corticosteroid creams, lotions, or aerosol sprays is preferred. Time-honored calamine lotion without phenol is helpful and does no harm. Antihistaminic ointments should be avoided because of their sensitization potential. This also applies to the local application of the “caine” topical anesthetics.
Other Toxicodendron-Related Dermatitides
Lacquer dermatitis is caused by a furniture lacquer made from the Japanese lacquer tree, used on furniture, jewelry, or bric-a-brac. Antique lacquer is harmless, but lacquer less than 1 or 2 years old is highly antigenic. Cashew oil is extracted from the nutshells of the cashew tree (Anacardium occidentale). This vesicant oil contains cardol, a phenol similar to urushiol in poison ivy. The liquid has many commercial applications, such as the manufacture of brake linings, varnish, synthetic glue, paint, and sealer for concrete.
Mango dermatitis is uncommon in natives of mango-growing countries (e.g., Philippines, Guam, Hawaii, Cuba) who have never been exposed to contact with Toxicodendron species. Many persons who have been so exposed, however, whether or not they had dermatitis from it, are sensitized by one or a few episodes of contact with the peel of the mango fruit. The palms carry the allergen, so the eyelids and the male prepuce are often early sites of involvement.
Ginkgo tree dermatitis simulates Toxicodendron dermatitis with its severe vesiculation, erythematous papules, and edema. The causative substances are ginkgolic acids from the fruit pulp of the ginkgo tree. Ingestion of the ginkgo fruit may result in perianal dermatitis. Ginkgo biloba given orally for cerebral disturbances is made from a leaf extract so it does no elicit a systemic contact allergy when ingested.
Flowers and Houseplants that causes dermatitis.
Among the more common houseplants, the velvety-leafed philodendron, Philodendron crystallinum (and its several variants), known in India as the “money plant,” is a frequent cause of contact dermatitis. The eruption is often seen on the face, especially the eyelids, carried there by hands that have watered or cared for the plant. English ivy follows philodendron in frequency of cases of occult contact dermatitis. Primrose dermatitis affects the fingers, eyelids, and neck with a punctate or diffuse erythema and edema. Formerly found most frequently in Europe, the primrose is now a common U.S. houseplant. Primin, a quinone, is the causative oleoresin abounding in the glandular hairs of the plant Primula obconica.
The popular cut flower, the Peruvian lily, is the most common cause of allergic contact dermatitis in florists. When handling flowers of the genus Alstroemeria, the florist uses the thumb and second and third digits of the dominant hand. Because it is chronic, fissured hyperkeratotic dermatitis results, identical to the “tulip fingers” seen among sensitized tulip workers (see Fig. 6.10). Testing is done with the allergen tuliposide A. It does not penetrate nitrile gloves. The geranium, scorpion flower (Phacelia crenulata or P. campanularia), hydrangea, creosote bush (Larvia tridentata), Heracula, daffodil, foxglove, pooja, lisianthus, lilac, lady slipper, magnolia, and tulip and narcissus bulbs are other flowers that commonly cause allergic reactions among florists. The poinsettia and oleander almost never cause dermatitis, despite their reputation for it, although they are toxic if ingested.
Chrysanthemums frequently cause dermatitis, with the hands and eyelids of florists most often affected. The α-methylene portion of the sesquiterpene lactone molecule is the antigenic site, as it is in the other genera of the Compositae family.
A severe inflammatory reaction with bulla formation may be caused by the prairie crocus (Anemone patens L.), the floral emblem of the province of Manitoba. Several species of ornamental “bottle
brush” from Queensland (Grevillea banksii, G. Robyn Gordon, G. robusta), may cause allergic contact dermatitis. It is exported to the United States and other Western countries. The allergen is a long-chain alkyl resorcinol. Cross-sensitivity to Toxicodendron has been demonstrated. Treatment of all these plant dermatitides is the same as that recommended for toxicodendron dermatitis.
Contact dermatitis may be caused by handling many other flowers, such as the geranium, scorpion flower (Phacelia crenulata or P. campanularia), hydrangea, creosote bush (Larvia tridentata), Heracula, daffodil, foxglove, lilac, lady slipper, magnolia, and tulip and narcissus bulbs. The poinsettia and oleander almost never cause dermatitis, despite their reputation for it, although they are toxic if ingested.
Parthenium hysterophorus is a photosensitizing weed. The welldeserved reputation for harmfulness of dieffenbachia, a common, glossy-leafed house plant, rests on the high content of calcium oxalate crystals in its sap, which burn the mouth and throat severely if any part of the plant is chewed or swallowed. Severe edema of the oral tissues may result in complete loss of voice, thus its common nickname, “dumb cane.” It does not appear to sensitize. The castor bean, the seed of Ricinus communis, contains ricin, a poisonous substance (phytotoxin). Its sap contains an antigen that may cause anaphylactic hypersensitivity and also dermatitis.
Fruit and Vegetables that cause dermatitis
Many vegetables may cause contact dermatitis, including asparagus, carrot, celery, cow-parsnip, cucumber, garlic, Indian bean, mushroom, onion, parsley, tomato, and turnip. Onion and celery, among other vegetables, have been incriminated in the production of contact urticaria and even anaphylaxis. Several plants, including celery, fig, lime, and parsley, can cause a phototoxic dermatitis because of the presence of psoralens. Phototoxic contact dermatitis from plants is discussed more fully in Chapter 3.
Trees that cause dermatitis
Fig. 6.11 Tea tree oil dermatitis.
Trees with timber and sawdust that may produce contact dermatitis include ash, birch, cedar, cocobolo, elm, Kentucky coffee tree, koa, mahogany, mango, maple, mesquite, milo, myrtle, pine, and teak. The latex of fig and rubber trees may also cause dermatitis, usually of the phototoxic type. Melaleuca oil (tea tree oil), which may be applied to the skin to treat a variety of maladies, can cause allergic contact dermatitis, primarily through the allergen D-limonene (Fig. 6.11). The exotic woods, especially cocobolo and rosewood are prominent among allergens that may produce erythema multiforme (EM) after cutaneous exposure. Toxicodendron, tea tree oil, various medicaments, and a variety of other allergens may induce this reaction.
Tree-Associated Plants that cause dermatitis
Foresters and lumber workers can be exposed to allergenic plants other than trees. Lichens are a group of plants composed of symbiotic algae and fungi. Foresters and wood choppers exposed to these lichens growing on trees may develop severe allergic contact dermatitis. Exposure to the lichens may also occur from firewood, funeral wreaths, and also fragrances added to aftershave lotions (oak moss and tree moss). Sensitization is produced by d-usnic acid and other lichen acids contained in lichens. The leafy liverwort (Frullania nisquallensis), a forest epiphyte growing on tree trunks, has produced allergic dermatitis in forest workers The eruption is commonly called “cedar poisoning.” It resembles Toxicodendron dermatitis; its attacks are more severe during wet weather. The allergen is sesquiterpene lactone.
Pollens and Seeds that cause dermatitis
The pollens in ragweed are composed of two antigens. The protein fraction causes the respiratory symptoms of asthma and hay fever, and the oil-soluble portion causes contact dermatitis. Ragweed oil dermatitis is a seasonal disturbance seen mainly during the ragweed growing season from spring to fall. Contact with the plant or with wind-blown fragments of the dried plant produces the typical dermatitis. The oil causes swelling and redness of the lids and entire face, and a red blotchy eruption on the forearms that, after several attacks, may become generalized, with lichenification. It closely resembles chronic atopic dermatitis, with lichenification of the face, neck, and major flexures, and severe pruritus. The distribution also mimics that of photodermatitis, with ragweed dermatitis differentiated by its involvement of the upper eyelids and the retroauricular and submental areas. Chronic cases may continue into the winter, although signs and symptoms are most severe at the height of the season. Sesquiterpene lactones are the cause. Coexisten sensitization to pyrethrum may account for prolongation of ragweed dermatitis. Men outnumber women in hypersensitivity reactions; farmers outnumber patients of all other occupations.
Marine Plants that cause dermatitis
Numerous aquatic plants are toxic or produce contact dermatitis. Algae are the worst offenders. Freshwater plants are rarely of concern. Seaweed dermatitis is a type of swimmer’s eruption produced by contact with a marine blue green alga, Lyngbya majuscula Gomont. The onset is within a few minutes of leaving the ocean, with severe itching and burning, followed by dermatitis, blisters, and deep, painful desquamation that affects the areas covered by the bathing suit, especially the scrotum, perineum, and perianal areas and occasionally the breasts in women). Patch tests with the alga are neither necessary nor helpful because it is a potent irritant. Bathing in fresh water within 10 or 15 minutes of leaving the ocean may prevent the dermatitis. The Bermuda fire sponge may produce contact erythema multiforme. Trawler fishermen in the Dogger Bank area of the North Sea develop allergic dermatitis after contact with Alcyonidium hirsutum. This seaweed-like animal colony becomes caught in nets and produces erythema, edema, and lichenification on the fishermen’s hands and wrists.
Dermatitis From Clothing
Fig. 6.12 Waistband clothing dermatitis.
A predisposition to contact dermatitis from clothing occurs in persons who perspire freely or who are obese and wear clothing that tends to be tight. Depending on the offending substance, various regions of the body will be affected. Regional location is helpful in identifying the sensitizing substance. The axillary folds are often involved; the vaults of the axillae are usually spared. Sites of increased perspiration and sites where evaporation is impeded, such as the intertriginous areas, will tend to leach dyes from fabrics to produce dermatitis. Areas where the material is tight against the skin, such as the waistband or neck, are frequently involved (Fig. 6.12). The thighs are affected when pants contain the offending allergen. The hands, face, and undergarment sites are usually spared, but otherwise these reactions may be scattered and generalized. Secondary changes of lichenification and infection occur frequently because of the chronicity of exposure.
Cotton, wool, linen, and silk fabrics were used exclusively before the advent of synthetic fabrics. Most materials are now blended in definite proportions with synthetics to produce superior lasting and esthetic properties. Dermatitis from cotton is virtually nonexistent. In most cases, there is no true sensitization to wool. Wool acts as an irritant because of the barbs on its fibers These barbs may produce severe pruritus at points of contact with the skin, especially in the intertriginous areas. In persons with sensitive skin, such as those with atopic dermatitis, the wearing of wool is not advisable because of its mechanical irritative properties. Silk is a sensitizer, but rarely; the nature of the allergen is not known. Many patients believe their detergent is the source of a dermatitis, but this is rarely the case.
Numerous synthetic fibers are available for clothing and accessory manufacture, all of which again are remarkably free of
sensitizing properties. Polyvinyl resins are the plastics used in such apparel as raincoats, rainhoods, wristbands, suspenders, plastic mittens, and gloves. These also are only infrequently found to be causes of contact dermatitis.
The most common causes of clothing dermatitis are the fabric finishers, dyes, and rubber additives. Fabric finishers are used to improve the durability, appearance, and feel of a material. Antiwrinkling and crease-holding chemicals are mostly resins, which are incorporated into the fibers as they are being manufactured or applied to the finished fabric. Fabrics are treated to make them less vulnerable to the effects of perspiration and ironing. Clothing may be treated with these substances to make it dry rapidly after washing. They are used to make clothing fabrics shrink resistant and water and stain repellent. When all these uses are taken into consideration, the low incidence of dermatitis from these formaldehyde resin materials is remarkable.
Ethylene urea melamine formaldehyde resin and dimethylol dihydroxyethylene urea formaldehyde resin are the best screening agents. Many persons also react to formaldehyde and the formaldehyde-releasing preservatives such as quaternium 15. Avoidance of exposure of the skin to formaldehyde resin is most difficult. New clothes should be thoroughly washed twice before wearing the first time. Even with this precaution, however, allergens may still be present in sufficient quantities to continue the dermatitis. T-shirts, sweat-shirts and pants, white underclothes suitable for bleaching, and garments of mixed synthetic fibers with cotton fibers added to make them drip-dry are most likely to cause problems in these patients.
Synthetic fabrics such as polyester and acetate liners in women’s clothing are also prime causes, and women are more affected than men. Even infants may be affected, however, with dyes in diapers accounting for some cases. Many patients do not react to paraphenylene diamine, but only to the disperse dye allergens. The best screening agents are disperse blue 106 and 124. Lymphomatoid contact allergy may result from clothing dye reactivity.
Suspected fabrics may be soaked in water for 15 minutes and applied under a patch for 72–96 hours. Jeans, Spandex, silk, 100% linen, 100% nylon, and 100% cotton that is not wrinkle resistant or colorfast are best tolerated. Spandex is a nonrubber (but elastic) polyurethane fiber. It is widely used for garments such as girdles, brassieres and socks, but is generally safe in the United States because it is free of rubber additives.
Shoe Dermatitis
Fig. 6.13 Acute shoe dermatitis.
Footwear dermatitis may begin on the dorsal surfaces of the toes and may remain localized to that area indefinitely (Fig. 6 13). There is erythema, lichenification, and, in severe cases, weeping and crusting. Secondary infection is frequent. In severe cases, an id reaction may be produced on the hands, similar to the reaction from fungal infection of the feet. A diagnostic po nt is the normal appearance of the skin between the toes, which has no contact with the offending substance. In fungal infections, the toe webs are usually involved. Another pattern seen is involvement of the sole with sparing of the instep and flexural creases of the toes. Also, purpuric reactions may occur to components of black rubber mix. Hyperhidrosis and atopy predispose to development of shoe allergy.
Shoe dermatitis is most frequently caused by the rubber accelerators mercaptobenzothiazole, carbamates, and tetramethylthiuram disulfide. Potassium dichromate in leather and the adhesives used in synthetic materials (especially p-tert-butylphenol formaldehyde resin) are also common shoe allergens. Diisocyanates are used in making foam rubber padding for athletic shoes and may cause allergy. Dimethyl fumarate is a preservative used in antihumidity sachets. It is a volatile substance and may deposit on shoes during its transport. Dimethyl fumarate is highly allergenic, and several outbreaks of shoe dermatitis in Europe have occurred secondary to this allergen. Other causative agents are felt, cork liners, formaldehyde, dyes, asphalt, and tar Shoe refresher sprays may also induce allergy. Patch testing with pieces of various shoe parts may be done by soaking them for 15 minutes in water and applying them to the back for 72–96 hours. Once the allergen has been identified, selection of shoes without the offending substance will lead to resolution. Unfortunately, this is a difficult process, because most shoes are made in areas without mandatory labeling requirements, and plastic, wooden, or fabric shoes that contain fewer allergens are often impractical.
Dermatitis seconday to nickel
Fig. 6.14 Nickel dermatitis caused by earring.
Because we are all constantly exposed to nickel, nickel dermatitis is a frequent occurrence. Although still most common among women, sensitization is increasing among men. A direct relationship between prevalence of nickel allergy and number of pierced sites has been documented. Nickel produces more cases of allergic contact dermatitis than all other metals combined.
Erythematous and eczematous eruptions, sometimes with lichenification, appear beneath earrings (Fig. 6.14), bracelets, rings, wrist watches, clasps, and jeans buttons. The snaps on clothing have been implicated in producing allergy in children; nickel is the most common cause of allergic contact dermatitis in children as well as adults. Laptop computers, cell phones, electronic cigarettes, and microneedling devices are newer products capable of causing nickel dermatitis. Metals, including nickel, are increasingly being recognized as a cause of cosmetic allergies. Nickel ranks highly on l sts of occupationally induced allergic contact dermatitis.
Nickel dermatitis is seen most frequently on the earlobes. Piercing the earlobes with nickel-plated instruments or wearing nickel-plated jewelry readily induces nickel sensitivity. Earlobes should be pierced only with stainless steel instruments, and only stainless steel earrings should be worn until the ears have healed. Exposure to the metal may not be readily apparent most of the time. Even with gold jewelry, the clasps and solder may contain nickel. Nickel objects may be plated with chrome but may still cause nickel dermatitis through the leaching of some of the nickel through the small pores of the chromium plating.
Nickel oxides in green paints may produce nickel dermatitis. Homeopathic and complementary medicaments may also contain enough nickel to produce a contact allergy. Sweat containing sodium chloride may combine with nickel to form nickel chloride. This affects the degree of nickel dermatitis, being more severe in persons who perspire profusely.
The diagnosis is established by a pos tive patch test reaction to nickel sulfate. Nickel may be detected by applying dimethylglyoxime solution to the test object In the presence of nickel, the cotton swab used to apply the solution will turn orange-pink. A positive test always means that nickel is present, but a negative test does not rule out its presence. Sweat, blood, or saline may leach nickel from stainless steel.
Prophylactic measures should include the reduction of perspiration in those sensitive to nickel. Topical corticosteroids applied before exposure to nickel, such as before putting on a wristband, may be successful. Clasps and other objects are available in plastic material so that some of the exposure to nickel may be decreased. Polyurethane varathane 91 applied in three coats will give protection for several months. Treatment of nickel dermatitis consists of the application of topical corticosteroids. In Europe, laws regulating the maximum content of nickel in jewelry have led to a marked decrease in sensitization. Dr. Sharon Jacob is leading an effort to have a similar law passed in the United States.
Hand eczema and pompholyx in nickel-sensitive or cobaltsensitive patients have rarely been aggravated by ingested metals in the diet. In severe, treatment-resistant dermatitis, a specific diet low in nickel and cobalt may be tried.
Dermatitis secondary to Gold
Fig. 6.15 Oral lichenoid dermatitis due to gold.
Gold dermatitis may rarely occur from the wearing of gold jewelry. A predisposing factor in such patients is the presence of dental gold. Oral lichenoid eruptions have also been reported with gold, similar to the situation with mercury-containing amalgams (Fig. 6.15). It is not uncommon to see positive reactions to gold when patch-testing patients with facial, eyelid, or widespread dermatitis of unknown cause. Although it is difficult to make a direc clinical correlation with any one piece of jewelry, occasionally patients will clear if they stop wearing all gold jewelry. One possible explanation is that titanium dioxide in sunscreen products may liberate gold particles from jewelry. In most patients, however, there is a lack of relevance. Gold reactions on patch testing may be delayed in onset and remain inflamed for months.
Rubber Dermatitis
Fig. 6.16 Rubber dermatitis from swim goggles.
Rubber dermatitis generally occurs on the hands from wearing rubber gloves, as by surgeons, nurses, and homemakers. The eruption is sually sharply limited to the gloved area but may spread up the forearms. Rubber dermatitis also develops from exposure to condoms, diaphragms, swim goggles (Fig. 6 16), caps and scuba masks, wet suits, bandages for chronic leg ulcers, respirators, gas masks, rubber sheets, and cosmetic sponges. Shoe dermatitis may be caused by rubber allergy to insoles or sneakers.
Natural and synthetic rubbers are used separately or in combination to make the final rubber product. The chemicals added in the rubber manufacturing process, most importantly the accelerators and antioxidants, are the common causes of allergic contact dermatitis. A similar list of additives is present in neoprene, a synthetic rubber, but also includes the dialkyl thioureas. These are not in the standard patch trays and thus may escape detection unless applied as a supplemen al allergen. Elastic in underwear is chemically transformed by laundry bleach into a potent sensitizing substance. The allergen is permanent and cannot be removed by washing. The offending garments must be thrown out and the use of bleaches interdicted.
Accelerators. During the manufacturing process, chemicals are used to hasten the vulcanization of rubber. Among the numerous chemicals available, tetramethylthiuram disulfide, mercaptobenzothiazole, and diphenylguanidine are frequently used. Tetramethylthiuram disulfide and its analogs, known as disulfiram and thiuram, may produce contact dermatitis when moist skin is exposed to the finished rubber product. In a 10-year study of 636 cases of allergy to rubber additives, thiuram mix was by far the most common sensitizer. Mercaptobenzothiazole is most often the cause in shoe allergy and thiuram in glove allergy.
Antioxidants. Antioxidants are used to preserve rubber. Amine antioxidants, such as phenyl-α-naphthylamine, are most effective. Hydroquinone antioxidants may cause depigmentation of the skin, as well as allergic contact dermatitis. A frequent antioxidant sensitizer, propyl p-phenylenediamine, is used in tires, heavy-duty rubber goods, boots, and elastic underwear.
Dermatitis secondary to fragrances
Fig. 6.17 Fragrance allergy, lyral.
Almost all cosmetic preparations, skin care products, and many medications contain fragrance; even those labeled “nonscented” often contain a masking fragrance that may be a sensitizer. Even “fragrance-free” products have been documented to contain the raw fragrance ingredients, such as rose oil in “allnatural” products. Fragrances are the most common cosmetic ingredient causing allergic contact dermatitis. Photodermatitis, irritation, contact urticaria, and dyspigmentation are other types of reactions that fragrances may produce.
The most common individual allergens identified are cinnamic alcohol, oak moss, cinnamic aldehyde, hydroxy citronellal, musk ambrette, isoeugenol, geraniol, coumarin, lyral (Fig. 6.17), and eugenol. Hyperperoxides of linalool and oxidized limonene are newer important fragrance allergens. Frequently, unspecified allergens are the cause, because they are not listed on labels, and fragrances are combinations of many different ingredients. Myroxylon pereirae (balsam of Peru) will identify approximately half of those often unsuspected cases of allergic dermatitis, and additional testing with the fragrance mixes will identify over 90%. Additionally, a natural fragrance mixture of jasmine absolute, ylang-ylang oil, narcissus absolute, spearmint oil, and sandalwood oil is recommended. Other essential oils may be missed if not individually tested. Fragrance mixes should be prepared the day of application as evaporation may compromise their reliability. New products should be tested for tolerance in patients with a history of fragrance sensitivity.
At least 1% of the population have fragrance sensitivity. Women still outnumber men, but as the frequency of fragrance contact reactions has increased over the years, men have shown a steeper increase in sensitivity. Fragrance is one allergen that may be transferred by skin-to-skin contact to a sensitive person, causing connubial contact dermatitis. Ingestion of balsam-related foods, such as tomatoes, citrus fruits, and spices, may cause a flare in some sensitive patients. In particularly difficult-to-treat patients, balsam-restricted diets may be beneficial but are not easy to follow.
Dermatitis secondary to hair dye
Fig. 6 18 Hair dye allergy.
Permanent hair dyes incorporate p-phenylenediamine (PPDA), a popular but potent sensitizer that may cross-react with many chemicals. In rinses and tints, the azo dyes, acid violet 6B, water-soluble nigrosine, and ammonium carbonate may sensitize and cross react with PPDA. Workers in the manufacture of PPDA, furr ers, hairdressers, and those in the photographic and rubber vulcanization industries develop eruptions first on the back of the hands, wrists, forearms, eyelids, and nose, consisting of an eczemaous, erythematous, oozing dermatitis. It will penetrate most protective gloves, but not nitrile gloves Lichenification and scaling are seen in the chronic type. In those with dyed hair, sensitivity is manifested by itching, redness, and puffiness of the upper eyelids, tops of the ears, temples, and back of the neck (Fig. 6.18). Beard/ mustache dermatitis may be caused by coloring of the facial hair and eyelid dermatitis by dying eyelashes. PPDA added to temporary henna tattoos to make them darker has resulted in acute vesicular allergic reactions, some with scarring and hyperpigmentation. Kumkum is a common cosmetic in India, primarily smeared on the forehead of women to denote their marital status; one of many reported allergens in the product is PPDA.
For those sensitive to this type of hair dye, use of semipermanent or temporary dyes might be the solution. In the case of sensitivity to these alternatives, vegetable dyes such as henna may be tried. Metallic dyes are usually not favored by women but are frequently used by men as “hair color restorers.” The metallic hair dyes may contain nickel, cobalt, chromium, or lead. Hair dyes containing FD&C and D&C dyes often do not cross-react with PPDA and 70% of PPDA-sensitive patients exposed to a dye containing the less allergenic PPDA derivative 2-methoxymehtyl-PPD tolerated it.
Topical Drug Contact Dermatitis
Fig. 6.19 Contact dermatitis to eyedrops. (Courtesy Shyam Verma, MBBS, DVD.)
Drugs, in addition to their pharmacologic and possible toxic action, also possess sensitizing properties. Sensitization may occur not only from topical application (Fig. 6.19) but also from ingestion, injection, or inhalation. Some drugs, such as the antihistamines, including topical doxepin, sensitize much more frequently when applied topically than when taken orally With the advent of transdermal patches for delivery of medications (e.g., nitroglycerin, hormones, nicotine, clonidine, fentanyl, lidocaine, and scopolamine)
reports of sensitization have been increasing. Clonidine induces the highest rate of allergic reactions. At times, EM-like reactions may occur with transdermally applied drugs.
Some drugs may produce sensitization of the skin when applied topically; if the medication is taken later internally, an acute flare at the site of the contact dermatitis may result. This anamnestic (recalled) eruption or systemic contact dermatitis can occur with antihistamines, sulfonamides, and penicillin. The same is true of the local anesthetic ointments containing “caine” medications, but not as a rule with lidocaine allergy. Usually, if sensitization occurs when using transdermal patches, the drugs do not cause systemic contact dermatitis when taken orally. The important topical medications that cause irritation or allergic contact dermatitis are discussed next.
Substances Causing Contact Urticaria.
Many different s stances can elicit such a reaction. Universal precautions not only led to a marked increase in delayed-type hypersensitivity reaction to rubber additives, but also to many reports of contact urticaria and anaphylaxis to latex. Most of these reactions occur in health professionals. Reactions are characterized by itching and swelling of the hands within a few minutes of donning the gloves, usually resolving within an hour after removing them. In patients with continued exposure, the eruption may eventually appear as chronic eczema. Glove powder may aerosolize the allergen and produce more generalized reactions. Although these reactions may occur on the job, many cases present as death or near-death events when sensitized individuals undergo surgery or other procedures, especially when there is mucosal exposure (e.g., dental care, rectal examination, childbirth).
In addition to health care workers, who have a reported incidence of 3%–10%, atopic persons and spina bifida patients are other risk groups for the development of type I allergy to latex protein. The sensitized individual should also be aware that up to 50% of patients have a concomitant fruit allergy to foods such as banana, avocado, kiwi, chestnut, and passion fruit.
Contact urticaria is seen in homemakers and food workers who handle raw vegetables, raw meats and fish, shellfish, and other foods. Raw potatoes have been shown to cause not only contact urticaria but also asthma at the same time. It has been seen in hairdressers who handle bleaches and hair dyes containing ammonium persulfate, in whom the contact urticaria is accompanied by swelling and erythema of the face, followed by unconsciousness. Caterpillars, moths, and hedgehogs may cause contact urticaria just by touching the skin.
Additional substances inducing this reaction are oatmeal, flour, meat, turkey skin, calf liver, banana, lemon, monoamylamine, benzophenone, nail polish, tetanus antitoxin, streptomycin, cetyl alcohol, stearyl alcohol, estrogenic cream, cinnamic aldehyde, sorbic acid, benzoic acid, castor bean, lindane, carrots, spices, wool, silk, dog and cat saliva, dog hairs, horse serum, ammonia, sulfur dioxide, formaldehyde, acrylic monomers, exotic woods, wheat, cod liver oil, and aspirin.
Bacitracin ointment may cause anaphylactic reactions when applied topically, especially to chronic leg ulcers; however, it may rarely occur after application to acute wounds (Fig. 6.20).
Fig. 6.20 Contact urticaria caused by bacitracin applied to punch biopsy site.
Exanthems (Morbilliform or Maculopapular Reactions)
Fig. 6.21 Morbilliform (exanthematous) drug eruption caused by exposure to an antibiotic.
Exanthems are the most common form of adverse cutaneous drug eruption. They are characterized by erythema, often with small papules throughout. Exanthems tend to occur within the first 2 weeks of treatment but may appear later, or even up to 10 days after the medication has been stopped. Lesions tend to appear first proximally, especially in the groin and axilla, generalizing within 1 or 2 days. The face is typically spared; facial involvement should prompt consideration for DRESS. Pruritus is usually prominent, helping to distinguish a drug eruption from a viral exanthema or graft-versus-host disease. Antibiotics, especially semisynthetic penicillins and TMP-SMX, are the most common causes of this reaction pattern (Fig. 6.21). Ampicillin-amoxicillin given during EBV infection causes an exanthem in 29%–69% of adults and 100% of children. TMP-SMX given to AIDS patients causes exanthems in about 40%. Antimalarials given to patients with dermatomyositis cause exanthems in 25%. Certain quinolones cause exanthems at a high rate: 4% overall and 30% in young women.
Morbilliform eruptions may rarely be restricted to a previously sunburned site, the so-called “UV recall–like” phenomenon. The sunburn may have occurred 1–7 months before the drug eruption. This pattern of eruption must be distinguished from a true UV recall caused by antimetabolites (see later section, “Adverse Reactions to Chemotherapeutic Agents”).
In the case of simple exanthems, treatment is supportive. The eruption will clear within 2 weeks of stopping the offending medication, and it may clear even if the drug is continued. Topical corticosteroids and antipruritics may be of benefit and allow the course of therapy to be completed. Rechallenge usually results in the reappearance of the eruption, except in the setting of HIV. In many HIV-infected patients with simple reactions to TMP-SMX, reexposure by slow introduction or full-dose reexposure may be tolerated. Infrequently in HIV patients, however, and rarely in persons with normal immune function, rechallenge may result in a more severe blistering reaction. The use of patch and intradermal testing for the confirmation of the incriminated drug in morbilliform exanthems is not standardized. Only 2%–10% of patients who experience the eruption on rechallenge will have a positive patch or intradermal test.
Cutaneous findings identical to simple exanthems may occur as part of DRESS Most patients with DRESS will have facial involvement facial edema, ear involvement, and many will have hand edema, all of which are uncommon in simple exanthems. In contrast to simple exanthems, in complex exanthems the inciting agent must be stopped immediately, and rechallenge should rarely be undertaken. Even outside the setting of DRESS, higher eosinophil counts correlate with more severe ADRs.
Characteristic features of Drug-Induced Hypersensitivity Syndrome or Drug Reaction With Eosinophilia and Systemic Symptoms (DIHS/DRESS)
All patients with DRESS share the characteristic features of fever, rash, and internal organ involvement. Characteristic features include the following:
- Rash developing late (>2, often 4–8 weeks) after the inciting medication is started
- Long-lasting symptoms after discontinuation of the causative drug
- Fever (>38°C)
- Multiorgan involvement
-
CBC abnormalities (usually an eosinophilia, but may have activated lymphocytosis instead):
- Eosinophilia (>1500 absolute eosinophilia; criteria vary, with some groups citing counts greater than 1500/µL and others more than 700/µL or above 10% if the leukocyte count is lower than 4000/µL)
- Lymphocyte activation (lymphocytosis, atypical lymphocytosis, lymphadenopathy)
- Frequent reactivation of HHV-6, HHV-7, EBV, and CMV (60%–80% of cases demonstrate HHV family reactivation)
Seven major medications/classes of medication are commonly implicated, though DRESS may occur with drugs from almost any category: (1) anticonvulsants—phenytoin, carbamazepine, phenobarbital, and lamotrigine primarily (can occur with the other antiepileptic agents as well); (2) long-acting sulfonamidessulfamethoxazole, sulfadiazine, and sulfasalazine (but not all sulfa-containing medications—sulfonylureas, thiazine diuretics, furosemide, and acetazolamide); (3) allopurinol; (4) nevirapine; (5) abacavir; (6) dapsone; and (7) minocycline.
DRESS has been reported with multiple other agents as well, including, but not limited to, antimicrobial agents (vancomycin, cephalosporins, fluoroquinolones, antituberculosis agents, other antibiotics), biologic agents (tocilizumab, IL-1 inhibitors, and more), targeted chemotherapeutics (vismodegib, imatinib, and more), other antiviral agents (telaprevir for hepatitis C before its removal from the market, raltegravir, and others), antipyretic agents (acetaminophen, ibuprofen, diclofenac, celecoxib), and more. Diagnosis of DRESS should be made based on clinical and laboratory features, and drug exposure history, with consideration given to any potential inciting agent, regardless of drug class.
The skin eruption accompanying DRESS/DIHS is typically morbilliform (with variable follicular accentuation [Fig. 6.22] and occas onal 2-zone targetoid lesions), and can vary from faint and mild to severe with exfoliative erythroderma. Facial erythema and edema with periorbital sparing often accompanies the skin eruption, and there may be impetigo-like crusting on the chin and/or superficial fine pustules, especially on the face. Mucositis is uncommon but may occur, typically in the mouth and milder than that of SJS. Patients with DRESS, AGEP, and SJS/TEN may share overlapping features and these SCARs may coexist; patients should be managed based on which features predominate and are most severe. In DRESS, adverse prognostic indicators include tachycardia, leukocytosis, tachypnea, coagulopathy, thrombocytopenia, and gastrointestinal bleeding. The internal organ involvement described in DRESS can be divided into two types: (1) organ dysfunction occurring during or immediately associated with the acute episode and (2) delayed involvement/late sequelae, possibly with an autoimmune basis. The first category includes hepatitis, interstitial nephritis, interstitial pneumonitis, and myocarditis, with rare other organ involvement (colitis/intestinal bleeding, encephalitis/aseptic meningitis, sialadenitis). Late sequelae include delayed myocarditis, autoimmune diseases from 4.8% up to 10% of patients (thyroiditis/ Graves, type 1 diabetes, vitiligo), syndrome of inappropriate secretion of antidiuretic hormone (SIADH), or rarely Systemic lupus erythematosus (SLE). Mortality rates from DRESS are cited as 5% to up to 10% of patients, usually from complications of fulminant hepatic involvement, myocarditis, or renal/lung disease. It is important to note that the manifestations of the syndrome may vary by drug (and possibly ethnicity, as patients of certain backgrounds are more likely to develop DRESS from certain agents); dapsone hypersensitivity has a weaker association with eosinophilia, and allopurinol hypersensitivity has more renal involvement, whereas minocycline-associated DRESS may have more pulmonary involvement.
Skin biopsy is not required to confirm a diagnosis of DRESS. The histopathologic features may vary, with epidermal spongiosis, interface dermatitis, superficial epidermal pustules (resembling
AGEP) and apoptotic keratinocytes (resembling EM) reported. Atypical lymphocytes can be seen; eosinophils may be observed but are not required. Small studies suggest a more severe histopathologic phenotype (with EM-like features) may be more associated with a severe illness.
First-line treatment for DRESS involves identifying and stopping the causative agent, and initiation of antiinflammatory therapy, generally with high dose systemic corticosteroids (1–2 mg/kg/day, sometimes administered in divided doses). Pulse intravenous (IV) steroids, intravenous immune globulin (IVIG), cyclosporine, and other agents have been employed in severe or recalcitrant cases. Patients often require a long, slow steroid taper over weeks to months after initial onset.
Fig. 6.22 Phenytoin-induced drug reaction with eosinophilia and systemic symptoms.
Fig. 6.23 Allopurinol hypersensitivity syndrome.
Allopurinol hypersensitivity syndrome typically occurs in patients wi h preexisting renal failure, or in those who develop acute kidney injury and whose dosing of allopurinol is not adjusted. Often, affected patients are treated unnecessarily for asymptomatic hyperuricemia, with clear indications for therapy present in only about one third of these patients. They are often given a dose not adjusted for their coexisting renal disease and are frequently taking a thiazide diuretic. Weeks to many months (average 7 weeks) after the allopurinol is begun, the patient develops a morbilliform eruption (50% of cases) that often evolves to an exfoliative erythroderma (20%) (Fig. 6.23). Bullae may occur, especially on the palms and soles, and oral ulcers may be present. Associated with the dermatitis are fever, eosinophilia, sometimes hepatitis (70% of cases), and typically worsening of renal function (40%–80%, the higher percentage in those with preexisting renal disease). Lung involvement and adenopathy occur infrequently. About 25% of patients die as a result of this syndrome, often from cardiovascular complications. Dialysis does not appear to accelerate the resolution of the eruption, suggesting that if a dr g metabolite is responsible, it is not dialyzable. There is a strong association between HLA-B5801 and the development of allopurinol hypersensitivity syndrome in the Han Chinese, but not in other races. HHV reactivation may be associated This syndrome may be steroid responsive but is extremely slow to resolve, frequently lasting for months after allopurinol has been stopped. Very gradual tapering of systemic corticosteroids with monitoring of eosinophil count and renal function is essential. Too rapid tapering may lead to relapse of the syndrome.
Manifestations of SJS/TEN
Fig. 6.24 Bullous drug reaction.
The clinical presentation may start with fever and influenza-like symptoms preceeding the eruption by a few days. Skin lesions appear on the face and trunk and rapidly spread, usually within 4 days, to their maximum extent. Initial lesions are often deep-red/ dusky macules, sometimes with a central nonblanching zone (2-zone lesions, targetoid lesions, atypical targets, “SJS with spots”); these may centrally desquamate or may form atypical targets with purpuric centers that coalesce, form bullae (Fig. 6 24), then slough. In SJS virtually always, two or more mucosal surfaces are inflamed, with peeling, erosions, and hemorrhagic crust forming. The oral mucosa and conjunctiva are most frequently affected (Fig. 6.25), but physical examination should include thorough inspection of
all mucosal surfaces (oral, ocular, urethral, vaginal, anal). The patient may have photophobia, difficulty with swallowing, rectal erosions, dysuria, and/or cough, indicative of ocular, alimentary, urinary, and respiratory tract involvement, respectively. In other patients, dusky macular erythema is present in a local or widespread distribution over the trunk. Mucosal involvement may not be found The epidermis in the areas of macular erythema rapidly becomes detached from the dermis, leading to extensive skin loss, often much more rapidly than occurs in the patients with atypical targets and extensive mucosal involvement. “Pure TEN” is a conceptual way of thinking of such patients. Rarely, SJS/TEN patients may present with lesions predominantly in sun-exposed areas, with a clear history of a recent significant sun exposure. This suggests that, in rare cases, SJS/TEN may be photo induced or photo exacerbated. Patients with SJS/TEN may have internal involvement similar to patients with DRESS/DIHS. These most frequently include eosinophilia, hepatitis, and worsening renal function.
Keratinocyte death in SJS and TEN is proposed to occur through more than one potential mechanism, and the relative importance of each of these mechanisms in SJS and TEN is not known. There is likely an immune response triggered to a drugtissue complex. Activated cytotoxic T cells and natural killer (NK) cells produce granulysin, TNF-α, TRAIL, and perforin-granzyme B, all of which can induce keratinocyte necrosis. T-cell, NK-cell, and NKT-cell–derived granullysin is a key mediator of tissue damage, and serum (and blister) granulysin levels may correlate with disease severity. Effector memory CD8+ T cells, regulatory
T cells, NK cells, and Th17 cells appear to play a role in mediating the disease. In addition, keratinocyte necrosis can be induced by the binding of soluble Fas ligand (sFasL) to Fas (also known as the death receptor or CD95). Soluble Fas ligand is elevated in the blood of patients with TEN, and its level correlates with body surface area (BSA) involvement. In addition, the peripheral blood mononuclear cells of patients with TEN secrete Fas ligand on exposure to the incriminated drug. The sera of patients with TEN induce necrosis of cultured keratinocytes, and a monoclonal antibody to Fas ligand in a dose-dependent manner inhibits keratinocyte necrosis exposed o TEN patient sera.
A skin biopsy is usually performed. Frozen-section analysis may lead to a rapid diagnosis, either by submitting the roof of a blister or portion of sloughed skin, or performing a biopsy of an area of impending necrosis. The histology of TEN and SJS is similar. There is a lymphocytic infiltrate at the dermoepidermal junction (DEJ) with necrosis of keratinocytes that at times may be full thickness. There is typically cellular necrosis out of proportion to the infiltrate. Paraneoplastic pemphigus may be excluded with direct immunofluorescence (DIF). Patients with graft-versus-host disease (GVHD) may also demonstrate a TEN-like picture with identical histology, although prominent follicular involvement may occasionally be a clue favoring GVHD.
Fig. 6.25 Stevens-Johnson syndrome.
Radiation-Induced Epidermal Necrolysis
Fig. 6.26 Phenytoin plus radiation-induced reaction
This rare reaction may occur if phenytoin is given prophylactically in neurosurgical patients who are receiving whole-brain radiation therapy and systemic steroids. As the dose of steroids is being reduced, erythema and edema initially appear on the head in the radiation ports. This evolves over 1 or 2 days to lesions with the clinical appearance and histology of SJS or even TEN. The eruption spreads caudad, and mucosal involvement may occur (Fig. 6.26). A similar syndrome has been reported with the use of amifostine, phenobarbital, or levetiracetam during radiation for head and neck cancers. This EM syndrome can rarely be seen with radiation therapy alone. If amifostine is used to reduce acute and chronic, radiation-associated head and neck xerostomia, there is a significant risk of SJS/TEN.
Fixed Drug Reactions (Eruptions)
Fig. 6.27 Fixed drug reactions caused by aspirin.
Fixed drug reactions are common. FDEs are so named because they recur at the same site with each exposure to the medication. The time from ingestion of the offending agent to the appearance of symptoms is between 30 minutes and 8 hours, averaging 2 hours. In most patients, six or fewer lesions occur, and often only one. Infrequently, FDEs may be multifocal with numerous lesions (generalized) and can blisters, termed generalized bullous fixed drug eruption (GBDFE), which can mimic SJS/TEN (Fig 6.27). They may present anywhere on the body, but half occur on the oral and genital mucosa. FDEs represent 2% of all genital ulcers evaluated at clinics for sexually transmitted diseases and can occur in young boys. In males, lesions are usually unifocal and can affect the glans or shaft of the penis. FDE of the vulva is often symmetric, presenting as an erosive vulvitis, with lesions on the labia minora and majora and extending to the perineum. Other unusual variants of FDE include eczematous, urticarial, papular, purpuric, linear, giant, and psoriasiform. At times, some lesions of FDE will not reactivate with exposure because of a presumed “refractory period” that may last from weeks to months.
Clinically, an FDE begins as a red round/oval patch that can develop a dusky, intensely inflamed central portion and resemble an iris or target esion similar to erythema multiforme, which may blister and erode. Lesions of the genital and oral mucosae usually present as erosions. Most lesions are 1 to several cm in diameter, but larger plaques may occur, mimicking cellulitis. Characteristically, prolonged or permanent postinflammatory hyperpigmentation results, although a nonpigmenting variant of an FDE is recognized. With repeated or continued ingestion of the offending medication, new lesions may be added, sometimes eventuating in a clinical picture similar to SJS with similar morbidity and mortality. Histologically, an interface dermatitis occurs with subepidermal vesicle formation, necrosis of keratinocytes, and a mixed superficial and deep infiltrate of neutrophils, eosinophils, and mononuclear cells. Pigment incontinence is usually marked, correlating with the pigmentation resulting from repeated FDEs at the same site. Because biopsies are generally performed during the acute stage of a recurrence, the stratum corneum is normal. Papillary dermal fibrosis and deep perivascular pigment incontinence are often present from prior episodes.
Medications inducing FDEs are usually those taken intermittently. Many of the NSAIDs, especially pyrazolone derivatives, paracetamol, naproxen, oxicams, and mefenamic acid, cause FDE, with a special predilection for the lips. Sulfonamides, trimethoprim, and TMP-SMX are now responsible for the majority of genital FDEs. Barbiturates, tetracyclines, fluconazole, fluoroquinolones, phenolphthalein, acetaminophen, cetirizine, celecoxib, dextromethorphan, hydroxyzine/cetirizine/levocetirizine, quinine, lamotrigine, phenylpropanolamine, erythromycin, metformin, sildenafil, mycophenolate, chemotherapeutic agents, and Chinese and Japanese herbs are also among the long list of possible causes. The risk of developing a FDE has been linked to HLA-B22. Patch tests with various concentrations of the offending medication can reproduce the lesion when placed on affected, but not on unaffected, skin Tape-stripping the skin before applying he suspected medication in various vehicles may increase the likelihood of a positive patch test.
Occasionally, FDEs do not result in long-lasting hyperpigmentation. The so-called nonpigmenting FDE is distinctive and has two variants. The pseudocellulitis or scarlatiniform type is characterized by large, tender, erythematous plaques that resolve completely within weeks, only to recur on reingestion of the offending drug. Pseudoephedrine hydrochloride is by far the most common culprit. The second variant is SDRIFE (formerly baboon syndrome; see “Allergic Contact Dermatitis” earlier). SDRIFE preferentially affects the buttocks, groin, and axillae with erythematous fixed plaques, and is most commonly due to antibiotic agents, particularly aminopenicillins. Histologically, a giant cell lichenoid dermatitis can be seen in this setting. Fixed sunlight eruption has been reported as multiple FDE-like lesions occurring in response to sunlight.
The diagnosis of FDE is often straightforward and is elucidated by the history. Antibiotics manufactured overseas are readily available in many ethnic markets, including reports of such agents as trimethoprim/sulfamethoxazole in over-the-counter cold medications, and the formulations may not be carefully regulated. In some patients, the reaction may be to a dye in a medication rather than the active ingredient. Fixed drug reaction may rarely be related to foods, including residual antibiotics in meat products and quinine contained in tonic water. Confirmation with provocation tests can be performed. Because of the “refractory period,” provocation tests need to be delayed at least 2 weeks from the last eruption. If an oral provocation test is considered, the initial challenge should be 10% of the standard dose, and patients with widespread lesions (SJS/TEN–like) should not be challenged. Patch testing using a drug concentration of 10%–20% in petrolatum or water applied to a previously reacted site is the recommended approach. In most patients, the treatment is simply to stop the medication. Desensitization can be successful.
Lesions of an FDE contain intraepidermal CD8+ T cells with the phenotypic markers of resident memory T cells. Tissue resident memory T cells are thought to remain in the skin to provide immunity to infection (e.g., herpes simplex virus). In FDE, once the medication is stopped, the abundant CD4+/FoxP3 T cells (Tregs) are believed to downregulate the eruption. In SJS/TEN patients, such Tregs are found in much fewer numbers than in FDE, which may explain the progression of SJS/TEN even after stopping the trigger. Resident mast cells in lesions of FDE may be the cells initially activated with drug exposure explaining the rapid onset of the lesion.
Fig. 6.28 Acute Generalized Exanthematous Pustulosis
Also known as toxic pustuloderma and pustular drug eruption, AGEP is an uncommon reaction with an incidence of 1–5 cases per million per year. The average age in Europe is in the fifties and about one decade younger in Israel and Taiwan. Children can be affected. Women have been affected slightly more than men until recently, when a strong female predominance was suggested. There may be a genetic predisposition, with HLA*B51, DR11, and DQ3 more association with AGEP. Drugs are the most common cause of this reaction pattern, although AGEP has also been reported after mercury exposure. AGEP following infections and insect bites, such as from the Loxosceles spider (e.g., brown recluse), has been reported, but some of these patients have also received antibiotics. A localized variant, “acute localized exanthematous pustulosis” (ALEP), has been rarely reported, usually acutely after antibiotic exposure.
The eruption is of sudden onset, within 1 day in many cases associated with antibiotics, and averaging 11 days in other cases. The rash is accompanied by fever in most patients. Initially, there is a scarlatiniform erythema. The eruption evolves and disseminates rapidly, consisting usually of more than 100 nonfollicular pinpoint pustules less than 5 mm in diameter; dermoscopy may aid in identifying pustules in some early cases (Fig. 6.28). The face and flexural folds are commonly affected first, with ex ension to the trunk and limbs. Nikolsky sign may be positive. Facial edema may be seen, and mucous membrane involvement is uncommon, and if present usually affects only one surface and is nonerosive. Laboratory abnormalities typically include a leukocytosis with neutrophilia (90%) and at times an eosinophilia (30%). Typically, the entire self-limited episode lasts up to 15 days. Characteristically, widespread superficial desquamation occurs as the eruption clears. AGEP can recur with seconder-exposure to the medication.
In more than 90% of patients, drugs are the cause of AGEP. Frequently implicated medications include antibiotics (penicillin and macrolide classes in particular, plus clindamycin, minocycline, sulfonamides, antimycotic agents, vancomycin, and quinolones), antiepileptic agents, and antihypertensives, particularly CCBs
(especially diltiazem, though cross-reactivity between CCBs has been described). Hydroxychloroquine is frequently implicated, including in atypical, prolonged courses, but may also induce psoriasis, and it is important to distinguish the two. Corticosteroids, allopurinol, oxicam NSAIDs, pseudoephedrine, terazosin, omeprazole, and sennoside have also caused AGEP. Chemotherapeutic agents, including small molecule/multikinase inhibitors and other targeted agents, are being reported as inciting agents with increasing frequency. Radiocontrast material and some forms of dialysates have been shown to cause AGEP. Infectious agents implicated include viruses (enteroviruses, CMV, EBV, hepatitis), rarely vaccinations, and other infections (mycoplasma, and other bacterial infections), though concomitant antibiotics were occasionally employed and may have been the inciting agent.
In the classic case, the diagnosis is straightforward, with the characteristic sudden and rapid onset, widespread pustulation, and self-limited course. Due to the severity of the eruption and potential for widespread erythroderma, patients with certain comorbidities may be at risk for complications such as high output heart failure. The facial edema and pustulation can simulate DRESS/DIHS from anticonvulsants. Cases of overlap between SJS/TEN, DRESS, an dAGEP exist, and patients with mixed features should be evaluated for each and treated based on the most severe features. Pustular psoriasis, especially pustular psoriasis of pregnancy, can be difficult to differentiate from AGEP. If there are no characteristic lesions of psoriasis elsewhere and no prior personal or family history of psoriasis, distinguishing these two entities may be impossible, and the patient may need to be followed for a final diagnosis to be made. A microbial pustulosis in the setting of a connective tissue disease can also resemble AGEP, but lesions are usually localized to the flexors, and the course is more chronic.
Histologically, early lesions show marked papillary edema, neutrophil clusters in the dermal papillae, and perivascular eosinophils. There may be an associated leukocytoclastic vasculitis. Well-developed lesions show intraepidermal or subcorneal spongiform pustules. Severe cases may demonstrate an interface dermatitis similar to EM. The presence of eosinophils and the marked papillary edema help to distinguish this eruption from pustular psoriasis, though pustular psoriasis of pregnancy is often associated with tissue eosinophilia.
Patch testing with the suspected agent may reproduce a pustular eruption on an erythematous base at 48 hours in about 50% of patients. Patch testing rarely will result in a recrudescence of AGEP. AGEP is mediated by T cells, and shares overlapping features and inflammatory pathways with pustular psoriasis, with dermal IL-17 and IL-23 and epidermal IL-8. IFN-γ, IL-4/IL-5, and GM CSF are also increased. IL36RN gene mutations have been demonstrated in both AGEP and pustular psoriasis patients.
Most patients with AGEP can be managed with topical corticosteroids and antihistamines. In over one third of cases, systemic corticosteroids may be required. In severe cases, cyclosporine, infliximab, or etanercept have rapidly stopped the pustulation and appeared to have hastened the resolution of the eruption.
Urticaria/Angioedema
Fig. 6.29 Angioedema.
Urticarial drug eruptions are the second most common type of cutaneous adverse drug eruption, and can be induced by mmunologic and nonimmunologic mechanisms. In either case, clinically the lesions are pruritic wheals or angioedema (Fig. 6.29). Urticaria, especially extensive disease, around the face or mouth, may be part of a more severe anaphylactic reaction with bronchospasm, laryngospasm, or hypotension. Immediate hypersensitivity skin testing and sometimes RAST is useful in evaluating risk for these patterns of reaction. Most patients are acutely managed with antihistamine therapy, with severe cases requiring systemic corticosteroids.
Aspirin and NSAIDs are the most common causes of nonimmunologic urticarial reactions. They alter prostaglandin metabolism, enhancing degranulation of mast cells. They may therefore also exacerbate chronic urticaria of other causes. The nonacetylated salicylates (trilisate and salsalate) do not cross-react with aspirin in patients experiencing bronchospasm and may be safe alternatives. Some patients have urticaria to only one medication in this family, without cross-reaction with other NSAIDs, suggesting that specific IgE-mediated mechanisms may also be possible in NSAID-induced urticaria. Other agents causing nonimmunologic urticaria include radiocontrast material, opiates, tubocurarine, and polymyxin B. Pretesting does not exclude the possibility of anaphylactoid reaction
to radiocontrast material. The use of low-osmolarity radiocontrast material and pretreatment with antihistamines, systemic steroids, and in those with a history of asthma, theophylline, may reduce he likelihood of reaction to radiocontrast material.
Immunologic urticaria is most often associated with penicillin and related β-lactam antibiotics and relates to the minor determinants rather than the β-lactam ring. It is associated with IgE antibodies to penicillin or its metabolites. Skin testing with major and minor determinants is useful in evaluating patients with a history of urticaria associated with penicillin exposure. Patients with penicillin allergy have an increased rate of reaction to cephalosporins. In the case of cefaclor, half of anaphylactic reactions occur in patients with a history of penicillin allergy Thirdgeneration cephalosporins, especially cefdinir, are much less likely to induce a reaction in a penicillin-allergic patient than are first- or second-generation agents.
Bupropion is often used for depression and smoking cessation. I can induce urticaria, which may be severe and associated with hepatitis and a serum sickness like syndrome. Two antihistamines, cetirizine and hydroxyzine, may induce urticaria, an apparent paradox that may lead to confusion in the clinical setting.
Angioedema is a known complication of the use of ACE inhibitors and angiotensin II antagonists. Blacks are at almost 5 times greater risk than whites. Lisinopril and enalapril produce angioedema more frequently than captopril. Angioedema typically occurs within a week of starting therapy but may begin after months of treatment. The episodes may be severe, requiring hospitalization in up to 45% of patients, intensive care in up to 27%, and intubation in up to 18%. One quarter of patients affected give a history of previous angioedema. The angioedema appears to be dose dependent, because it may resolve with decreased dose All these factors suggest that the angioedema may represent a consequence of a normal pharmacologic effect of the ACE nhibitors. The blocking of kininase II by ACE inhibitors may increase tissue kinin levels, enhancing urticarial reactions and angioedema. Although this is dose dependent, ACE inhibitor sers with one episode of angioedema have a 10-fold risk of a second episode, and the recurrent episodes may be more severe. The treatment of urticaria is discussed in Chapter 7.
Fig. 6.30 Amiodarone hyperpigmentation.
Amiodarone photosensitivity develops in up to 75% of treated patients and occurs after a cumulative dose of 40 g and at least 4 months on therapy. A reduced minimal erythema dose (MED) to UVA, but not UVB, occurs, and gradually returns to normal between 12 and 24 months after stopping the medication. Stinging and burning may occur as soon as 30 minutes after sun exposure. Less frequently, a dusky, blue-red erythema of the face and dorsa of the hands occurs (Fig. 6.30). At times, papular reactions are also seen. This reaction may be dose dependent, and acute burning may be relieved by dose reduction; amiodarone has a long half-life and can persist for weeks to months after stopping. Narrow-band UVB may desensitize patients with persistent phototoxicity after stopping amiodarone.
Fig. 6.31 Piroxicam photosensitivity.
The NSAIDs, especially piroxicam, are frequently associated with photosensitivity (Fig. 6.31). The characteristic reaction is a vesicular eruption of the dorsa of the hands, sometimes associated wi h a dyshidrosiform pattern on the lateral aspects of the hands and fingers. In severe cases, even the palms may be involved. Histologically, this reaction pattern shows intraepidermal spongiosis, exocytosis, and perivascular inflammatory cells—a pattern typical of photoallergy. However, this reaction may occur on the initial exposure to the medication, but phototoxicity tests in animals and humans have been negative. Patients with photosensitivity to piroxicam may also react to thiosalicylic acid, a common sensitizer in thimerosal. Half of patients having a positive patch test to thimerosal with no prior exposure to piroxicam test positive to piroxicam. This suggests that piroxicam reactions seen on initial exposure to the medication may be related to sensitization during prior thimerosal exposure.
Sulfonamide antibiotics, related hypoglycemic agents, and the sulfonylurea diuretics may all be associated with photosensitivity reactions. Notably, patients may tolerate one of the medications from this group, but when additional members of the group are added, clinical photosensitivity occurs. The typical pattern is erythema, scale, and, in chronic cases, lichenification and hyperpigmentation.
Fluoroquinolone antibiotics are frequently associated with photosensitivity reactions. Sparfloxacin is highly photosensitizing; enoxacin, ciprofloxacin, and sitafloxacin are mildly photosensitizing; and levofloxacin rarely, if ever, causes photosensitivity.
Photodistributed lichenoid reactions have been reported most often from thiazide diuretics, quinidine, and NSAIDs, but also occur from diltiazem and clopidogrel bisulfate. They present as erythematous patches and plaques. Sometimes, typical Wickham striae are observed in the lesions. Histologically, photodistributed lichenoid reactions are often indistinguishable from idiopathic lichen planus. Marked hyperpigmentation may occur, especially in persons of higher skin types (IV–VI) and diltiazem-induced cases. The lichenoid nature of the eruption may not be clinically obvious, and histology is required to confirm the diagnosis. This hyperpigmentation may persist for months. UVA-associated phototoxicity is also common with vemurafenib, with reduced UVA MED in 94% of those tested.
Azathioprine can cause photosensitivity to UVA, and there are scattered reports of antimalarial agents inducing photosensitivity. These reactions rare reactions are important to keep in mind as the diseases for which these agents may be prescribed, such as connective tissue disorders, can also exhibit photosensitivity.
Some newer medications have generated multiple reports of photosensitivity, including combination an ivirals for hepatitis C, particularly simeprevir; newer chemotherapeutic agents (discussed at length later in the chapter), including vemurafenib, which is strikingly photosensitizing; and emerging reports with other agents (imatinib, ibrutinib, vandetanib, EGF-receptor inhibitors, and more). Flutamide has been reported to induce photoleukomelanoderma, a mosaic mix of hypopigmentation and hyperpigmentation after erythema in sun-exposed areas.
Voriconazole, a second-generation triazole, has been associated with an unusual combination of photosensitive phenomena. Photosensitivity occurs in 8%–10% of patients taking voriconazole for more than 12 weeks. It appears to be UVA induced, and is not dose dependent. Usually, the photosensitivity is mild, with facial erythema and chelitis, and may resemble a sunburn. In these cases, with the use of sun protection and topical treatment, voriconazole can be continued. Occasionally, more severe reactions occur. Pseudoporphyria, eruptive lentigines, atypical nevi, premature
aging, and even the development of melanoma and highly aggressive and potentially fatal squamous cell carcinomas (SCCs) have been reported. Multiple studies, including a large 20-year retrospective study of lung cancer patients, have shown that voriconazole is an independent risk factor for SCC development, and 17% can be unusually aggressive. Any exposure to voriconazole is associated with a 2.6-fold increased risk of SCC, and the risk increases with cumulative exposure. Affected patients can closely resemble patients with xeroderma pigmentosa. Photodistributed granuloma annulare has also been seen This severe form of photosensitivity rapidly resolves on stopping voriconazole. Patients with aggressive SCC or melanoma are advised to stop voriconazole and transition to an alternate agent if possible; posaconazole can be an effective alternative. Emerging studies suggest hydrochlorothiazide may be associated with an increased risk of skin cancer.
Photodistributed telangiectasia is a rare complication of CCBs (nifedipine, felodipine, amlodipine). UVA appears to be the action spectrum. Cefotaxime has also been reported to produce this reaction. Corticosteroids, oral contraceptives, isotretinoin, IFNs, lithium, thiothixene, methotrexate, and other medications may induce telangiectasia, but not through photosensitivity.
Fig. 6.32 Sixteen-year-old with scarring from pseudo–porphyria cutanea tarda reaction to tetracycline.
Pseudoporphyria is a photodistributed bullous reaction clinically and histologically resembling porphyria cutanea tarda (Fig. 6.32). Patients present with blistering on sun-exposed skin of the face and hands and skin fragility. Varioliform scarring occurs in 70% of patients. Facial scarring is especially common in children with pseudoporphyria Hypertrichosis is rarely found; dyspigmentation and sclerodermoid changes are not reported. Porphyrin studies are normal. The blistering usually resolves gradually once the offending medication is stopped. However, skin fragility may persist for years. Naproxen is the most frequently reported cause. Up to 12% of children with JIA treated with NSAIDs may develop pseudoporphyria. Pseudoporphyria has also been reported to other NSAIDs (oxaprozin, nabumetone, ketoprofen, mefenamic acid; but not piroxicam), tetracycline, furosemide, nalidixic acid, isotretinoin, acitretin, 5-fluorouracil, bumetanide, dapsone, oral contraceptives, rofecoxib, celecoxib, cyclosporine, imatinib, vemurafenib, voriconazole, and pyridoxine. Tanning booth (sunbed) exposure and even excessive sun exposure can produce pseudoporphyria. Cases in women outnumber men by 24 : 1. Some women with sunbed-induced pseudoporphyria are taking oral contraceptives. Patients on dialysis may develop pseudoporphyria, and N-acetylcysteine in doses up to 600 mg twice daily may lead to improvement in these cases. Histologically, a pauciinflammatory subepidermal vesicle is seen. DIF may show immunoglobulin and complement deposition at the DEJ and perivascularly, as seen in porphyria cutanea tarda.
Anticoagulant-Induced Skin Necrosis
Fig. 6.33 Warfarin-induced necrosis. (Courtesy Steven Binnick, MD.)
Both warfarin and heparin induce lesions of cutaneous necrosis, although by different mechanisms. Obese, postmenopausal women are predisposed, and lesions tend to occur in areas with abundant subcutaneous fat, such as the breast, abdomen, thigh, or buttocks. The clinical appearance overlaps with calciphylaxis, and patients with warfarin-induced calciphylaxis have been described.
Warfarin-induced skin necrosis (WISN) usually occurs 3–5 days after therapy is begun, and a high initial dose increases the risk. Patients with a much more delayed onset (up to 15 years) are ascribed to noncompliance, drug-drug interactions, or liver dysfunction. WISN occurs in 1 : 1000 to 1 : 10,000 patients treated with warfarin. Hereditary or acquired deficiency of protein C, and less often protein S, is associated with warfarin necrosis. Other hypercoaguable states, such as antithrombin III or factor V Leiden mutations, or lupus anticoagulant syndrome may be associated as well. Lesions begin as red, painful plaques that develop petechiae, then form a large bulla (Fig. 6.33). Necrosis follows. Priapism can complicate warfarin necrosis. A less common variant seen in patients
with a deep venous thrombosis (DVT) of an extremity is necrosis of a distal extremity, usually the one with the DVT. Warfarininduced venous limb necrosis is most often seen in cancer patients, but also in the setting of heparin-induced thrombocytopenia (HIT) and antiphospholipid syndrome.
Early in warfarin treatment, the serum levels of the vitamin K–dependent antithrombotic protein C fall. Because the half-life of antithrombotic protein C is shorter than that of the vitamin K–dependent prothrombotic factors II, X, and IX, an acquired state of reduced protein C level occurs before the clotting factors are reduced. This creates a temporary prothrombotic state. This is more likely to occur if the levels of protein C are already low, if other antithrombotic proteins are deficient, or if the patient has an associated hypercoagulable state. This explains why the syndrome does not always recur with gradual reinstitution of warfarin and why it has been reported to resolve with continued warfarin treatment. Histologically, noninflammatory thrombosis with fibrin in the vessels is seen. Treatment is to stop the warfarin, administer vitamin K to reverse the warfarin, and begin heparin or low-molecular-weight (LMW) heparin. Administration of purified protein C can rapidly reverse the syndrome, as well as associated priapism. Other vitamin K antagonists, such as fluindione, may cause a similar reaction. Rivaroxaban, a direct inhibitor of activated factor X that does not inhibit other vitamin K–dependent proteins, may be considered an alternative anticoagulant. Dabigatran etexilate has been suggested for prevention of WISN in the patient with protein C deficiency.
Heparin induces necrosis both at the sites of local injections and in a widespread pattern when infused intravenously or given by local injection. Local reactions are the most common. Heparin can also induce local allergic reactions at injection sites, which are distinct from the necrosis syndrome. Independent of its method of delivery, heparin-induced skin necrosis lesions present as tender red plaques that undergo necrosis, usually 6–12 days after the heparin treatments are started. Intraepidermal hemorrhagic bullae have also been described. Unfractionated heparin is more likely to cause this complication than fractionated LMW heparin, and postsurgical patients are at greater risk than medical patients. Even the heparin used for dialysis or to flush arterial catheters may be associated with cutaneous necrosis.
Some necrotic reactions to local injections, and most disseminated reactions occurring with IV heparin, are associated with HIT. Patients with underlying prothrombotic conditions, such as factor V Leiden and prothrombin mutations or elevated levels of factor VIII, may develop severe skin lesions if they develop HIT and heparin necrosis. A heparin-dependent antiplatelet antibody is the pathogenic basis of HIT and apparently of heparin-induced skin necrosis. This antibody causes both the thrombocytopenia and the aggregation of platelets in vessels, leading to thrombosis (white clot syndrome). The antibody may appear up to 3 weeks after the heparin has been discontinued, so the onset of the syndrome may be delayed. Histologically, fibrin thrombi are less reproducibly found in affected tissues, because the vascular thrombosis is the result of platelet aggregation, not protein deposition. The process may not only produce infarcts in the skin, but also cause arterial thrombosis of the limbs, heart, lung, and brain, resulting in significant morbidity or mortality. Bilateral adrenal necrosis caused by hemorrhagic infarction can occur and, if not detected early may lead to death from acute addisonian crisis. The syndrome must be recognized immediately in any patient receiving heparin with late-developing thrombocytopenia. The treatment is to stop the heparin and give a direc thrombin inhibitor and vitamin K. After the platelet count has returned to normal, warfarin therapy is typically given for 3–6 months. Patients with HIT cannot be treated with warfarin immediately, as the warfarin would be ineffective in stopping the thrombosis (it is not antithrombotic) and may worsen the thrombosis by enhancing coagulation. The diagnosis of HIT can be delayed because the
antiplatelet antibody may not be present while the platelet count is falling. Adding warfarin at this time can lead to disastrous widespread acral thrombosis resembling disseminated intravascular coagulation (DIC).
Skin necrosis has also been associated with other anticoagulants, such as fluindione enoxaparin. Patients with cancer, an acquired prothrombotic state, are at increased risk for DVT. If they are treated with heparin and develop HIT, patients are at extreme risk for development of a prothrombotic state if treated with warfarin. In this setting, digital and limb gangrene has occurred in the face of normal peripheral pulses and supertherapeutic anticoagulation by standard measures (international normalized ratio). The consumptive coagulopathy induced by the cancer is the underlying trigger.
Vitamin K Reactions
Fig. 6.34 Vitamin K allergy.
Several days to 2 weeks after injection of vitamin K, an allergic reaction at the injection site may occur (Fig. 6.34). Most affected patients have liver disease and are being treated for elevated prothrombin time. The lesions are pruritic red patches or plaques that can be deep seated, involving the dermis and subcutaneous tissue. There may be superficial vesiculation. Lesions occur most often on the posterior arm and over the hip or buttocks Plaques on the hip tend to progress around the waist and down the thigh, forming a “cowboy gunbelt and holster” pattern. Small, generalized eczematous papules may occur on other skin sites in severe reactions. These reactions usually persist for 1–3 weeks, but may persist much longer, or resolve only to recur spontaneously. On testing, patients with this pattern of reaction are positive on intradermal testing to the pure vitamin K1 .
In Europe a second pattern of vitamin K reaction has been reported. Subcutaneous sclerosis with or without fasciitis appears at the injection site many months after vitamin K treatment. There may have been a preceding acute reaction as previously described. Peripheral eosinophilia may be found. These pseudosclerodermatous reactions have been termed Texier disease and last several years.
The addition of vitamin K 1 to cosmetics has led to allergic contact dermatitis from the vitamin K, confirmed by patch testing.
Drug-Induced Pigmentation
Fig. 6.35 Minocycline-induced hyperpigmentation.
Pigmentation of the skin may result from drug administration. The mechanism may be postinflammatory hyperpigmentation in some patients but frequently is related to actual deposition of the drug in the skin.
Minocycline induces many types of hyperpigmentation, which may occur in various combinations. Classically, three types of pigmentation are described. Type I is a blue-black discoloration appearing in areas of prior inflammation, often acne, sarcoidal plaques, or surgical scars (F g. 6.35). This may be the most common type seen by dermatologists. It does not appear to be related to the total or daily dose of exposure. In all other types of pigmentation resulting from minocycline, the incidence increases with total dose, with up to 40% of treated patients experiencing hyperpigmentation with more than 1 year of therapy. The second type (type II) is the appearance of a similar-colored pigmentation on the normal skin of the anterior shins. In most cases, types I and II minocycline pigmentation occur after 3 months to several years of treatment. Generalized black hyperpigmentation has occurred after several days or a few weeks of treatment in Japanese patients. In type I and type II minocycline hyperpigmentation, histologic evaluation reveals pigment granules within macrophages in the dermis and at times in the fat, resembling a tattoo. These granules usually stain positively for both iron and melanin. At times, the macrophages containing minocycline are found only in the subcutaneous fat. Stains for iron may be negative in some cases. Calcium stains may also be positive because minocycline binds calcium. The least common type (type III) is generalized, muddybrown hyperpigmentation, accentuated in sun-exposed areas. Tigecycline may produce similar hyperpigmentation. Histologic examination reveals only increased epidermal and dermal melanin. This may represent the consequence of a low-grade photosensitivity reaction
Fig. 6.36 Minocycline hyperpigmentation.
action
In addition to the skin, minocycline types I and II pigmentation may also involve the sclera, conjunctiva, bone, thyroid, ear cartilage (simulating alkaptonuria), nail bed, oral mucosa, and permanent teeth (Fig. 6.36). Black veins have been reported following sclerotherapy in a patient on minocycline. Tetracycline staining of the teeth is usually related to childhood or fetal exposure, is brown, and is accentuated on the gingival third of the teeth. Dental hyperpigmentation caused by minocycline, in contrast, occurs in adults, is gray or gray-green, and is most marked in the midportion of the tooth. Some patients with affected teeth do not have hyperpigmentation elsewhere. The blue-gray pigmentation of the skin may be improved with the Q-switched ruby laser and pulsed dye laser, or fractional photothermolysis.
Chloroquine, hydroxychloroquine, and quinacrine all may cause a blue-black pigmentation of the face, extremities, ear cartilage,
oral mucosa, and nails, in up to 29% of patients. Generally this occurs after long duration or higher cumulative dose (over 300 g). Pretibial hyperpigmentation is the most common pattern and is similar to that induced by minocycline. The gingiva or hard palate may also be discolored Quinidine may also rarely cause such a pattern of hyperpigmentation. Quinacrine is yellow and concentrated in the epidermis. Generalized yellow discoloration of the skin and sclera (mimicking jaundice) occurs reproducibly in patients but fades within 4 months of stopping the drug. In dark skinned patients, this color is masked and less significant cosmetically. Histologically pigment granules are present within macrophages in the dermis.
Amiodarone causes photosensitivity in 30%–57% of treated patients after 3–6 months. In 1%–10% of patients, a slate-gray hyperpigmentation develops in the areas of photosensitivity. The pigmentation gradually fades after the medication is discontinued. Histologically, periodic acid–Schiff (PAS)–positive, yellow-brown granules are seen within the cytoplasm of macrophages in the dermis. Electron microscopy reveals membrane-bound structures resembling lipid-containing lysosomes. It responds to treatment with the Q-switched ruby laser.
Clofazimine treatment is reproducibly complicated by the appearance of a pink discoloration that gradually becomes reddish blue or brown and is concentrated in the lesions of patients with Hansen disease. This pigmentation may be disfiguring and is a major cause of noncompliance with this drug in the treatment of Hansen disease. Histologically, a PAS-positive, brown, granular pigment is variably seen within foamy macrophages in the dermis. This has been called “drug-induced lipofuscinosis.”
Zidovudine causes a blue or brown hyperpigmentation that is most frequently observed in the nails. The lunula may be blue, or the whole nail plate may become dark brown. Diffuse hyperpigmentation of the skin, pigmentation of the lateral tongue, and increased tanning are less common. It occurs in darkly pigmented persons, is dose dependent, and clears after zidovudine is discontinued. Hydroxyurea causes a similar pattern of hyperpigmentation, including the melanonychia.
Fig 6.37 Chlorpromazine hyperpigmentation
Chlorpromazine, thioridazine, imipramine, and clomipramine may cause a slate-gray hyperpigmentation in sun-exposed areas after long periods of ingestion (Fig. 6.37). Frequently, corneal and lens opacities are also present, so all patients with hyperpigmentation from these medications should have an ophthalmologic evaluation. The pigmentation from the phenothiazines fades gradually over years, even if the patient is treated with another phenothiazine. The corneal, but not the lenticular, changes also resolve. Imipramine hyperpigmentation has been reported to disappear within 1 year. Histologically, in sun-exposed but not sun-protected skin, numerous refractile golden-brown granules
are present within macrophages in the dermis, along with increased dermal melanin. The slate-gray color comes from a mixture of the golden-brown pigment of the drug and the black color of the melanin viewed in the dermis.
The heavy metals gold, silver, and bismuth produce blue to slate-gray hyperpigmentation. Pigmentation occurs after years of exposure, predominantly in sun-exposed areas, and is permanent. Silver is by far the most common form of heavy metal–induced pigmentation seen by dermatologists. It occurs in two forms, local or systemic. Local argyria typically follows the topical use of silver sulfadiazine or silver-containing dressings (Acticoat). Blue-gray pigmentation occurs at the site of application. Implantation into the skin by needles or pierced jewelry may lead to focal areas of argyria. Systemic argyria can also arise from topical application to the skin (in burn and epidermolysis bullosa patients), by inhalation, by mucosal application (nose drops or eyedrops), or by ingestion. Patients may purchase or build devices that allow them to make colloidal silver solutions, which they then ingest in the belief that it will improve their health. After several months of such exposure, the skin becomes slate-gray or blue-gray, primarily in areas of sun exposure. Histologically, granules of silver are found in basement membranes around adnexal (especially eccrine) and vascular structures. Sun exposure leads to the silver binding to either sulfur or selenium in the skin, increasing deposition The deposited silver activates tyrosinase, increasing pigmentation. Most patients with argyria have no systemic symptoms or consequences of the increased silver in their body. Q-switched 1064-nm neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser may be used. Gold deposition was more common when gold was used as a treatment for rheumatoid arthritis. Cutaneous chrysiasis also presents as blue-gray pigmentation, usually after a cumulative dose of 8 g. Chrysiasis is also more prominent in sun-exposed sites. Dermatologists should remain aware of this condition, because patients treated with gold, even decades earlier, may develop disfiguring hyperpigmentation after Q-switched laser therapy for hair removal or lentigines lightening. Chrysiasis has been treated effectively in one patient using repeated 595-nm pulsed dye laser therapy. Bismuth also pigments the gingival margin. Histologically, granules of the metals are seen in the dermis and around blood vessels. Arsenical melanosis is characterized by black, generalized pigmentation or by a pronounced truncal hyperpigmentation that spares the face, with scattered depigmented macules that resemble raindrops.
The CCB diltiazem can cause a severe photodistributed hyperpigmentation. This is most common in African American or Hispanic women and occurs about 1 year after starting therapy. The lesions are slate-gray or gray-blue macules and patches on the face, neck, and forearms. Perifollicular accentuation is noted.
Histology shows a sparse lichenoid dermatitis with prominent dermal melanophages. The action spectrum of the drug appears to be in the UVB range, but hyperpigmentation is induced by UVA irradiation. The mechanism appears to be postinflammatory hyperpigmentation from a photosensitive lichenoid eruption rather than drug or drug metabolite deposition. Treatment is broad-spectrum sunscreens, stopping the diltiazem, and bleaching creams if needed. Other CCBs can be substituted without the reappearance of the hyperpigmentation.
Some chemotherapeutic agents have been reported to result in pigmentary changes of the skin, hair, and nails (see later discussion). Imatinib in particular has multiple reports of melasma-like hyperpigmentation particularly in darker skin types, and may also cause darkening in other sites, such as the palate Multiple other agents can cause darkening of the hair, including antiviral drugs, valproate, retinoids, and CCBs; propofol has been reported to cause the hair to appear green in one case
Periocular hyperpigmentation occurs in patients treated with prostaglandin analogs for glaucoma These agents also cause pigmentation of the iris. Eyelash length increases. The periocular hyperpigmentation may gradually resolve when the medications are discontinued.
Toxic Erythema of Chemotherapy (Chemotherapy-Induced Acral Erythema, Palmoplantar Erythrodysesthesia Syndrome, Hand-Foot Syndrome, Intertriginous Eruptions)
Fig. 6.38 Hand-foot syndrome.
The unifying term toxic erythema of chemotherapy was proposed by Bolognia in 2008. Many traditional chemotherapeutic agents can induce this relatively common reaction (taxanes, especially docetaxel, cytarabine, anthracyclines, 5-fluorouracil [5-FU] capecitabine, methotrexate, and others less commonly). In the case of pegylated liposomal doxorubicin, localization of the chemotherapeutic agent to the sweat glands has been demonstrated, and one report demonstrated a strikingly intertriginous/flexural erythema and peeling that spared only one axilla, which had been previously radiated and lacked adnexal structures. Cases of neutrophilic eccrine hidradenitis and syringometaplasia, all induced by the same agents, suggest that the eccrine glands are unique targets for adverse reactions to antineoplastic agents.
The initial manifestation is often dysesthesia or tingling of the palms and soles, usually 2–3 weeks after administration of chemotherapy. This is followed in a few days by painful, symmetric erythema and edema most pronounced over the distal pads of the digits. Painful erythema and skin peeling can occur and the skin becomes dusky, deep red-brown, and may blister and desquamate either superficially or involving most of the epidermis (Fig. 6.38). The desquamation is often the most prominent part of the syndrome. The eruption generally involves sites of contact, friction, rubbing, or high concentrations of eccrine ducts/sweat, presumably due to accumulation of toxic metabolites plus occlusion or mild trauma. A localized plaque of fixed erythrodysesthesia has been described proximal to the infusion site of docetaxel, and cytarabine can cause striking localized ear erythema.
The histopathology is nonspecific, with necrotic keratinocytes and vacuolar changes along the basal cell layer. Acute GVHD is in the differential diagnosis. Histologic evaluation may not be useful in the acute setting to distinguish these syndromes. The clinical distribution, timing, and presence or absence of extracutaneous involvement (gastrointestinal or liver findings of GVHD) are more helpful.
Most patients require only local supportive care. Cold com presses and elevation are helpful, and cooling the hands during treatment may reduce the severity of the reaction. Modification of the dose schedule can be beneficial. Pyridoxine, 100–150 mg daily, decreased the pain of 5-FU–induced acral erythema in one study, but benefits are not proven. Cox-2 inhibitors have also been suggested. Local or systemic corticosteroids may be considered, depending on the severity. Lidocaine patches may help with pain. IVIG has been reported to be beneficial in a methotrexate-induced case of acral erythema. Cyclosporine has been reported to result in worsening of the condition.
Sorafenib and sunitinib are small, multikinase-inhibiting molecules with blocking activity for numerous tyrosine kinases, including vascular endothelial growth factor (VEGF), plateletderived growth factor (PDGFRβ), and c-kit ligand (stem cell factor). Both agents induce a condition similar to acral erythema, also referred to as hand-foot skin reaction (HFSR). Patients also present with acral pain and dysesthesia, but usually less severe than with classic chemotherapeutic agents. In contrast to classic acral erythema, multikinase inhibitor–induced HFSR causes lesions over areas of friction, either blisters or patchy hyperkeratotic plaques. The HFSR is dose dependent, high grade in 9% of cases (with blisters, ulceration, and functional loss) and results in the sorafenib being stopped in about 1% of patients. The addition of another VEGF inhibitor, bevacizumab, leads to worse HFSR. Olmutinib was reported to induce a palmoplantar keratoderma in 3 patients. The development of hand-foot syndrome in patients receiving sorafenib for metastatic renal cell carcinoma is associated with better tumor response and improved progression-free survival.
Histologically, there are horizontal layers of necrotic keratinocytes within the epidermis (if biopsy is taken in first 30 days) or in the stratum corneum (later biopsies). Topical tazarotene, 40% urea, heparin ointment, and fluorouracil cream have been used to treat HFSR from multikinase inhibitors.
Chemotherapy-Induced Dyspigmentation
Many traditional chemotherapeutic agents (especially the antibiotics bleomycin, doxorubicin, and daunorubicin) and the alkylating agents (cyclophosphamide and busulfan) cause various patterns of cutaneous hyperpigmentation; the risk of pigmentary changes with targeted chemotherapeutic agents is gaining recognition. Adriamycin (doxorubicin) causes marked hyperpigmentation of the nails, skin, and tongue. This is most common in black patients and appears in locations where constitutional hyperpigmentation is sometimes seen. Hydroxyurea can also cause this pattern of hyperpigmentation. Cyclophosphamide causes transverse banding of the nails or diffuse nail hyperpigmentation beginning proximally. Bleomycin and 5-FU cause similar transverse bands. Busulfan and 5-FU induce diffuse hyperpigmentation that may be photoaccentuated.
Bleomycin induces characteristic flagellate erythematous urticarial wheals associated with pruritus within hours or days of infusion (Fig. 6.39). Lesions continue to appear for days to weeks. Although investigators have not always been able to induce lesions, the pattern strongly suggests scratching is the cause. Bleomycin hyperpigmentation may be accentuated at areas of pressure, strongly supporting trauma as the cause of the peculiar pattern.
Fig. 6.39 Bleomycin-induced flagellate hyperpigmentation.
Fig. 6.40 Shiitake mushroom–induced dermatitis. (Courtesy Don Adler, DO.)
Patients may present with linear erythematous wheals 1–2 days after eating raw or cooked shiitake mushrooms (Fig. 6.40). This so-called toxicodermia, or shiitake flagellate dermatitis, is thought to be caused by a toxic reaction to lentinan, a polysaccharide component of the mushrooms. It is self-limited and resolves within days to weeks of its appearance, but can be treated with topical corticosteroids to relieve the associated pruritus some patients experience. Other associations with flagellate eruptions include adult-onset Still disease, dermatomyositis, and docetaxel therapy.
Fig. 6.41 Methotrexate-induced vascular hyperpigmentation.
5-FU, and less frequently other chemotherapeutic agents such as methotrexate, may produce a serpentine hyperpigmentation overlying the veins proximal to an infusion site (Fig. 6.41). This represents hyperpigmentation from a direct cytotoxic effect of the chemotherapeutic agent.
Targeted chemotherapeutic agents may also induce a variety of patterns of pigmentary changes, with one review showing 17% of patients with skin and 21% of patients with hair pigmentation sequelae. Most established is imatinib, which leads to dose-related generalized or localized hypopigmentation in 40% or more of pigmented persons (possibly due to inhibiting tyrosinase activity). Paradoxic hyperpigmentation of the skin, nails, and hair caused by imatinib has been reported. It starts an average of 4 weeks after treatment and progresses over time if treatment with imatinib is continued. Patients also complain of an inability to tan and “photosensitivity.” Imatinib-induced pseudoporophyria has been reported. One patient with vitiligo had significant progression with imatinib therapy. Multikinase inhibitors (such as cabozantinib, pazopanib, sorafenib, and sunitinib) may inhibit C-kit, which is a regulator of melanogenesis, and may induce skin pigmentary changes through this mechanism, such as sunitinib-related depigmentation of the hair after 5–6 weeks of treatment. Sunitinib may lead to yellow pigmentation of the skin from the drug or its metabolites being deposited, though some mTOR inhibitors have also been reported to cause yellowing temsirolimus). Eruptive melanocytic nevi and lentigines with an acral predisposition have been seen with sorafenib therapy. Ipilimumab, pembrolizumab, and nivolumab are immune-stimulating agents that likely induce vitiligo through autoimmune-activited CD8+ T cells targeting the melanocytes. EGF-receptor inhibitors, VEGF-receptor inhibitors, and other targeted agents have also been reported to cause both skin and hair hypopigmentation as well. Although in general targeted agents induce less alopecia (14% overall) than cytoxic chemotherapy, some (particularly vismodegib, at over 50%) have high rates.
Cutaneous Side Effects of Epidermal Growth Factor Receptor Inhibitors
Fig. 6.42 Epidermal growth factor receptor (EGFR) inhibitor–induced paronychia.
Epidermal growth factor receptor (EGFR) inhibitors are used for a variety of tumors, and include both monoclonal antibodies (cetuximab and panitumumab) and tyrosine kinase inhibitors. EGFR is expressed by basal keratinocytes, sebocytes, and the outer root sheath, explaining why up o 90% of patients treated with EGFR inhibitors may develop cutaneous side effects, including xerosis (19%), pruritus (24%), trichomegaly, hair curling, and signs of skin aging, and painful periungual or finger pulp fissures and paronychia (with or without periungual pyogenic granulomas) may develop in 15%–25% (Fig. 6.42).
The most common side effect is an acneiform rash, which is severe in up to 18% of cases. The severity of the reaction may indicate more drug metabolism and possibly better tumor response rates. When severe, however, the eruption can be dose limiting. The eruption begins 7–10 days after initiation of therapy, attaining maximum severity in the second week. The seborrheic areas of the scalp, central face, upper back, and retroauricular regions are mainly affected. The primary lesion is a follicular papule or pustule with few or no comedones. Crusting and confluence can occur. Cultures should be performed to rule out secondary infection in patients with severe disease. Radiation therapy during EGFR inhibitor therapy will enhance the skin toxicity, but previously radiated skin is often spared from inhibitor toxicity. Treatment is oral tetracycline antibiotics and corticosteroids. It is recommended that prophylactic sun protection and oral doxycycline be used in many cases. Effective topical therapies have included metronidazole, clindamycin, hydrocortisone, pimecrolimus, tretinoin, and possibly dapsone. In the most severe cases, isotretinoin or acitretin can be used. TNF-α and IL-1 are involved in the pathogenesis of EGFR inhibitor toxicity. Etanercept and anakinra, therefore, may also be therapeutically useful.
Other Cutaneous Side Effects of Multikinase Inhibitors
Fig. 6.43 Bevacizumab-induced ulceration of striae. (Courtesy Farber SA, Samimi S, Rosenbach M. Ulcerations within striae distensae associated with bevacizumab therapy. J Am Acad Dermatol 2015;72;1:e33-35.)
In addition to the reactions previously listed, multikinase inhibitors may cause other skin reactions. Psoriasis exacerbation, acral psoriasiform hyperkeratosis, and pityriasis rosea-like eruptions have been described with imatinib. Both imatinib and sunitinib cause facial edema, with a periocular predilection. Increased vascular permeability caused by PDGFR inhibition has been the proposed mechanism. Dasatinib has caused a lobular panniculitis. Bevacizumab, a VEGF inhibitor, causes bleeding, painful distal subungual splinter hemorrhages, and wound healing complications. Extensive cutaneous surgery should probably be delayed for 60 days after bevacizumab therapy, and 28 days should elapse after surgery before initiation of bevacizumab therapy. Bevacizumab has also been associated with ulceration of striae distensae (Fig 6.43). VEGF inhibitors in general can lead to mucosal bleeding (epistaxis).
Radiation Enhancement and Recall Reactions
Fig. 6.44 Radiation recall induced by vemurafenib.
Radiation dermatitis, in the form of intense erythema and vesiculation of the skin, may be observed in radiation ports. Administration of many chemotherapeutic agents, during or about the time of radiation therapy, may induce an enhanced radiation reaction. In some patients, however, months to years after radiation treatment, the administration of a chemotherapeutic agent may induce a reaction within the prior radiation port, with features of radiation dermatitis (Fig. 6.44). This phenomenon has been termed “radiation recall,” reported with numerous chemotherapeutic agents (gemcitabine, small molecule inhibitors, tamoxifen, methotrexate, taxanes, and multiple other agents), high-dose IFN-α, and simvastatin. Besides the skin, internal structures such as the gut may also be affected. A similar reaction of reactivation of a sunburn after methotrexate therapy also occurs. Exanthems restricted to prior areas of sunburn are not true radiation recall, but may represent “locus minoris resistentiae,” or a nonspecific eruption showing up at a site of prior damage.
Tumor Necrosis Factor Inhibitors
The TNF inhibitors are associated with palmoplantar pustulosis, pustular folliculitis, new or worsening of psoriasis, interface dermatitis neutrophilic eccrine hidradenitis, Sweet syndrome, lupus (systemic and subacute cutaneous), granulomatous reactions (sarcoidosis, granuloma annulare), and vasculitis. ISRs are common with etanercept therapy for rheumatologic disease, with 20%–40% of patients developing ISR. ISRs present as erythematous, mildly
swollen plaques, appearing 1–2 days after the injection. Pruritus occurs in 20% of patients. ISR is most common early in the treatment course (median number of injections, four) and stops appearing with continued treatment. Individual lesions resolve over 2–3 days. Recall ISR (reappearance of eruption at previous ISR site) occurs in 40% of patients. This adverse reaction appears to be mediated by CD8+ T cells. IL-1 (anakinra) therapy is associated with high rates of local ISRs (>50% in one study of 140 patients) and diffuse rash (25% of patients), which may be urticarial.
The paradoxic appearance of psoriasis or a psoriasiform dermatitis is now a well-recognized complication of TNF inhibitor herapy. It occurs with all of the TNF inhibitors. The psoriasis can appear from days to years after anti-TNF therapy. There is no age or gender predisposition Several clinical patterns have been described. Palmoplantar pustulosis represents about 40% of cases. Generalized pustular disease may accompany the palmoplantar lesions. Plaque-type psoriasis occurs in about one third of TNF inhibitor–induced psoriasis (Fig. 6.45). New-onset guttate psoriasis occurs in 10% of cases. Stopping the TNF inhibitor led to improvement or resolution in the vast majority of patients. In some cases, therapy was continued and the eruption resolved. Experts disagree as to whether switching to a different anti-TNF agent may be tolerated in these patients. Many patients have been rechallenged with other TNF inhibitors. In severe cases, this is probably not prudent, but in milder or localized cases, this could be considered. The psoriasis caused by anti TNF agents can be treated with topical corticosteroids, UV phototherapy, topical vitamin D analogs, methotrexate, acitretin, cyclosporine, or other antipsoriatic biologics. The proposed mechanism for the appearance with psoriasis with anti-TNF therapy is either overactivity of Th1 cells or increased IFN-α production by skin-resident plasmacytoid dendritic cells. Systemic IFN-α and topical imiquimod (an IFN inducer) have been reported to exacerbate psoriasis, supporting this hypothesis. Sarcoidosis induced by anti-TNF agents could also be related to increased IFN production.
Many patients on biologic therapy may develop new antinuclear antibodies (ANAs; 11% of etanercept patients for RA, similar rates with infliximab), though most of those do not have overt lupus. True drug-induced lupus (DIL) with features of SLE may occur. It begins on average after 41 weeks of treatment. Compared with DIL from other medications, the TNF inhibitors cause more skin disease with malar rash, discoid lesions, and photosensitivity. Many of the patients fulfill the American Rheumatology Association (ARA) criteria for SLE, and significant internal organ involvement can occur, including renal and central nervous system (CNS) involvement. Etanercept seems to cause skin lesions more frequently. Etanercept patients also developed vasculitis more often. The vast
majority of patients improve about 10 months after therapy has been discontinued. Switching from one TNF inhibitor to another has been reported to be successful. Subacute cutaneous lupus erythematosus (SCLE) may also occur. This is important to keep in mind as the appearance may be psoriasiform, rather than the classic annular morphology, and can be mistaken for TNF-induced psoriasis. Dermatomyositis has also been caused by TNF inhibitor treatment.
Vasculitis is also a well-recognized complication of treatment with TNF inhibitors. Etanercept is the most common agent reported to induce vasculitis. The lesions of vasculitis may begin around the injection sites in some etanercept-induced vasculitis cases. More than 85% of patients present with skin lesions, usually a leukocytoclastic vasculitis. Ulcerations, nodules, digital lesions, chilblains, livedo, and other morphologies have also been described. Visceral vasculitis occurs in about one quarter of patients. They may be ANA positive or antineutrophil cytoplasmic antibody (ANCA) positive (usually p-ANCA) or may have cryoglobulins. Drug-induced antiphospholipid syndrome with TNF inhibitors can be associated with DIL or vasculitis and presents with thrombosis as well as cutaneous lesions. Some patients with TNF inhibitor–induced vasculitis have died Stopping the TNF inhibitor leads to resolution of the vasculitis in more than 90% of cases. Rechallenge leads to new vasculitic lesions in 75% of cases. Other neutrophilic disorders induced by TNF inhibitors include Sweet syndrome–like reactions and neutrophilic eccrine hidradenitis. New onset vitiligo has also been reported with a variety of biologics, primarily the TNF inhibitors.
Lichenoid drug eruptions have been reported from anti-TNF agents. They are typically pruritic and affect areas typically involved by lichen planus: the flexor wrists. However, gluteal cleft lesions are also common. In some cases, the lichenoid eruption superimposes itself on psoriatic lesions, presenting as an exacerbation of the “psoriasis.” Biopsies show features of both lichen planus and psoriasis, and stopping the anti-TNF therapy leads to improvement of the “psoriasis.” Despite these agents’ immunosuppressive properties, patients can still develop allergic contact dermatitis while taking them, and patch testing during anti-TNF treatment may identify relevant allergens. It appears that patients receiving anti-TNF agents are at slightly increased risk for development of nonmelanoma skin cancers, especially if they also have used methotrexate.
Fig. 6.45 Plaque-type psoriasis.
Iododerma
Fig. 6.46 Follicular iododerma.
Iodides may cause a wide variety of skin eruptions. The most common sources of exposure are oral and IV contrast materials and when iodides are used to treat thyroid disease. Application of povidone-iodine to the skin, mucosa, or as a tub soak has produced iododerma. The most common type is the acneiform eruption with numerous acutely inflamed follicular pustules, each surrounded by a ring of hyperemia (Fig. 6.46). Dermal bullous lesions are also common and may become ulcerated and crusted, resembling pyoderma gangrenosum or Sweet syndrome. The eruption may involve the face, upper extremities, trunk, and even the buccal mucosa. Acne vulgaris and rosacea are unfavorably affected by iodides. Acute iododerma may follow IV radiocontrast studies in patients with renal failure. The lesions may be associated with severe leukocytoclastic vasculitis, intraepidermal spongiform pustules, and suppurative folliculitis. The lesions respond to prednisone.
Adverse Reactions to Topical Corticosteroids
Fig 6.47 Topical steroid-induced atrophy.
The prolonged topical use of corticosteroid preparations may produce distinctive changes in the skin. The appearance of these side effects depends on four factors: strength of the steroid, area to which it is applied, amount of coexistent sun damage at the site of application, and patient’s predisposition to certain side effects. Atrophy, striae, telangiectasia, skin fragility, and purpura are the changes most frequently seen. The most striking changes of telangiectasia are seen in fair-skinned individuals who use fluorinated corticosteroids on the face (Fig. 6.47). The changes in the skin are enhanced by occlusion. When these side effects occur, the strength of the steroid should be reduced or substituted with pimecrolimus or tacrolimus. Weekly pulse dosing of a potent topical corticosteroid can also reduce the incidence of side effects. Adjunctive measures to reduce steroid requirement could include addition of topical doxepin, pramoxine, or menthol and camphor to the regimen. Usually, the telangiectases disappear a few months after corticosteroid applications are stopped.
When corticosteroid preparations are applied to the face over weeks or months, persistent erythema with telangiectases, and often small pustules, may occur. Perioral dermatitis and rosacea may be caused by topical corticosteroids. Steroid rosacea has been reported from long-term use of 1% hydrocortisone cream. For this reason, the authors do not recommend chronic topical corticosteroid preparations of any strength in the adjunctive treatment of rosacea. A topical calcineurin inhibitor may be used instead as an antiinflammatory, although it can also induce a rosacea-like eruption. When a rosacea-like eruption appears in the setting of a topical antiinflammatory, a pustule should be opened and the contents examined for overgrowth of Demodex mites.
Repeated application of corticosteroids to the face, scrotum, or vulva may lead to marked atrophy of these tissues, including the red scrotum syndrome. The tissues become “addicted” to the topical steroid, so that withdrawing treatment results in severe itching or burning and intense erythema. Topical application of corticosteroids can produce epidermal atrophy with hypopigmentation. If used over large areas, sufficient topical steroids may be absorbed to suppress the hypothalamic-pituitary axis. This may affect the growth of children with atopic dermatitis and has led to addisonian steroid dependency and also Cushing syndrome. Atopic children with more than 50% BSA involvement have short stature. This may be related to their increased use of potent topical corticosteroids. In addition, bone mineral density is reduced in adults with chronic atopic dermatitis severe enough to require corticosteroid preparations stronger than hydrocortisone.
