5 - ECZEMA, ATOPIC DERMATITIS, AND NONINFECTIOUS IMMUNODEFICIENCY DISORDERS Flashcards
What is eczema?
The word eczema seems to have originated in 543 ad and is derived from the Greek word ekzein, meaning to “to boil forth” or “to effervesce.” The term encompasses such disorders as dyshidrotic eczema and nummular eczema (NE), but at times is used synonymously for atopic dermatitis (atopic eczema). The acute stage generally presents as a red edematous plaque that may have grossly visible, small, grouped vesicles. Subacute lesions present as erythematous plaques with scale or crusting. Later, lesions may be covered by a drier scale or may become lichenified. In most eczematous reactions, severe pruritus is a prominent symptom. The degree of irritation at which itching begins (the itch threshold) is lowered by stress. Itching is often prominent at bedtime and usually results in insomnia. Heat and sweating may also provoke episodes of itching.
What is the hallmark of all eczematous eruptions?
Histologically, the hallmark of all eczematous eruptions is a serous exudate between cells of the epidermis (spongiosis), with an underlying dermal perivascular lymphoid infiltrate and exocytosis (lymphocytes present in overlying epidermis singly or in groups).
Spongiosis is generally out of proportion to the lymphoid cells in the epidermis. This is in contrast to mycosis fungoides, which demonstrates minimal spongiosis confined to the area immediately surrounding the lymphocytes.
In most eczematous processes, spongiosis is very prominent in the acute stage, where it is accompanied by minimal acanthosis or hyperkeratosis. Subacute spongiotic dermatitis demonstrates epidermal spongiosis with acanthosis and hyperkeratosis. Chronic lesions may have minimal accompanying spongiosis, but acute and chronic stages may overlap because episodes of eczematous dermatitis follow one another. Scale corresponds to foci of parakeratosis produced by the inflamed epidermis. A crust is composed of serous exudate, acute inflammatory cells, and keratin. Eczema, regardless of cause, will manifest similar histologic changes if allowed to persist chronically. These features are related to chronic rubbing or scratching and correspond clinically to lichen simplex chronicus or prurigo nodularis. Histologic features at this stage include compact hyperkeratosis, irregular acanthosis, and thickening of the collagen bundles in the papillary portion of the dermis. The dermal infiltrate at all stages is predominantly lymphoid, but an admixture of eosinophils may be noted. Neutrophils generally appear in secondarily infected lesions. Spongiosis with many intraepidermal eosinophils may be seen in the early spongiotic phase of pemphigoid, pemphigus, and incontinentia pigmenti, as well as some cases of allergic contact dermatitis.
chronic, inflammatory skin disease characterized by pruritus and a chronic course of exacerbations and remissions
Atopic dermatitis (AD)
It is associated with other atopic conditions, including food allergies, asthma, allergic rhinoconjunctivitis, eosinophilic esophagitis, and eosinophilic gastroenteritis. Because AD usually precedes the appearance of these other atopic conditions, it has been proposed that AD is the first step in an “atopic march” whereby sensitization to allergens through the skin may lead to allergic responses in the airways or digestive tract. Although this sequence of atopic conditions does occur in many children, whether the AD is causal in the development of the other manifestations of atopy is unproved but plausible. For this reason, early and effective treatment of AD is encouraged in an effort to prevent other atopic conditions. The genetic defect(s) predisposing at-risk individuals to the development of AD is the same for asthma and allergic rhinoconjunctivitis, and thus it has been difficult to prove that AD is causal in the development of other atopic conditions.
Epidemiology of Atopic dermatitis
The prevalence of AD, asthma, and allergic rhinoconjunctivitis increased dramatically in the last half of the 20th century, becoming a major health problem in many countries. The increase began first in the most developed nations, and as the standard of living has increased worldwide, so has the prevalence of AD. Rates of AD are about 30% in the most developed nations and exceed 10% in many countries, resulting in a worldwide cumulative prevalence of 20% In the most developed nations, the rates of AD plateaued in the 1990s, whereas developing nations have rates that continue to increase. Factors associated with high rates of AD are high latitude (perhaps associated with low levels of annual sun exposure) and lower mean annual temperature. A role for exposure to allergens thought to “trigger” AD is not supported by epidemiologic studies. Iceland has a very high rate of AD (27%) yet has no dust mites, few trees, and low pet ownership. However, children in Iceland often have positive skin prick tests to environmental allergens (24%). This questions the value of such tests in predicting causal environmental allergens in AD. Girls are slightly more likely to develop AD. In the United States an increased risk of AD during the first 6 months of life is noted in infants with African and Asian race/ethnicity, male gender, greater gestational age at birth, and a family history of atopy, particularly a maternal history of eczema. Other factors that increase the risk for the development of AD early in childhood include consumption of a Western diet, birth order (first children at greater risk), and delivery by cesarean section, all of which alter the intestinal microbiome. Exposure to antibiotics prenatally during the first or second and third trimesters also increases risk of AD. Therefore biodiversity in the gut microbiome seems to be protective. Gut colonization with Clostridium cluster I is associated with development of AD. Dog ownership before age 1 year decreases the risk of developing AD by age 4, but cat ownership has no effect. The hygiene hypothesis suggests that being raised on a farm lowers the risk of AD whereas living in modernized, cleaner indoor environments leads to a higher risk of AD.
About 50% of cases of AD appear in the first year of life, the vast majority within the first 5 years of life, and the remaining cases of “adult” AD usually before age 30. Atopy is now so common in the population that most individuals have a family history of atopy. Elevated immunoglobulin E (IgE) levels are not diagnostic of atopic disease in the adult. Therefore elevated IgE and a family history of “atopy” in an adult with new-onset dermatitis should not be used to confirm the diagnosis of adult AD Adult AD should only be considered when the dermatitis has a characteristic distribution and when other significant diagnoses, such as allergic contact dermatitis, photodermatitis, and cutaneous T-cell lymphoma, have been excluded. Rather, a dermatologist should infrequently make the diagnosis of adult “atopic dermatitis” for a dermatitis appearing for the first time after age 30.
Genetic Basis and Pathogenesis of atopic dermatitis
Eighty percent of identical twins show concordance for AD. A child is at increased risk of developing AD if either parent is affected. More than one quarter of offspring of atopic mothers develop AD in the first 3 months of life. If one parent is atopic, more than half the children will develop allergic symptoms by age 2. This rate rises to 79% if both parents are atopic. All of these findings strongly suggested a genetic cause for AD. Filaggrin is a protein encoded by the gene FLG, that resides in the epidermal differentiation complex (EDC) on chromosome 1q21. Filaggrin is processed by caspase 14 during terminal keratinocyte differentiation into highly hydroscopic pyrrolidone carboxylic acid and urocanic acid, collectively known as the “natural moisturizing factor” (NMF). Null mutations in FLG lead to reduction in NMF, which probably contributes to the xerosis that is almost universal in AD. Transepidermal water loss (TEWL) is increased. This may be caused by subclinical dermatitis, but also by abnormal delivery of lamellar body epidermal lipids (especially ceramide) to the interstices of the terminally differentiated keratinocytes. The resulting defective lipid bilayers retain water poorly, leading to increased TEWL and clinical xerosis. Ichthyosis vulgaris is caused by mutations in the FLG gene and is frequently associated with AD. Four FLG mutations have an estimated combined allelic frequency of 7%–10% in individuals of European descent. Different FLG gene mutations are associated with AD in other ethnicities although the rates do not necessarily match AD prevalence, demonstrating that the disease is multifactorial. Filaggrin 2 (FLG2), also in the EDC and w th similar function to FLG, is associated with persistent AD in African Americans. Inheriting one null FLG mutation slightly ncreases one’s risk of developing AD, and inheriting two mutations, either as a homozygote or a compound heterozygote, dramatically increases one’s risk. Between 42% and 79% of persons with one or more FLG null mutations will develop AD. However, 40% of carriers with FLG null mutations never have AD. FLG mutations are associated with AD that presents early in life, tends to persist into childhood and adulthood, and is associated with wheezing in infancy and with asthma. FLG mutations are also associated with allergic rhinitis and keratosis pilaris, independent of AD. Hyperlinear palms are strongly associated with FLG mutations, with a 71% positive predictive value (PPV) for marked palmar hyperlinearity. LAMA3 gene mutations, encoding the alpha chain of laminin 5, may also predispose to AD. In murine models, decreased Claudin 3 expression can lead to leakage of sweat in the superficial dermis contributing to impaired sweating in atopic dermatitis.
Not all cases of AD are associated with FLG mutations. AD patients often demonstrate immunologic features consistent with a T-helper 2 (Th2) phenotype, with elevated IgE, eosinophils on skin biopsy, and positive skin tests and radioallergosorbent test (RAST). The cytokines, especially interleukin-4 (IL-4) and interleukin-13 (IL-13), that are released due to the Th2 immune response play an important role in AD by increasing inflammatory cell infiltration and stimulating the inflammatory feedback loop. Basophils and innate type 2 lymphoid cells can also secrete IL-4 and IL-13. Thymic stromal lymphopoietin (TSLP) is an important interleukin-7 (IL-7)–like cytokine that, through its interaction with Th2 cells, basophils, mast cells, and dendritic cells, promotes the secretion and production of Th2 cytokines and the development of inflammatory Th2 CD4+ T cells (through production of OL40L). TSLP is produced by keratinocytes and is found in high levels in AD skin lesions. In addition, interleukin-31 (IL-31) is produced by Th2 and Th22 cells. IL-31 binds directly to nerves leading to itching and also downregulates expression of filaggrin. The JAKSTAT pathway is also critical in causing overactivation of the TH2 response and itch. Interleukin-17 (IL-17) and interleukin-22 (IL-22), which are released by Th17 cells, are also elevated in AD. Thus AD appears to represent a disorder characterized by a barrier defect that activates a specific Th2 response leading to a cycle of inflammation mediated by various inflammatory signals. The cytokines produced then worsen the already defective barrier. This leads to a vicious cycle of barrier failure and progressive inflammation, producing a chronic, relapsing, pruritic disorder, and explains why moisturization alone is not enough once the inflammatory cascade has started.
Preventionof AD in High-Risk Children
Extensive studies have been undertaken to determine whether it is possible to prevent the development of AD in children at high risk—those with parents or siblings with atopy. The most promising studies now repeated multiple times show that early moisturization, starting before 3 weeks of life, with thick emollient, may prevent AD in children at high risk of developing AD. Twice daily moisturization with various emollients such as petrolatum, sunflower seed oil, and others leads to an approximately 50% reduction in the expected rate of AD development in the first 6 months of life. This supports the idea that breaks in the skin barrier are an essential step in developing AD.
Switching to soy formula does not appear to reduce the risk of developing AD. Prolonged exclusive breastfeeding beyond 3–4 months of age is not protective for the development of AD. Extensively hydrolyzed casein formulas may be used as a supplement or substitute for breast milk during the first 4 months of life. Maternal allergen avoidance during pregnancy does not reduce the risk of AD in the offspring. Probiotic administration during and after pregnancy has been shown to decrease AD incidence by 14% based on data from a meta-analysis However, the type of probiotic to use, exactly when to start, and the safety during pregnancy are not fully elucidated. House dust mite (HDM) avoidance does not reduce AD, even in sensitized individuals, and high levels of HDMs in the environment in early life reduce AD risk.
Role of Food allergy in AD
The role of food allergy in AD is complicated, and the purported role of foods in AD has changed in recent years. Approximately 35% of children with moderate to severe AD have food allergies. However, 85% of children with AD will have elevated IgE to food or inhalant allergens, making a diagnosis of food allergy with serum or prick tests alone challenging due to the high false-positive rate of testing. Before food allergy testing is undertaken, treatment of the AD should be optimized. Parents are often seeking a “cause” for the child’s AD, when in fact it could be controlled with appropriate topical measures. Food restriction diets can be difficult and could put the child at risk for malnourishment and possibly development of allergy and should never be pursued without the oversight of an allergist and nutritionist to ensure proper nutrition. Food allergy should be pursued only in younger children with moderate to severe AD in whom standard treatments have failed. These children should also have a history of possible triggering of AD by specific food exposures. Testing, if performed, should be targeted foods to which the child is likely to be exposed, but generally wheat, egg, soy, cow’s milk, and peanut testing has been the most relevant to the AD. Double-blind placebo-controlled food challenges are
the “gold standard” for diagnosing food allergy. Skin prick tests have a high negative predictive value (>95%) but a PPV of only 0%–65%. For example, more than 8% of the U.S. population has a positive prick test to peanut, but only 0.4% are actually clinically allergic. Possible food allergy detected by testing should be confirmed by clinical history A positive RAST or skin prick test for a food that the child rarely or never ingests is probably not causally relevant to the child’s AD. Higher serum IgE levels and larger wheal sizes (>8–10 mm) are associated with greater likelihood of reacting to these foods when challenged. About 90% of food allergy is caused by a limited number of foods, as follows:
- Infants: cow’s milk, egg, soybean, wheat
- Children (2–10 years): cow’s milk, egg, peanut, tree nuts, fish, crustacean shellfish, sesame, kiwi fruit
- Older children: peanut, tree nuts, fish, shellfish, sesame, pollenassociated foods
Breastfeeding mothers must avoid the incriminated foods if their infant has been diagnosed with a food allergy.
There has been a rapid rise in peanut allergy in the United States. Recommendations to limit peanut exposure in childhood has been revised. A large randomized placebo control trial showed that early exposure in children at high risk for peanut allergy (due to strong family history of atopy) decreased the rate of development of peanut allergy by 86%. Therefore the revised guidelines that were developed in conjunction with dermatologists and allergists for peanut exposure are based on AD in the child. Of course a whole peanut should never be given to an infant due to choking hazard; therefore this was done with smooth peanut butter or the peanut snack Bamba (trademark).
1 Children with severe AD or egg allergy should be considered for peanut testing before exposure to peanuts around 4–6 months of age.
- Mild to moderate AD: Introduce peanuts around 6 months.
- No AD or food allergy: Introduce peanuts in accordance with family and cultural preferences.
Role of aeroallergens in AD
It is debated how much of a role aeroallergens play in the pathophysiology of AD. Although early exposure to allergens may lessen the incidence of AD, exposure to dust mites, animal allergens, mold, pollen, tree allergens, and other airborne allergens in those who are allergic may exacerbate AD. Testing for IgE responses to aeroallergens may not be predictive of their effect on patients with AD. In patients who note worsening around specific allergens, they should avoid these. Common allergens to avoid if possible include tobacco smoke, pollen, house dust mites, cats, and dogs (if allergic) although early exposure to dogs may prevent AD. Reduction of dust mite exposure can be achieved through vacuuming with a filtered vacuum, using dust mite covers on mattresses, avoidance of stuffed animals, and wall to-wall carpeting if feasible.
3 stages of AD
AD can be divided into three stages:
- infantile AD, occurring from 2 months to 2 years of age;
- childhood AD, from 2–10 years; and
- adolescent/adult AD.
What are the clinical manifestations of AD?
In all stages, pruritus is the hallmark. Itching often precedes the appearance of lesions, thus the concept that AD is “the itch that rashes.” Useful diagnostic criteria include those of Hannifin and Rajka, the UK Working Party, and the American Academy of Dermatology’s Consensus Conference on Pediatric Atopic Dermatitis (Boxes 5 1 and 5.2). These criteria have specificity at or above 90% but have much lower sensitivities (40%–100%). Therefore these criteria are useful for enrolling patients in studies and ensuring that they have AD, but less practical in diagnosing a specific patient with AD.
Hannifin and Rajka Criteria for Atopic Dermatitis
Modified Criteria for Children With Atopic Dermatitis
Infantile Atopic Dermatitis
Fifty percent or more of AD cases present in the first year of life, but usually not until after 2 months. Widespread dermatitis in children under 2 months may be from an irritant, ichthyosis, or a hallmark of severe immunodeficiency. AD in infancy usually begins as erythema and scaling of the cheeks (Fig. 5.1). The eruption may extend to the scalp, neck, forehead, wrists, extensor extremities, and buttocks. There can be overlap with seborrheic dermatitis on the scalp and in the folds, but papular or nodular involvement in the ax llae and inguinal folds is more typical of scabies infestation. Children with AD who have FLG gene mutations specifically have more cheek and extensor arm/hand involvement. There may be significant exudate; secondary effects from scratching, rubbing, and infection include crusts, infiltra ion, and pustules, respectively. Occlusion of saliva due to teething, extensive breastfeeding, and drooling may cause the cheeks and upper chest to flare and thick emollients can help prevent this. Breastfeeding should not be curtailed. The infiltrated plaques eventually take on a characteristic lichenified appearance The infantile pattern of AD usually disappears by the end of the second year of life.
Worsening of AD is often observed in infants after immunizations and viral infections likely due to activation of the immune system. Partial remission may occur during the summer, with relapse in winter. This may relate to the therapeutic effects of ultrav olet (UV) B light and humidity in many atopic patients, as well as the aggravation by wool and dry air in the winter. Extensive airborne environmental allergies may lead to worsening in the warmer months.
Childhood Atopic Dermatitis
Fig. 5.2 Flexural involvement in childhood atopic dermatitis.
During childhood, lesions tend to be less exudative. The classic locations are the antecubital and popliteal fossae (Fig. 5.2), flexor wrists, ankles, eyelids, face, and around the neck. Lesions are often lichenified, indurated plaques. These are intermingled with isolated, excoriated, 2–4 mm papules that are scattered more widely over the uncovered parts. Nummular morphology and involvement of the feet are more common in childhood AD.
Pruritus is a constant feature, and most of the cutaneous changes are secondary to it. Itching is paroxysmal. Scratching induces lichenification and may lead to secondary infection. A vicious cycle may be established, the itch-scratch cycle, as pruritus leads o scratching, and scratching causes secondary changes that in them cause itching. Instead of scratching causing pain, in the atopic patient the “pain” induced by scratching is perceived as itch and induces more scratching. The scratching impulse is beyond the control of the patient. Severe bouts of scratching occur during
sleep, leading to poor rest and chronic tiredness in atopic children. This can affect school performance. Parents often scold children who are scratching, and this leads to more anxiety and thus more scratching.
Severe AD involving a large percentage of the body surface area BSA) can be associated with growth retardation (Fig. 5.3). Restriction diets and steroid use may exacerbate growth impairment. Aggressive management of such children with phototherapy or systemic immunosuppressive agents may allow for rebound growth. Children with severe AD may also have substantial psychological disturbances. Parents should be questioned with regard to school performance and socialization. Although using light therapy and systemic immunosuppressive or immunomodulatory therapy in children can be daunting for patients and practitioners, the benefits to quality of life can dramatically outweigh the risks.
Fig. 5.3 Severe, widespread atopic dermatitis.
Atopic Dermatitis in Adolescents and Adults
Fig. 5.4 Prurigo-like papules in adult atopic dermatitis.
Most adolescents and adults with AD will give a history of childhood disease. AD will begin after age 18 years in only 6%–14% of patients diagnosed with AD. One exception is the patient who moves from a humid, tropical region to a more temperate area of higher latitude. This climatic change is often associated with the appearance of AD. In older patients, AD may occur as localized erythematous, scaly, papular, exudative, or lichenified plaques. In adolescents, the eruption often involves the classic antecubital and popliteal fossae, front and sides of the neck, forehead, and area around the eyes. In older adults, the distribution is generally less characteristic, and localized dermatitis may be the predominant feature, especially hand, nipple, or eyelid eczema. At times, the eruption may generalize, with accentuation in the flexures. The skin generally is dry and somewhat erythematous. Lichenification and prurigo-like papules are common (Fig. 5.4). Papular lesions tend to be dry, slightly elevated, and flat topped. They are almost always excoriated and often coalesce to form plaques. Staphylococcal colonization is common. In darker-skinned patients, the lesions are often hyperpigmented, frequently with focal hypopigmented areas related to healed excoriations.
Itching usually occurs in crises or paroxysms. Adults frequently complain that flares of AD are triggered by acute emotional upsets. Stress, anxiety, and depression reduce the threshold at which itch is perceived and result in damage to the epidermal permeability barrier, further exacerbating AD. Atopic persons may sweat poorly and may complain of severe pruritus related to heat or exercise. Physical conditioning and liberal use of emollients improve this component, and atopic patients can participate in competitive sports.
Even in patients with AD in adolescence or early adulthood, improvement usually occurs over time, and dermatitis is uncommon after middle life. In general, these patients retain mild stigmata of the disease, such as dry skin, easy skin irritation, and itching in response to heat and perspiration. They remain susceptible to a flare of their disease when exposed to a specific allergen or environmental situation. Photosensitivity develops in approximately 3% of AD patients and may manifest as either a polymorphous light eruption–type reaction or simply exacerbation of the AD by UV exposure. The average age for photosensitive AD is the middle to late thirties. Human immunodeficiency virus (HIV) infection can also serve as a trigger, and new-onset AD in an at-risk adult should lead to counseling and testing for HIV if warranted.
The hands, including the wrists, are frequently involved in adults, and hand dermatitis is a common problem for adults with a history of AD. It is common for irritant or atopic hand dermatitis to appear in young women after the birth of a child, when increased exposure to soaps and water triggers their disease. There is a new trend in children who can buy kits or mix their own various household liquids such as glue, borax, contact solution, baking soda and others to make “slime” This can lead to irritant dermatitis or worsening of hand atopic dermatitis. Wet work is a major factor in hand eczema in general, including those patients with AD.
Fig. 5.5 Atopic hand dermatitis.
Atopic hand dermatitis can affect both the dorsal and the palmar surface (Fig. 5.5). Keratosis punctata of the creases, a disorder seen almost exclusively in black persons, is also more common in atopic patients. Patients with AD have frequent exposure to preservatives and other potential allergens in the creams and lotions that are continually applied to their skin. Contact allergy may manifest as chronic hand eczema. Patch testing can help differentiate an allergic contact dermatitis.
Fig. 5.6 Periocular atopic dermatitis.
Eyelids are often involved (Fig. 5.6). In general, the involvement is bilateral and the condition flares with cold weather. As in hand dermatitis, irritants and allergic contact allergens must be excluded by a careful history and patch testing.
linear transverse fold just below the edge of the lower eyelids
Dennie-Morgan fold - indicative of the atopic diathesis, although it may be seen with any chronic dermatitis of the lower lids
In atopic patients with eyelid dermatitis, increased folds and darkening under the eyes is common.
When there is extensive facial involvement, the nose is still typically spared. This is called the ______
“headlight sign.”
The axillary vault and inguinal folds are also typically spared likely due to high humidity in these areas.
A prominent nasal crease may also be noted due to chronic upward wiping of the nose when there is rhinitis secondary to seasonal allergies. This is called the _____
“nasal salute.”
Other manifestations of AD
The less involved skin of atopic patients is frequently dry and slightly erythematous and may be scaly. Histologically, the apparently normal skin of atopic patients is frequently inflamed subclinically. The dry, scaling skin of AD may represent low-grade dermatitis. Pityriasis alba is a form of subclinical dermatitis, frequently atopic in origin. It presents as poorly marginated, hypopigmented, slightly scaly patches on the cheeks, upper arms, and trunk, typically in children and young adults with types III to V skin. It usually responds to emollients and mild topical steroids, preferably in an ointment base.
consists of horny follicular lesions of the outer aspects of the upper arms, legs, cheeks, and buttocks and is often associated with AD, AD and occurs in patients with filagrin mutations.
Keratosis pilaris (KP)
The keratotic papules on the face may be on a red background, a variant of KP called keratosis pilaris rubra faceii. KP is often refractory to treatment. Moisturizers alone are only partially beneficial. Some patients will respond to topical lactic acid, urea, or retinoids but they can easily irritate the skin of atopic patients and should be avoided in young children. If older patients desire, treatment should begin with applications only once or twice a week. KP must be differentiated from follicular eczema which tends to affect the trunk and is often more prominent in patients with skin ypes III-VI.
Thinning of the lateral eyebrows is sometimes present in AD
Hertoghe sign
This apparently occurs from chronic rubbing caused by pruritus and subclinical dermatitis. Hyperkeratos s and hyperpigmentation, which produce a “dirty neck” appearance, are also common in AD patients.
blanching of the skin at the site of stroking or scratching
White dermatographism
Chronic exposure to the vasoconstrictive effects of topical and oral steroids may lead to erythroderma due to vasodilation when steroids are tapered. This can lead to dysesthesias and belies the importance of using maintenance therapies that limit steroid exposure or lessen strength.
Atopic patients are at increased risk of developing various forms of urticaria, including contact urticaria. Episodes of contact urticaria may be followed by typical eczematous lesions at the affected site because skin that is scratched may flare with AD.
Ophthalmologic Abnormalities in AD
Up to 10% of patients with AD develop cataracts, either anterior or posterior subcapsular. Posterior subcapsular cataracts in atopic individuals are indistinguishable from corticosteroid-induced cataracts. Development of cataracts is more common in patients with severe dermatitis. Keratoconus is an uncommon finding, occurring in approximately 1% of atopic patients. Contact lenses, keratoplasty, and intraocular lenses may be required to treat this condition. Environmental allergies may also lead to allergic rhinoconjunctivitis.
Susceptibility to Infection of patients with AD
Fig. 5.7 Recurrent herpes simplex in atopic dermatitis.
Chronic eczematous lesions are often colonized with Staphylococcus aureus. Staphylococcus epidermitis may actually be protective as it is predominates in patients with fewer flares. In addition, the apparently normal nonlesional skin of atopic patients may also be colonized by S. aureus. The finding of increasing numbers of pathogenic staphylococci on the skin of a patient with AD is frequently associated with weeping and crusting of skin lesions, retroauricular and infraauricular and perinasal fissures, folliculitis, and adenopathy. In a flaring atopic patient, the possibility of
secondary infection must be considered. IgE antibodies directed against Staphylococcus and its toxins have been documented in some atopic individuals. Staphylococcal production of superantigens is another possible mechanism for staphylococcal flares of disease. Treatment of lesions of AD with topical steroids is associated with reduced numbers of pathogenic bacteria on the surface, even if antibiotics are not used. Despite the frequent observation that the presence of staphylococcal infection of lesions of AD is associated with worsening of disease, it has not been proven that oral antibiotics make a long term difference in the course of AD. Nonetheless, treatment of the “infected” AD patient with oral antibiotics is a community standard of dermatologists worldwide.
With the widespread presence of antibiotic-resistant S. aureus, dermatologists have shifted from the chronic use of oral antibiotics in managing patients with frequent flares of AD associated with staphylococcal infection. Rather, dilute sodium hypochlorite (bleach) baths and reduction of nasal carriage have become the basis for preventing infection-triggered AD. The typical formula is one quarter of a US cup (approximately 60 milliliters) of plain, unscented, NOT concentrated, NOT splashproof bleach per 20 gallon bathtub of water. In patients with AD and frequent infections, chronic suppressive oral antibiotic therapy may stabilize the disease. Options include cephalosporins, trimethoprim-sulfamethoxazole (TMP-SMX), clindamycin, and (in older patients) doxycycline. Identifying and treating S. aureus carriers in the family and pets may also be of benefit. An unusual complication of S. aureus infection in patients with AD is subungual infection, with osteomyelitis of the distal phalanx. In atopic patients with fever who appear very toxic, the possibility of streptococcal infection must be considered. These children may require hospital admission and intravenous antibiotics. Group A streptococcal superinfection of AD typically presents with a more vesiculopustular look that may mimic herpes simplex virus (HSV). Culture of the skin can differentiate and guide therapy typically with a penicillin- or cephalosporin-based antibiotic.
Patients with AD have increased susceptibility to viral superinfection, especially from HSV, varicella-zoster virus (VZV), enteroviruses (Coxsackie), vaccinia, and molluscum. Kaposi varicelliform infection is a term used to describe an acute vesicular eruption on top of AD and is usually caused by HSV, VZV, or enterovirus superinfection. Eczema herpeticum is seen most frequently in young children and is usually associated with HSV type 1 transmitted from a caretaker or sibling Once infected, there can be frequent flares of eczema herpeticum. Eczema herpeticum presents as the sudden appearance of vesicular, pustular, crusted, or eroded lesions concentrated in the areas of dermatitis (Fig. 5.7). The patients may have a fever and appear toxic. The lesions may continue to spread, and mos of the skin surface may become involved Secondary staphylococcal or streptococcal infection is common and local edema and regional adenopathy frequently occur. If lesions of eczema herpeticum occur on or around the eyelids, ophthalmologic evaluation is recommended. The severity of eczema herpeticum is quite variable, but most cases require sys emic antiviral therapy and an antistaphylococcal antibiotic. Delayed administration of acyclovir in hospitalized patients is associated with prolonged hospital stay. Genetic variants in TSLP and interferon regulatory factor 2 (IFR-2) in addition to DOCK 8 mutations are associated with AD and eczema herpeticum.
Recently a more virulent form of “hand foot and mouth” caused by enterovirus A6 instead of the typical A16 (also termed Coxackie A16) has been recognized and labeled “eczema coxsackium ” Superinfection with the A6 strain often leads to very widespread papules and vesicles with low-grade fever. There will typically be at least a few lesions on the palms and soles and in the mouth but there is not the typical predominance in these areas compared with areas of AD. Therapy is supportive.
Vaccination against smallpox is contraindicated in persons with AD, even when the dermatitis is in remission. Widespread and even fatal vaccinia can occur in patients with an atopic diathesis.
Atopic individuals may also develop extensive flat warts or molluscum contagiosum (MC). If the infection is extremely exuberant, an immunodeficiency such as DOCK-8 mutation should be ruled out. A common presentation of MC in children is a new patch of AD in an unusual area such as an axilla due to MC causing an immune response leading to a flare of AD. Chemical therapies such as salicylic acid and cantharidin may cause severe irritation within lesions of AD. Destruction with curettage (for molluscum), cryosurgery, or electrosurgery may be required to clear the lesions.
Give diferential diagnosis for AD
Typical AD in infancy and childhood is straightforward because of its characteristic morphology; predilection for symmetric involvement of the face, neck, and antecubital and popliteal fossae; and association with food allergy, asthma, and allergic rhinoconjunctivitis. Dermatoses that may resemble AD include seborrheic dermatitis (especially in infants), irritant or allergic contact dermatitis, nummular dermatitis, photodermatitis, scabies, and cases of psoriasis with an eczematous morphology. Certain immunodeficiency syndromes (see later discussion) may exhibit a dermatitis remarkably similar or identical to AD. In older patients with new onset dermatitis, cutaneous T cell lymphoma and allergic contact dermatitis should be considered.
Histopathologic findings of AD
The histology of AD varies with the stage of the lesion, with many of the changes induced by scratching. Hyperkeratosis, acanthosis, and excoriation are common
Staphylococcal colonization may be noted histologically. Although eosinophils may not be seen in the dermal infiltrate, staining for eosinophil major basic protein (MBP) reveals deposition in many cases.
Education and support measures for AD
Parental and patient education is of critical importance in the management of AD. In the busy clinic setting, dermatologists frequently have insufficient time to educate patients adequately regarding the multiple factors that are important in managing AD. Educational formats that have proved effective have been immediate nursing education on the correct use of medications, weekly evening educational sessions, and multidisciplinary day treatment venues. There are also now multiple online resources from major academic centers, professional societies, and associations that can be helpful. In all cases, “written action plans” outlining a “stepwise approach” have been important for parent/patient education. In addition, patients with chronic disease often become disenchanted with medical therapies or simply “burn out” from having o spend significant amounts of time managing their skin disease. The psychological support that can be incorporated into educational sessions can help motivate parents/patients and keep them engaged in the treatment plan. Having a child with AD is extremely stressful and generates significant stress within the family. Sleep is lost by both the patient and the parents. Supportive educational techniques and sometimes professional behavioral health consultation can help the family cope with this burden. In addition, the dermatologist must consider the complexity and time commitment of any prescribed regimen and ensure that the parents/patient understand and are committed to undertaking the treatments proposed.
Barrier repair in AD
AD patients have an impaired epidermal barrier The cornerstone of treatment and prevention of AD lies in addressing this problem. Patients should moisturize daily, especially immediately after bathing, ideally while the skin is still damp within a few minutes of getting out of the water. This may be with petrolatum or a petrolatum-based product, an oil-based product, a dimethiconebased product, vegetable shortening, or a “barrier repair” moisturizer that contains the essential lipids of the epidermal barrier. These special barrier repair moisturizers have similar benefits in AD to low-potency topical steroids. They are easier to apply and, if available to the patient, may enhance compliance. Petrolatum and petrolatum-based moisturizers are most often recommended and are often the least expensive. However, men with significant body hair, AD patients triggered by heat, and the very rare patient with true allergic contact dermatitis to petrolatum may be unable to tolerate petrolatum-based agents. Moisturizers should ideally be fragrance and formaldehyde free because these are two of the most common allergens in patients with AD. The ratio and content of ceramides in the epidermis of patients with AD is abnormal. Moisturizers with ceramides added have been shown to provide some benefit beyond the actual emollient. Patients should be instructed on the barrier-damaging properties of soaps, hot water, and scrubbing. The pH of the skin that promotes normal epidermal function is slightly acidic (the acid mantle) so synthetic detergents that have a more acidic pH are preferred to more basic soaps that have a high concentration of surfactant. Detergent use should be restricted to the axilla, groin, face, soles, and scalp. Oil-based cleansers can be used to “wash” the skin without water. For flares of AD, the soak and smear technique (soak in tub, then seal in water with a heavy moisturizer or medicated ointments) or wet dressings (wet wraps) with topical steroids can be very effective. In dry climates, AD patients may note some benefit with humidifiers. α-Hydroxy acid–containing products (lactic acid, glycolic acid) can be irritating and can exacerbate inflamed AD. These products should only be used for the xerosis of AD when there is absolutely no inflammation or pruritus.
Atimicrobial therapy for AD
When the AD patient has evidence of infection, treatment with topical or systemic antibiotics may be appropriate. Rather than treating once an infection occurs, it appears that the key in AD is to reduce nasal staphylococcal carriage preemptively and to keep the skin decolonized from Staphylococcus. Dilute sodium hypochlorite (bleach) baths have rapidly become a mainstay in AD patients. Twice-weekly bathing in a tepid bath with one quarter of a US cup (approximately 60 ml) of standard household bleach (5–6%) diluted in 20 gallons of water dramatically improves AD on the trunk and extremities, but less so on the face. For a smaller baby bathtub this is typically 2.5 mL = 1 2 teaspoon per gallon of water. Many bleach manufacturers make splashless or double-concentrated bleach, which should be avoided. This treatment combines decolonization of the skin with hydration, addressing two of the major factors in worsening of AD. Dilute bleach baths have been shown to decrease Nuclear Factor (NF) kappa-beta and thus may serve a role as a primary antiinflammatory therapy as well. Adequate moisturizing after bathing is critical. Intranasal application of mupirocin is beneficial in reducing nasal carriage although resistance is emerging. In 80% of families, at least one parent is carrying the same staphylococcal strain as a colonized AD child. If the AD patient has recurrent infections, other carriers in the family and their pets are sought and treated aggressively. Recurrent infections, especially furunculosis, are a cardinal feature of children and adults with AD who have systemic immunologic abnormalities, especially hyper-IgE syndrome.
Environmental factors in AD
Stress, heat, sweating, and external irritants may precipitate an attack of itching and flare in the AD patient Wool garments should be avoided. Addressing these triggers may improve the AD. Itch nerves are more active at higher emperatures, so overheating should be avoided. Irritants and allergens in the numerous products that AD patients may use can lead to flares of AD. Patients should avoid products that contain common allergens and should be evaluated for allergic contact dermatitis if a topical agent is associated with worsening of their AD.
Antipruritic therapy for AD
The primary treatment for the pruritus of AD is to reduce the severity of the AD. Antihistamines are frequently used for the pruritus of AD but are mainly beneficial for their sedative properties. If the patient has environmental allergies that lead to itch, the scratched skin can flare with AD, so in these patients long-acting histamine-2 blockers such as cetirizine, loratadine, and fexofenadine may help by decreasing the symptoms of the environmental allergies. Sedating antihistamines can lose some of their sedative effect if used consistently, so ideally they are only used when needed. Diphenhydramine, hydroxyzine, and doxepin can all be efficacious. Nonsedating antihistamines do not appear to benefit the pruritus of AD in standard doses. In some patients, gabapentin, selective serotonin reuptake inhibitors (SSRIs), mirtazapine, and even opiate antagonists may reduce pruritus. Applying ice during intense bouts of itch may help to “break” an itch paroxysm. Moisturizing lotions containing menthol, phenol, or pramoxine can be used between steroid applications to moisturize and reduce local areas of severe itch. More widespread use of topical doxepin (Sinequan) is limited by systemic absorption and sedation.
most common class of medications, along with moisturizers, used for the treatment of AD
Topical corticosteroids
They are effective and economical. Ointments are preferred because they can serve a do ble purpose as an emollient, they do not burn when applied, and they typically have fewer ingredients leading to lower of a chance of allergic contact dermatitis
In infants, low-potency steroid ointments, are preferred. Regular application of emollients must be emphasized Once corticosteroid receptors are saturated, additional applications of a steroid preparation contribute nothing more than an emollient effect. In most body sites, once-daily application of a corticosteroid is almost as effective as more frequent applications, at lower cost and with less systemic absorption and likely increased compliance. In some areas, twice-daily applications may be beneficial, but more frequent applications are almost never of benefit. Steroid phobia is common in parents and patients with AD. Less frequent applications of lower-concentration agents or intermittent use of steroids 2–5 times weekly, with emphasis on moisturizing, address these concerns. It can also be useful to point out that the human body must produce endogenous steroids daily to function Application of topical corticosteroids under wet wraps or vinyl suit occlusion especially after soaking in a tub of water (soak and smear) can increase efficiency. For refractory areas, a stronger corticosteroid may be used. A more potent molecule is more appropriate than escalating concentrations of a weaker molecule because the effect of the latter plateaus rapidly as receptors become saturated, and the potent medication should be stopped when the flare subsides. Because AD is an inflammatory cascade that must be halted, it is important not to undertreat. Undertreatment leads to loss of faith on the part of the patient/parents and prolongs the suffering of the patient. For severe disease, using more potent topical steroids in short bursts of a few days to a week can help gain con rol of the disease. In refractory and relapsing AD, twice-weekly steroid application to the areas that commonly flare may reduce flares. Another maintenance method is to mix 1 part of hydrocortisone 2.5% ointment in with 1 to 4 parts of the patient’s preferred emollient 2–5 days per week, lessening the amount this is used as tolerated.
In older children and adults, medium-potency steroids are often used, except on the face, where milder steroids or calcineurin inhibitors are preferred. For thick plaques and lichen simplex chronicus–like lesions, extremely potent steroids may be necessary. Ointments are more effective because of their moisturizing properties and require no preservatives, reducing the likelihood of allergic contact dermatitis. If an atopic patient worsens or fails to improve after the use of topical steroids and moisturizers, the possibility of allergic contact dermatitis to a preservative or the corticosteroids must be considered. Contact allergy to the corticosteroid itself can occur. Corticosteroid allergy seldom manifests as acute worsening of the eczema Instead, it manifests as a flare of eczema whenever the corticosteroid is discontinued, even for a day. This may be difficult to differentiate from stubborn AD.
Although the potential for local and even systemic toxicity from corticosteroids is real, the steroid must be strong enough to control the pruritus and remove the inflammation. Even in small children, strong topical steroids may be necessary in weekly pulses to control severe flares. Monitoring of growth parameters should be carried out in infants and young children.
Ideally prevention of AD flares is with just emollients, but patients with more severe disease often need some consistent antiinflammatory medicines (similar to the paradigm used for asthma). Maintenance therapy with topical steroids as discussed earlier can be with twice-weekly application, mixing a low-potency steroid in with an emollient or with nonsteroidal antiinflammatory medications.
Topical Calcineurin Inhibitors for AD
Topical calcineurin inhibitors (TCIs) such as tacrolimus or pimecrolimus offer an alternative to topical steroids. Systemic absorption is generally not significant with either of these agents.
Although a 0.03% tacrolimus ointment is marketed for use in children, it is unclear whether it really offers any safety advantage over the 0.1% formulation. Patients may experience a warm or stinging feeling in the skin when the medicines are first started. This tends to resolve and tolerability is improved if the ointment is applied to “bone-dry” skin Patients experience less burning if eczematous patches are treated initially with a corticosteroid, with transition to a TCI after partial clearing. Improvement tends to be steady, with progressively smaller areas requiring treatment. TCIs are particularly useful on the eyelids and face, in areas prone to steroid atrophy, when steroid allergy is a consideration, or when systemic steroid absorption is a concern. Tacrolimus is more effective than pimecrolimus, with tacrolimus 0.1% ointment equivalent to triamcinolone acetonide 0.1%, and pimecrolimus equivalent to a class V or VI topical corticosteroid. There is a black box warning on calcineurin inhibitors in the United States, but a recent study that followed patients after marketing found no increase in malignancy in over 26,000 patient-years studied.
an antiinflammatory topical PDE4 inhibitor introduced in 2017 for AD in children over 2 years.
Crisaborole
It can be used on the face and skinfolds without concern for striae but may sting when applied. It may be most useful as a maintenance medication or for mild to moderate disease.
Tar for AD
Crude coal tar 1%–5% in white petrolatum or hydrophilic ointment USP, or liquor carbonis detergens (LCDs) 5%–20% in hydrophilic ointment USP, is sometimes helpful for an area of refractory AD. Tar preparations are especially beneficial when used for intensive treatment for adults in an inpatient or day care setting, especially in combination with UV phototherapy. Goeckerman therapy with tar and UVB in a day treatment setting will lead to improvement in more than 90% of patients with refractory AD, and prolonged remission can be induced.
Phototherapy for AD
If topical modalities fail to control AD, phototherapy is another step on the therapeutic ladder. Narrow-band (NB) UVB is highly effective and has replaced broadband UV for treating AD. When acutely inflamed, AD patients may tolerate UV poorly. Initial treatment with soak and smear topical steroids or a systemic immunosuppressive may cool off the skin enough to institute UV treatments. Patients with significant erythema must be introduced to UV at very low doses to avoid nonspecific irritancy and flaring of the AD. Often, the initial dose is much lower and the dose escalation much slower than in patients with psoriasis. In acute flares of AD, UVA I can be used. For patients unresponsive to NB UVB, photochemotherapy with psoralen plus UVA (PUVA) can be effective but the benefits must outweigh the risks. It requires less frequent treatments, and can be given either topically (soak/ bath PUVA) or systemically (oral PUVA).
Fig. 5 8 Ear eczema.
Eczema of the ears or otitis externa may involve the helix, postauricular fold, and external auditory canal. By far the most frequently affected site is the external canal, where eczema is often a manifestation of seborrheic dermatitis or allergic contact dermatitis caused by topical medications, especially neomycin (Fig. 5.8), benzocaine, and preservatives or earphones. Secretions of the ear canal derive from the specialized apocrine and sebaceous glands, which form cerumen. Rubbing, wiping, scratching, and picking exacerbate the condition. Secondary bacterial colonization or infection is common. Infection is usually caused by staphylococci, streptococci, or Pseudomonas. Pseudomonas aeruginosa can result in malignant external otitis with ulceration and sepsis. Earlobe dermatitis in people with pierced ears is virtually pathognomonic for metal contact dermatitis (especially nickel).
Treatment should be directed at removal of causative agents, such as topically applied allergens. First, examine the ear with an otoscope and be sure there is not a perforated tympanic membrane. If there is drainage from a perforated tympanic membrane, management should be in consultation with an otolaryngologist. This purulent fluid can be the cause of an ear eczema—infectious eczematoid dermatitis. If the tympanic membrane is intact, scales and cerumen should be removed by gentle lavage with an ear syringe. A topical steroid otic solution can be used for noninfectious causes. For very weepy lesions, aluminum acetate optic solution (e.g., Domeboro) may be drying and beneficial.
Breast Eczema (Nipple Eczema)
Fig. 5.9 Nummular eczema of the breast.
Eczema of the breasts usually affects the areolae and may extend onto the surrounding skin (Fig. 5.9). The area around the base of the nipple is usually spared, and the nipple itself is less frequently affected. The condition is more common in women but can be seen in infants as well. Usually, eczema of the nipples is of the moist type with oozing and crusting. Painful fissuring is frequently seen, espec ally in nursing mothers. AD is a frequent cause, and nipple eczema may be the sole manifestation of AD in adult women. It frequently presents during breastfeeding. The role of secondary infection with bacteria and Candida should be considered in breastfeeding women. Other causes of nipple eczema are allergic contact dermatitis and irritant dermatitis. Irritant dermatitis occurs from friction (jogger’s nipples), or from poorly fitting brassieres with seams in women with asymmetric and large breasts. In patients in whom eczema of the nipple or areola has persisted for more than 3 months, especially if it is unilateral, a biopsy is mandatory to rule out the possibility of Paget disease of the breast. Topical corticosteroids or TCIs are often effective in the treatment of non-Paget eczema of the breast. Nevoid hyperkeratosis of the nipples is a chronic condition that may mimic nipple eczema, but it is not responsive to corticosteroids.
Nipple eczema in the breastfeeding woman is a therapeutic challenge and can be from AD, ACD, irritant dermatitis, infection or food allergy. A lactation consultant or nurse may be helpful in managing these patients, because poor positioning during breastfeeding is a common cofactor in the development of nipple eczema. The dermatitis may appear in an atopic woman when her child begins to ingest solid foods rarely due to contact dermatitis to a
food. Allergic contact dermatitis may develop to topical protective creams (containing vitamin A and E, aloe, lanolin, chamomile, or preservatives). Staphylococcal superinfection may develop and can be identified by culture. Oral antibiotics are the preferred treatment for bacterial secondary infection.
Candidal infection of the areola may present as normal skin, erythema, or an acute or chronic eczema. The area of the areola immediately adjacent to the nipple tends to be involved, sometimes with fine hairline cracks. Associated conditions include oral thrush in the infant, antibiotic use, and a personal history of vaginal candidiasis in mother. Cultures are typically positive from the affected areola/nipple. Oral thrush in the infant in the setting of nipple eczema in the mother would warrant treatment of the mother and infant. Patients frequently complain of severe pain, especially with nursing. Analgesia may be required, and breastfeeding may need to be suspended for a period. Pumping and the use of a silicone nipple shield may be helpful. Therapy with topical or systemic antifungal agents may be required. Topical gentian violet 0.5%, applied once daily to the nipple for up to 1 week, may be helpful but should not be ingested by the infant. Guaiazulene (Azulon) is a dark-blue hydrocarbon used in Europe for nipple “cracks” with breastfeeding.
Hand Eczema
Hand eczema is a common and important skin condition. The genetic risk factors for the development of hand dermatitis are unknown but patients with AD are more susceptible. The risk for persistence of the hand eczema is doubled if there is associated eczema at other sites at presentation, if there is a childhood history of AD, and if the onset of the hand eczema was before age 20. Atopic patients with the FLG null mutation may have a specific form of hand dermatitis characterized by dorsal hand and finger dermatitis, volar wrist involvement, and hyperlinear palms, but limited palmar dermatitis. Hand eczema is the most common occupational skin condition, accounting for more than 80% of all occupational dermatitides. About 1 per 1000 workers are affected annually. Women are at increased risk, most of which is accounted for by a “spike” in the rate of hand eczema in the 20–29 age-group, when increased environmental exposures increase women’s risk (e.g., child care). As noted above, children with new hand dermatitis
should be asked about making or handling “slime” which is an often home-made play substance that can cause irritant or allergic contact dermatitis.
Chronic hand eczema, especially if severe, significantly reduces the patient’s quality of life and can be associated with symptoms of depression. Persons at high risk for hand eczema can be identified and counseled to avoid high-risk occupations such as those that involve consistent exposure to water or sensitizing chemicals such as hairdressers. If occupational hand eczema develops, some occupation-specific strategies can lead to improvement and prevent recurrence.
The evalua ion and management of hand eczema has been hampered by the lack of a uniform classification system and a dearth of controlled therapeutic trials. The diagnostic dilemma in hand dermatitis is in part related to two factors. The clinical appearance of the skin eruption on the palms and soles may be very similar, independent of the etiology. In addition, virtually all chronic hand dermatitis demonstrates a chronic dermatitis histologically, again independent of pathogenic cause. For instance, psoriasis on the palms and soles may show the same spongiosis as a dermatitis (Fig. 5.10). As a result, the proposed classification schemes rely on a combination of morphologic features, history of coexistent illnesses, occupational exposure, and results of patch testing.
What are the primary lesions of dyshidrosis?
Vesiculobullous Hand Eczema (Pompholyx, Dyshidrosis).
Primary lesions of dyshidrosis are deep-seated multilocular vesicles resembling tapioca on the sides of the fingers (Fig. 5.11), palms, and soles.
Fig. 5 11 Pompholyx.
The eruption is symmetric and pruritic, with pruritus often preceding the eruption. Coalescence of smaller lesions may lead to bulla formation severe enough to prevent ambulation. Individual outbreaks resolve spontaneously over everal weeks. Acute pompholyx, also known as cheiropompholyx if it affects the hands, presents with severe, sudden outbreaks of intensely pruritic vesicles. Idiopathic acute vesicular hand dermatitis is not related to blockage of sweat ducts, although palmoplantar hyperhidrosis is common in these patients, and control of hyperhidrosis improves the eczema. Bullous tinea or an id reaction from a dermatophyte should be excluded, and patch testing should be considered to rule out allergic contact dermatitis.
The eruption presents as hyperkeratotic, fissure-prone, erythematous areas of the middle or proximal palm. Vesicles are not seen The volar surfaces of the fingers may also be involved (Fig. 5.12).
Fig. 5.12 Hyperkeratotic hand dermatitis.
Plantar lesions occur in about 10% of patients. Males outnumber females by 2 : 1, and the patients are usually older adults. Histologically, the lesions show chronic spongiotic dermatitis. The most important differential diagnosis is psoriasis, and some of the patients with chronic hyperkeratotic hand dermatitis will ultimately prove to be psoriatic. The presence of sharply demarcated plaques, nail pitting, or occasional crops of pustules is an important clue to psoriatic hand involvement.
Give diferential diagnosis of diaper dermatitis
The differential diagnosis of diaper dermatitis should include napkin psoriasis (Fig. 5.13), seborrheic dermatitis, AD, langerhans cell histiocytosis, tinea cruris, acrodermatitis enteropathica, aminoacidurias, biotin deficiency, and congenital syphilis. Allergic contact dermatitis is becoming more frequently recognized as a cause of dermatitis in the diaper area. Allergens include sorbitan sesequioleate, fragrances, disperse dye, cyclohexylthiopthalimide, and mercaptobenzothiazole (in rubber diaper covers). Given the skill of most pediatricians in the management of diaper dermatitis, dermatologists should think about these conditions in infants who have failed the standard interventions used by pediatricians. Refractory diaper dermatitis may require a biopsy to exclude some of these conditions.
Fig. 5.13 Napkin psoriasis.
dehydrated skin showing redness, dry scaling, and fine crackling that may resemble crackled porcelain or the fissures in the bed of a dried lake
Xerotic eczema, also known as winter itch, eczema craquelé, and asteatotic eczema. The primary lesion is an erythematous patch covered with an adherent scale. As the lesion enlarges, fine cracks in the epidermis occur (Fig. 5.14).
Fig. 5.14 Eczema craquelé.
Nummular lesions may occur. Xerotic “nummular” eczema is less weepy than classic nummular dermatitis. Favored sites are the anterior shins, extensor arms, and flank. Elderly persons are particularly predisposed, and xerosis is the most common cause of pruritus in older individuals. Xerotic eczema is seen most frequently during the winter, when there is low relative humidity. Bathing with hot water and harsh soaps contributes. The epidermal water barrier is impaired, and TEWL s increased. Epidermal barrier repair begins to decrease after age 55, correlated with an increase in epidermal pH (see later discussion). The loss of barrier repair ability is improved by acidifying the epidermis, showing the benefit of mild acids in treating xerosis. Heterozygous null mutation of the FLG gene is associated with xerosis.
Taking short tepid showers, limiting use of soap to soiled and apocrine-bearing areas, using acid pH synthetic detergents, and promptly applying an emollient after bathing are usually effective.
White petrolatum and emollients containing 10% urea or 5% lactic acid are effective. Topical corticosteroids in ointment vehicles are useful for inflamed areas.
What are the primary lesions of Nummular Eczema (Discoid Eczema)?
Fig. 5.15 Nummular eczema. (Courtesy Steven Binnick, MD )
The primary lesions are discrete, coin-shaped, erythematous, edematous, vesicular, and crusted patches (Fig. 5.15).
NE usually begins on the lower legs, dorsa of the hands, or extensor surfaces of the arms. In younger adults, females predominate, but most patients older than 40 are male. Alcohol consumption has been associated with NE in adult males. A single lesion often precedes the eruption and may be present for some time before other lesions appear.
Most lesions are 2–4 cm in diameter. Lesions may form after trauma (conditioned hyperirritability). As new lesions appear, the old lesions expand as tiny papulovesicular satellite lesions appear at the periphery and fuse with the main plaque. In severe cases, the condition may spread into palm-sized or larger patches. Pruritus is usually severe and of the same paroxysmal, compulsive quality and nocturnal timing seen in AD and prurigo nodularis.
AD frequently has nummular morphology in adolescents, but in atopy the lesions tend to be more chronic and lichenified. Histologically, NE is characterized by acute or subacute spongiotic dermatitis. The skin lesions of nummular dermatitis are frequently colonized with S. aureus, in frequency similar to that seen in AD. Relevant positive patch tests are found in one quarter to one third of patients with NE. This may represent the primary cause of the dermatitis or a secondary allergy that developed from products used to treat the NE.
heterogeneous disorder and is the most common immunodeficiency syndrome after IgA deficiency.
Common variable immunodeficiency (CVID)
Fig. 5.16 Common variable immunodefic ency with granulomas in vitiligo.
Patients have low levels of IgG and IgA, and 50% also have low levels of IgM. Lymphocyte counts may be normal or low. Multiple genetic defects have been found in CVID, including mutations in ICOS (CVID type 1), TNFRSF13B (type 2), CD19 (type 3), TNFRSF13C (type 4), MS4A1 (type 5), CD81 (type 6), CR2 (type 7), LRBA (type 8), PRKCD (type 9), and NFKB2 (CVID 10). These patients do not form antibodies to bacterial antigens, and have recurrent sinopulmonary infections. They have a predisposition to autoimmune disorders, such as vitiligo and alopecia areata, GI abnormalities, lymphoreticular malignancy (10-fold increase of lymphoma), and gastric carcinoma. Noninfectious granulomas have been reported in as many as 22% of CVID (Fig. 5.16) In some patients with CVID and multiple other immunodeficiencies, vaccine strain rubella has been found within the granulomas. Therefore it is hypothesized that the granulomas form due to difficulty processing the live rubella vaccination that is often given before diagnosis of CVID. Seven percent of CVID patients with granulomas have cutaneous granulomas, and virtually all patients with cutaneous granulomas also have visceral granulomas. These patients are more often female and have higher risk for lymphoma than other CVID patients. The granulomas can show multiple histologic patterns: granuloma annulare-like, sarcoidal, and even caseating. They show a CD4/CD8 ratio of less than 1, distinguishing these granulomas from sarcoidosis. CVID patients who develop granulomas have more severe depletion of isotype-switched memory B cells and naïve T cells, an immunologic profile also seen in ataxia telangiectasia patients with cutaneous granulomas Replacement of the reduced immunoglobulins with IVIG may help reduce infections. Topical, systemic, and intralesional corticosteroids may be used for the granulomas, depending on heir extent. Infliximab and etanercep have been effective in steroid-refractory cases.
Wiskott-Aldrich syndrome, an X-linked recessive syndrome, consists of a triad of ______
Fig. 5.17 Eczematous eruption with purpura in Wiskott-Aldrich syndrome.
- chronic eczematous dermatitis resembling AD (Fig. 5.17);
- increased susceptibility to bacterial infections, such as pyoderma or otitis media; and
- thrombocytopenic purpura with small platelets.
- Levels of IgM are variable, IgA is normal to high, and IgE is elevated, as is IgG. On a complete blood cell count the mean platelet volume (MPV) is decreased. T cells (especially naïve T cells) are low in infancy and progressively decline in number and activity over time. Untreated survival is about 15 years, with death from infection, bleeding, or lymphoma (25% of patients).
an autosomal recessive condition caused by mutations in a single gene on chromosome 11 (ATM), which encodes a protein called ATM
Ataxia Telangiectasia
Fig. 5.18 Granulomatous lesions in ataxia teleangiectasia.
When ATM is absent, the cell cycle does not stop to repair DNA damage, particularly double-stranded breaks, or for B(D)J recombination of immunoglobulin and TCR genes. This results in immunodeficiency and an increased risk for malignancy. The initial prominent skin feature is progressive ocular and cutaneous telangiectasias starting at age 3–6 years. These begin on the bulbar conjunctiva but later develop on the eyelids, ears, and flexors of the arms and legs. The ATM protein seems to be important in maintaining mitochondrial homeostasis, and this defect may be responsible for the premature aging (with loss of subcutaneous fat and graying of hair) and neurodegeneration.
Cutaneous noninfectious granulomas may occur and can be ulcerative and painful (Fig. 5.18). Rubella virus has been recovered by PCR from active ulcerations. Live vaccinations such the measles mumps and rubella vaccination should not be given to immunodeficient children, but because AT presents typically after age 1, children are often already vaccinated. Therefore the likely mechanism of granuloma formation is the ineffective processing of the rubella (or other infectious antigens) in live vaccinations. The granulomas tend to worsen with biopsy and manipulation. Other cutaneous features include large, irregular segmental café au lait spots, vitiligo, seborrheic dermatitis, AD, recurrent impetigo, and acanthosis nigricans. Late tightening of the skin can occur and resembles acral sclerosis. Sinopulmonary infections are common, especially otitis media, sinusitis, bronchitis, and pneumonia. Varicella (at times severe), herpes simplex, molluscum contagiosum, and herpes zoster can occur Refractory warts occur in more than 5% of patients. Aside from candidal esophagitis, unusual opportunistic infections are rare.
lls occurring in the majority of patients. Th-cell counts can be less than 200. IgA, IgG4, IgG2, and IgE deficiencies can all be present. Paradoxically, IgM, IgA, and IgG can be elevated in some patients, including the presence of monoclonal gammopathy in more than 10%. The immunologic abnormalities are not progressive. Lymphoma risk is increased more than 200-fold (especially B-cell lymphoma), and leukemia (especially T-cell chronic lymphocytic leukemia) is increased 70-fold. Treatment includes high vigilance for infection and malignancy. In patients with low CD4 counts, prophylaxis to prevent Pneumocystis pneumonia can be considered. When IgG deficiency is present and infections are frequent, IVIG may be beneficial. IVIG and intralesional corticosteroids may be used for the cutaneous granulomas. Carriers of ataxia telangiectasia have an increased risk for breast cancer. Because of the accumulation of chromosomal breaks after radiation exposure, both the ataxia telangiectasia patients and the carriers should minimize radiation exposure.
autosomal dominant disorder with hypogammaglobulinemia, reduced B-cell numbers, and neutropenia
The warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome
Fig. 5.19 Warts in WHIM syndrome
The most common genetic cause is a gain of function mutation of the CXCR4 gene. Additional mutations that are not in the CXCR4 gene can also cause WHIM, but all of them lead to functional hyperactivity of CXCR4. CXCR4 causes retention of neutrophils in the bone marrow and is the basis of the neutropenia and myelokathexis (increased apoptotic neutrophils in bone marrow). There is profound loss of circulating CD27+ memory B cells, resulting in hypogammaglobulinemia, with the observation that WHIM patients have normal antibody response to certain antigens but fail to maintain this antibody production. However, normal immunoglobulin levels do not exclude the diagnosis of WHIM. Almost 80% of WHIM patients have warts at the time of their diagnosis (Fig. 5.19). These include common and genital wart types. A significant number of female WHIM patients have cervical and vulval dysplasia, which can progress to carcinoma. WHIM patients have disproportionately more HPV infections than SCID patients but have little problem resolving other viral infections However, they may develop Epstein-Barr virus (EBV)induced lymphomas. The vast majority of patients in early childhood have recurrent sinopulmonary infections, skin infections, osteomyelitis, and urinary tract infections. Recurrent pneumonias lead to bronchiectasis. There is a CXCR4 antagonist in trials but standard treatment is G-CSF, IVIG prophylactic antibiotics, and aggressive treatment of infections. There is one report recently of a cure of WHIM by chromothripsis in a hematopoietic stem cell. Chromothripsis is a catastrophic disruption of chromosomes in a cell in this case the new stem cell had a selective advantage due to the lack of the WHIM mutation. Untreated, the HPV infections can progress to fatal carcinomas, and therefore male patients must be regularly examined by dermatologists and female patients by gynecologists; a low threshold for biopsy of genital lesions is required.
associated with hyper-IgE syndrome (see later discussion). However, unlike other genetic causes of hyper-IgE, this deficiency is uniquely associated with a susceptibility to cutaneous viral infections, including HSV, molluscum contagiosum, and HPV (Fig. 5.20).
DOCK8 Deficiency
Fig. 5.20 Warts in DOCK8 immunodeficiency
Warts can be flat or verrucous and affect about two thirds of patients.
Four major functions that result from complement activation
cell lysis, opsonization/ phagocytosis, inflammation, and immune complex removal
In the “classical” complement pathway, complement is activated by an antigen-antibody reaction involving IgG or IgM. Some complement components are directly activated by binding to the surface of infectious organisms; this is called the “alternate” pathway. The central component common to both pathways is C3. In the classical pathway, antigen-antibody complexes sequentially bind and activate three complement proteins, C1, C4, and C2, leading to the formation of C3 convertase, an activator of C3. The alternate pathway starts with direct activation of C3. From activated C3, C5–C9 are sequentially activated. Cytolysis is induced mainly through the membrane attack complex (MAC), which is made up of the terminal components of complement. Opsonization is mainly mediated by a subunit of C3b, and inflammation by subunits of C3, C4, and C5.
Inherited deficiencies of complement are usually autosomal recessive traits. Deficiencies of all 11 components of the classical pathway, as well as inhibitors of this pathway, have been described. Genetic deficiency of the C1 inhibitor is the only autosomal dominant form of complement deficiency and results in hereditary angioedema (see Chapter 7). In general, deficiencies of the early components of the classical pathway result in autoimmune connective tissue diseases, whereas deficiencies of the late components of complement lead to recurrent neisserial sepsis or meningitis. Overlap exists, and patients with late-component deficiencies may exhibit connective tissue diseases, and patients with deficiencies of early components, such as C1q, may manifest infections. Deficiency of C3 results in recurrent infections with encapsulated bacteria such as Pneumococcus, H. influenzae, and Streptococcus pyogenes. C3 inactivator deficiency, as with C3 deficiency, results in recurrent pyogenic infections Properdin (component of alternate pathway) dysfunction is inherited as an X-linked trait and predisposes to fulminant meningococcemia. Deficiency of C9 is the most common complement deficiency in Japan but is uncommon in other countries Most patients appear healthy. MASP2 deficiency, resulting in absent hemolytic activity by the lectin pathway, is considered a complement deficiency and results in a syndrome resembling SLE and increased pyogenic infection. Factor I deficiency results in recurrent infections, including Neisseria meningitides. Partially deficient family members may also have increased infections.
C2 deficiency is the most common complement deficiency in the United States and Europe Most patients are healthy, but SLE-like syndromes develop in 10%. C1q-, C3-, and C4-deficient patients have SLE at rates of 90%, 31%, and 75%, respectively, and C1r deficiency was recently reported in early-onset SLE. Complement deficiency–associated SLE typically has early onset, photosensitivity less renal disease, and Ro/La autoantibodies in two thirds of patients. C2- and C4-deficient patients with LE typically have subacute annular morphology (Fig 5.21), Sjögren syndrome, arthralgias, and oral ulcerations. CH50 is a functional assay of the complement system and is typically low in active systemic lupus. Cell-bound complement activity products such as C4d and C3d, which are the byproducts of complement activation, are deposited on other cells such as erythrocytes and can be detected to monitor systemic lupus disease activity. Frequent infections, anaphylactoid purpura, dermatomyositis, vasculitis, and cold urticaria may be seen. A patient with C1q deficiency presented with macrophage activating syndrome. Renal disease, anti-dsDNA antibodies, and anticardiolipin antibodies are uncommon. Patients with C4 deficiency may have lupus and involvement of the palms and soles.
Many of the complement component deficiencies can be acquired as an autoimmune phenomenon or a paraneoplastic finding. Examples include acquired angioedema, as when C1 inhibitor is the target, or lipodystrophy and nephritis, when C3 convertase is the target.
When complement deficiency is suspected, a useful screening test is a CH50 (total hemolytic complement) determination, because deficiency of any of the complement components will usually result in CH50 levels that are dramatically reduced or zero.
Fig 5 21 Subacute lupus erythematosus as can be seen in complement deficiency disorders.
What are the 3 elements required for the development of GVHD?
- First, the transplanted cells must be immunologically competent.
- Second, the recipient must express tissue antigens that are not present in the donor and therefore are recognized as foreign.
- Third, the recipient must be unable to reject the transplanted cells.
Immunologic competence of the transplanted cells is important, because ablating them too much may lead to failure of engraftment, or, more often, incomplete eradication of the recipient’s malignancy (graft-vs.-tumor effect). Therefore some degree of immunologic competence of the transplanted cells is desired. For this reason, the prevalence of GVHD still remains about 50% after HSCT. Another important factor in determining the development and severity of the GVHD is the preconditioning regimen. Chemotherapy and radiation cause activation of dendritic cells (antigenpresenting cells [APCs]) in tissues with high cell turnover—the skin, gut, and liver. These APCs increase their expression of HLA and other minor cell surface antigens, priming them to interact with transplanted lymphoid cells. Host APCs are important in presenting these antigens to the active lymphoid donor cells. Cytokines, especially IL-2, TNF-α, and IFN-γ, are important in enhancing this host-donor immunologic interaction. Reducing this early inflammatory component in GVHD can delay the onset of the GVHD but may not reduce the prevalence. The indications for HSCT, age limits, and allowable degree of HLA incompatibility have resulted in greater use of HSCT, increasing the number of persons at risk for GVHD.
Initially, only reactions that occurred within the first 100 days after transplantation were considered acute GVHD, but it is now recognized that classic acute GVHD can occur up to 1 year or more after HSCT, especially with tapering of anti-GVHD immunosuppressives. Acute GVHD is based on the clinical presentation, not the time of onset after transplantation. In acute GVHD, the cutaneous eruption typically begins between the 14th and 42nd days after transplantation, with a peak at day 30 (Fig. 5.22). Acu e GVHD is characterized by an erythematous morbilliform eruption of the face and trunk, which may become confluent and result in exfoliative erythroderma. Ear involvement is common. It often begins with punctate lesions corresponding to hair follicles and eccrine ducts, resembling keratosis pilaris. In many cases, a fine scale can be appreciated on the skin lesions. GVH is often described as more monomorphous than similar-appearing morbilliform drug eruptions, and tends to involve the upper back, rather than the lower back and dependent areas. GVHD is staged clinically, with stage 1 as less than 25% BSA, stage 2 as 25%–50% BSA, stage 3 as greater than 50% BSA, and stage 4 as erythroderma with bullae. In children, the diaper area is often involved The eruption may appear papular and eczematous, involving web spaces, periumbilical skin, and ears, and bears some resemblance to scabies.
The differential diagnosis for the eruption of acute GVHD includes the eruption of lymphocyte recovery, engraftment syndrome, viral exanthem, and drug eruption. The cutaneous histology in the early phases of acute GVHD may not be able to completely distinguish these entities. Grade IV GVHD is characterized by full-thickness slough and may resemble toxic epidermal necrolysis, and it may be impossible to distinguish the two entities clinically or histologically. The mucous membranes and the conjunctivae can be involved as well, which can be difficult to distinguish from chemotherapy-induced and infectious mucositis. Often, about the same time, the patient develops the other characteristic features of acute GVHD: cholestatic hepatitis with elevated bilirubin and high-volume diarrhea Autologous GVHD usually involves only the skin and is self-limited, and it is thought to occur from preconditioning regimen–induced loss of “self-tolerance.”
The “eruption of lymphocyte recovery” is a mild, self-limited morbilliform eruption that may be associated with a brief fever, occurring when lymphocyte counts first return following chemotherapy. This can closely resemble GVHD, though without liver or gut involvement; patients may progress to overt aGVHD. Engraftment syndrome is a combination of symptoms that occur about the time of engraftment and neutrophil recovery. Patients
develop fever (without infectious source), diarrhea, pulmonary infiltrates with hypoxia, and capillary leak syndrome with edema and weight gain. It occurs as soon as 7 days after autologous HSCT and 11–16 days after allogeneic transplants. The associated skin eruption is clinically and histologically identical to acute GVHD. Ocular involvement with keratitis can occur. This syndrome occurs in 7%–59% of post-HSCT patients and is a significant cause of morbidity and mortality in autologous peripheral blood progenitor cell transplant patients. It is mediated by cytokine production and neutrophil infiltration of the organs damaged by the conditioning chemotherapy, especially the lungs. Administration of G-CSF and autologous transplantation are risk factors for its development. Treatment is high-dose systemic corticosteroids.
With improved support for GVHD patients after HSCT, more are surviving, and 60%–70% develop chronic GVHD (cGVHD). It is the second most common cause of death in HSCT patients. It is unclear whether cGVHD is mediated by the same pathologic mechanisms as acute GVHD. Certain conditioning regimens may increase risk of cGVHD, particularly total body irradiation and the risk of scleroderma-like cGVHD. Chronic disease has features more typical of an autoimmune disease. Diagnostic criteria have been adopted, with “diagnostic” and “distinctive” cutaneous manifestations. The most common diagnostic feature, occurring in 80% of patients who develop cGVHD, is a lichen planus–like eruption. It typically occurs 3–5 months after grafting, usually beginning on the hands and feet but becoming generalized It may present with a malar rash resembling LE. The chronic interface dermatitis can leave the skin with a poikilodermatous appearance. Similar lichen planus–like lesions may occur on the oral mucosa and can result in pain and poor nutrition. Lichen sclerosus–like lesions can also occur. Involvement of the vaginal or esophageal mucosa can result in severe scarring and strictures. About 20% of men with cGVHD have genital skin changes, and 13% have cGVHD of the penis. cGVHD of the skin and oral mucosa is associated with genital involvement. Lichen sclerosus–like lesions, phimosis, and inflammatory balanitis are most common; 80% of men with penile cGVHD report erectile dysfunction. Patients may underreport their genital cGVH, and a thorough physical and history is important.
Fig. 5.22 Acute graft-versus-host disease. (Courtesy Jennifer Huang, MD.)
Fig. 5.23 Chronic graft-versus-host disease.
Sclerosis is the other “diagnostic” family of skin lesions. This can include lesions resembling superficial morphea, which can have overlying lichen sclerosus–like changes. The morphea-like lesions demonstrate an isomorphic response, favoring areas of pressure, especially the waistband and brassiere-band areas. Deeper sclerotic lesions resembling eosinophilic fasciitis (resulting in joint contractures, Fig. 5.23) and restriction of the oral commissure due to sclerosis can occur. These sclerotic plaques may ulcerate.
The extent of involvement of the deep tissues, such as muscle and fascia, cannot be easily defined by clinical examination and may be aided by magnetic resonance imaging. Rarely, the myositis of cGVHD may be accompanied by a skin eruption similar to dermatomyositis. Other features of GVHD may include depigmentation resembling vitiligo; scarring or nonscarring alopecia; nail dystrophy (e.g., longitudinal ridging, brittle thin nails, pterygium, nail loss); and xerostomia and other, Sjögren-like mucosal symptoms. Atypical forms of GVHD resembling Pityriasis Rubra Pilaris (PRP), psoriasis, eczematous eruptions, isolated follicular hyperkeratosis, and Pityriasis Rosea (PR)-like eruptions have been reported. GVHD associated angiomatosis, with vascular lesions within sclerotic-type cGVHD, is a newly described and challenging subtype of cGVHD.
Biopsy may not be necessary to diagnose GVHD, particularly aGVHD. Punch biopsy is generally adequate, unless evaluating scleroderma-like disease, where incisional biopsy is preferred. Histologically, aGVHD demonstrates vacuolar interface dermatitis. Individual keratinocyte necrosis with adjacent lymphocytes (satellite necrosis) is typically present, suggesting cell-mediated cytotoxicity. The height and extent of keratinocyte necrosis, bulla formation, and slough are used in grading schemes (grade 0 is normal, grade 1 is basal vacuolization, grade 2 includes necrotic epidermal cells, grade 3 has clefting, and grade 4 has bulla formation). Eosinophils may be more common in drug reactions, but can be seen in GVH and cannot be used to distinguish the two. GVHD inflammation histologically often involves follicles, corresponding to the characteristic clinical perifollicular inflammation. Elafin has been proposed as a possible marker for GVHD but cannot reliably distinguish GVHD from drug reactions, though high levels of elafin may correspond to a poorer prognosis. The histologic findings in early disease may be nonspecific, and many treatment protocols do not depend on histologic features to initiate therapy. A background of epidermal disorder and atypia may be present in later lesions of acute GVHD, but similar epidermal changes may be seen after chemotherapy and may be unreliable in distinguishing GVHD from drug reactions. Chronic GVHD demonstrates lichenoid dermatitis or dermal sclerosis with hyalinization of collagen bundles and narrowing of the space between bundles.
Acute GVHD is managed on the skin with topical corticosteroids, TCIs, and rarely UV phototherapy. Most patients have associated systemic symptoms, in which case systemic corticosteroids, tacrolimus, and occasionally other suppressive agents are instituted. When aGVH is not responsive to steroids, multidisciplinary discussions and individual regimens based on comorbidities, infectious history, and status of underlying disease are often necessary. Mesenchymal stem cells, antithymocyte globulin, and extracorporeal photopheresis (ECP) are novel options being evaluated. TNF inhibitors, rituximab, and targeted small molecule inhibitors are also being studied. Ruxolitinib and other JAK inhibitors have shown promise in early studies and are being actively evaluated for both acute and chronic GVHD. For cGVHD, ECP can be considered as a nonsuppressive, disease-stabilizing, steroid-sparing agent for patients unresponsive to these first-line therapies. Phototherapy, particularly UVA-based regimens (PUVA with or without retinoids, UVA1), may improve sclerotic cGVHD. Rituximab has shown some benefit in steroid-refractory cGVHD. Sirolimus and everolimus appear to have activity against fibrosis and may be useful in fibrotic cGVHD. Imatinib may also be useful in cGVHD with fibrosis. Hydroxychloroquine has also been reported. In cGVHD, topical steroids may help lichen planus–like disease but are unlikely to affect scleroderma-like disease. Physical therapy is essential in patients with sclerosis, especially if it involves joints.
