Erythroderma in adults

INTRODUCTION — Erythroderma (literally, "red skin"), also sometimes called exfoliative dermatitis, is a severe and potentially life-threatening condition that presents with diffuse erythema and scaling involving all or most of the skin surface area (≥90 percent, in the most common definition).

Erythroderma is a clinical sign and, as such, may be the clinical presentation of a wide range of cutaneous and systemic diseases (including psoriasis and atopic dermatitis), drug hypersensitivity reactions, and more rarely, Sézary syndrome, a leukemic subtype of cutaneous T cell lymphoma. Although uncommon in pediatric patients, erythroderma may similarly be the clinical presentation of a wide range of acquired and inherited diseases. The differential diagnosis for erythroderma in pediatric patients includes infections, inflammatory skin diseases, ichthyoses, and congenital immunodeficiencies.

This topic will discuss the clinical manifestations, diagnosis, and treatment of erythroderma in adults. Erythroderma in neonates and infants and Sézary syndrome are discussed separately.

●(See "Erythroderma in children".)

●(See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

EPIDEMIOLOGY — Erythroderma is a rare condition. The annual incidence has been estimated to be approximately 1 per 100,000 in the adult population [1]. In a retrospective study, erythroderma accounted for 13 in 100,000 patients presenting with skin diseases in China [2]. Erythroderma can occur at any age and in all patients but is more frequent in older adults (mean age 42 to 61 years) and in males [2-6]. Erythroderma is exceedingly rare in children; its prevalence is estimated to be approximately 0.1 percent in pediatric dermatology clinic populations [7,8].

ETIOLOGY — A wide range of cutaneous or systemic diseases can evolve to or cause erythroderma (table 1):

●Exacerbation of a pre-existing inflammatory dermatosis – The most common cause of erythroderma is the exacerbation of a pre-existing inflammatory dermatosis, most often psoriasis or atopic dermatitis [3-6,9,10]. In patients with psoriasis or atopic dermatitis, triggers of erythroderma include the abrupt discontinuation of systemic corticosteroids or other immunosuppressant therapy, medications (eg, lithium salts and antimalarials in patients with psoriasis), and phototherapy burns [11].

●Hypersensitivity drug reaction – A hypersensitivity drug reaction is the second most frequent cause of erythroderma. A wide variety of drugs have been reported to be associated with erythroderma, including penicillins, sulfonamides, carbamazepine, phenytoin, and allopurinol (table 2) [4,12]. Multiple patterns of drug reaction, from maculopapular/morbilliform eruption to drug reaction with eosinophilia and systemic symptoms to toxic epidermal necrolysis, may present with erythroderma.

●Inflammatory dermatoses appearing de novo – Pityriasis rubra pilaris often presents with erythroderma. (See "Pityriasis rubra pilaris: Pathogenesis, clinical manifestations, and diagnosis".)

●Uncommon causes – Uncommon causes of erythroderma include cutaneous T cell lymphoma and other hematologic and systemic malignancies, immunobullous diseases, connective tissue diseases, and infections (table 1).

●Idiopathic – In approximately 30 percent of cases of erythroderma, no underlying cause is identified and erythroderma is classified as idiopathic (sometimes called "red man syndrome," a term which is also used to describe an infusion reaction to vancomycin) [11,13,14].

PATHOGENESIS — The pathogenesis of erythroderma is incompletely understood. A complex interaction of cytokines (eg, interleukin [IL] 1, 2, and 8; and tumor necrosis factor [TNF]), chemokines, and intercellular adhesion molecules is believed to play a role in the massive recruitment of inflammatory cells to the skin and elevated epidermal turnover. The increased mitotic rate and decreased transit time of epidermal cells through the skin layers results in exfoliation, with significant loss of proteins, amino acids, and nucleic acids through the skin.

Increased circulating levels of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin) have been demonstrated in patients with erythroderma secondary to psoriasis or eczema and in patients with Sézary syndrome [15,16].

Immunohistochemical studies demonstrate a predominantly Th1 cytokine profile in the dermal infiltrates of patients with erythroderma associated with inflammatory dermatoses and a Th2 profile in the dermal infiltrates of patients with Sézary syndrome [17]. These findings suggest that different pathophysiologic mechanisms may lead to the relatively uniform clinical presentation of erythroderma.

CLINICAL MANIFESTATIONS

Onset — Erythroderma may develop acutely over hours or days or evolve gradually over weeks to months.

The onset is usually abrupt in drug hypersensitivity reactions. A morbilliform or urticarial eruption may first appear anywhere on the skin, then erythematous patches increase in size and coalesce into a generalized bright red erythema with occasional islands of sparing (picture 1A-B). Organ involvement (eg, hepatitis, nephritis, pneumonia) may occur in DRESS (drug reaction with eosinophilia and systemic symptoms). (See "Exanthematous (maculopapular) drug eruption" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Erythroderma from underlying cutaneous or systemic diseases usually develops more gradually. Erythematous patches may occur anywhere on the skin, enlarge and coalesce over hours to days to weeks to involve nearly the entire skin surface. Initially, the erythematous patches may have the characteristics of the underlying disease, but the specific features of the underlying diseases are often lost after erythroderma has fully developed.

Cutaneous signs and symptoms — By definition, over 90 percent of the skin is involved; the skin is red and warm to the touch (picture 1B). In patients with lightly pigmented skin, the color of the skin varies from bright pink (characteristic of a drug reaction) to a dusky red (characteristic of chronic erythroderma from many causes). In patients with darkly pigmented skin, these features may be more subtle. Most patients complain of severe skin pain or itching.

Linear crusted erosions and secondary lichenification may result from rubbing and scratching in chronic erythroderma. On palpation, the skin may feel leathery and indurated. Scaling is a common feature, particularly in erythroderma that has been present for more than a week. Scales can be large, small, or bran-like, and are particularly abundant in patients with underlying psoriasis.

Palmoplantar keratoderma (hyperkeratosis of the palms and soles) is most often associated with pityriasis rubra pilaris (picture 2A) but may also occur in patients with Sézary syndrome (picture 3). Nail pitting is characteristic of psoriasis (picture 4). (See 'Physical examination' below.)

Moist, crusted lesions on the face and upper trunk often precede the development of erythroderma in patients with pemphigus foliaceous (picture 5A-B). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus'.)

Hair (eg, telogen effluvium, scaling of the scalp) and nail changes (paronychia, nail dystrophy, and onychomadesis [nail shedding]) may be present. Involvement of the eyelids manifests with blepharitis, epiphora (excessive tearing), and ectropion (eyelid eversion). These features may be particularly prominent in patients with chronic erythroderma secondary to Sézary syndrome. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Skin'.)

Extracutaneous findings — Patients with erythroderma often appear uncomfortable, shiver, and complain of feeling cold. Constitutional symptoms (eg, malaise, fatigue, fever, or hypothermia) and signs of high-output cardiac failure (eg, peripheral edema, tachycardia) may also be present. (See "Clinical manifestations, diagnosis, and management of high-output heart failure", section on 'Clinical manifestations'.)

Lymphadenopathy and hepatomegaly or splenomegaly may be observed in chronic erythroderma. Lymph node biopsy often shows only the features of dermatopathic lymphadenopathy (a benign, reactive lymph node enlargement) but may be diagnostic of lymphoma in patients with cutaneous T cell lymphoma. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy'.)

Laboratory abnormalities — Nonspecific laboratory abnormalities may occur in patients with erythroderma due to various causes, including leukocytosis, anemia, and elevated erythrocyte sedimentation rate. Eosinophilia may be found in patients with DRESS. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Systemic symptoms and laboratory abnormalities'.)

Atypical lymphocytes with cerebriform nuclei (Sézary cells) are often observed in erythroderma regardless of cause. Counts of Sézary cells greater than 20 percent of the circulating peripheral blood lymphocytes or of at least 1000 cells/microL are found in Sézary syndrome, a leukemic variant of cutaneous T cell lymphoma. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Blood assessment'.)

CLINICAL COURSE — Depending upon the cause, the erythema may become generalized in hours to days, weeks, or months. Exfoliation typically begins two to six days after the onset of erythema, starts in flexural areas, and rapidly extends to the entire body surface. Scaling is particularly pronounced in patients with underlying psoriasis. Over weeks to months, hair and nail changes may occur. (See 'Cutaneous signs and symptoms' above.)

The duration of erythroderma is highly variable. Erythroderma due to drug reactions usually resolves in two to six weeks after stopping the culprit drug. In patients with drug reaction with eosinophilia and systemic symptoms (DRESS), resolution of erythroderma may require many weeks to months. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Erythroderma due to underlying cutaneous or systemic diseases may persist for weeks, months, or years.

COMPLICATIONS — Erythroderma is relatively well tolerated by many patients. However, some patients, particularly those at the extremes of age and patients with comorbidities, may experience complications. (See 'Hemodynamic and metabolic disturbances' below and 'Infection' below.)

Hemodynamic and metabolic disturbances — Profound disturbances in fluid and electrolyte regulation, thermoregulation, and metabolic balance occur with erythroderma. Increased skin perfusion leads to fluid loss by transpiration, and consequent electrolyte imbalance. Heat loss, hypothermia, and compensatory hypermetabolism associated with hyperthermia may occur. The shunting of the blood through the skin due to peripheral vasodilation may result in high-output cardiac failure, especially in older or compromised patients. (See "Causes and pathophysiology of high-output heart failure".)

Exfoliation of the skin results in significant protein loss that may exceed 9 g/m² body surface per day, particularly in patients with erythrodermic psoriasis [18]. The protein loss causes negative nitrogen balance, hypoalbuminemia, edema, and muscle wasting.

Infection — Inflammation, fissuring, and excoriation increase the susceptibility of the erythrodermic skin to bacterial colonization. Sepsis from Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), has been reported in erythrodermic patients and is of particular concern in those who are HIV positive [19-22]. Widespread superinfection with herpes simplex virus (Kaposi varicelliform eruption) also has been reported in erythrodermic patients [23,24]. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia" and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Eczema herpeticum'.)

DIAGNOSIS — The diagnosis of erythroderma is straightforward; it is made clinically in a patient presenting with diffuse and generalized erythema and scaling involving 90 percent or more of the body surface area (picture 1A-B). Determining the cause of erythroderma is more difficult and requires meticulous clinical assessment and clinicopathologic correlation.

DETERMINING THE UNDERLYING CAUSE — The underlying cause of erythroderma is often difficult to determine and may remain elusive. In approximately one-third of patients, the cause cannot be determined, and erythroderma is classified as idiopathic. However, ongoing evaluation of patients with idiopathic erythroderma is important, since the underlying cause may become apparent over time [13,14].

The evaluation of the erythrodermic patient to determine the underlying cause involves a detailed history, physical examination, skin biopsies, and laboratory tests. Specific tests are performed based upon the suspected cause.

History — A detailed history is of key importance in establishing the cause of erythroderma.

Important elements of history are:

●History of presenting illness – Onset of symptoms and course of erythroderma

●Past dermatologic and medical history – History of inflammatory skin disease (eg, psoriasis, atopic dermatitis), pre-existing systemic diseases or neoplasia

●Medication history – Including most recently introduced prescription and over-the-counter medications and supplements

●Family history – Family history of inflammatory skin diseases

Physical examination — Physical examination should include a complete examination of the skin, hair, nails, and mucosae for any sign of underlying skin disease. Lymph node and organ enlargement should be assessed.

Clinical signs that are nonspecific but may be helpful in suggesting the cause of erythroderma include:

●Color of erythema – In light-skinned patients, the color of the erythema may be helpful in ascertaining the diagnosis. Salmon pink/orange color with islands of sparing is typical of pityriasis rubra pilaris (picture 1A) [25]. A deeper red color associated with exfoliation is associated with psoriasis (picture 6A-B) or cutaneous T cell lymphoma (picture 1B). In patients with skin of color, the erythema may be subtle, presenting with discrete and confluent, red-brown or brown-black patches.

●Scaling – Severe scaling may indicate psoriasis. Crusted scales are seen in pemphigus foliaceus, whereas exfoliation of large skin sheets is seen in drug reactions. Scaling between the fingers or burrows involving the web spaces may indicate scabies.

●Bullae – The presence of bullae and the involvement of the mucous membranes may indicate immunobullous disease (eg, pemphigus, bullous pemphigoid). Moist, crusted lesions on the face and upper trunk often precede the development of erythroderma in patients with pemphigus foliaceous (picture 5A-B). (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Pemphigus foliaceus'.)

●Keratoderma – Waxy keratoderma of palms and soles with an orange hue is characteristic of pityriasis rubra pilaris (picture 2A-B), but may also be observed in Sézary syndrome (picture 3).

●Nail abnormalities – Nail thickening, subungual hyperkeratosis, and splinter hemorrhages are found in psoriasis and pityriasis rubra pilaris (picture 7) [2,26,27]. The presence of nail pitting is a clue to the diagnosis of erythrodermic psoriasis (picture 4).

●Hair abnormalities – Diffuse alopecia is common in erythroderma from all causes but may be particularly prominent in Sézary syndrome (picture 8) [28].

●Oral involvement – Oral mucositis is seen in most cases of erythroderma associated with immunobullous disease, Stevens-Johnson syndrome/toxic epidermal necrolysis, and graft-versus-host disease.

●Eye involvement – Conjunctival involvement is frequently seen in erythroderma associated with immunobullous diseases, such as mucous membrane pemphigoid, and Stevens-Johnson syndrome/toxic epidermal necrolysis. Chronic conjunctivitis may be complicated by the development of trichiasis and symblepharon and may be associated with the development of sicca syndrome and corneal perforation.

●Genitourinary involvement – The genitourinary tract may be involved in erythroderma associated with mucous membrane pemphigoid or Stevens-Johnson syndrome/toxic epidermal necrolysis.

Skin biopsy and histopathologic examination — Multiple skin biopsies may be necessary to identify the cause of erythroderma. Skin samples are usually obtained by punch biopsy of multiple involved sites. (See "Skin biopsy techniques", section on 'Punch biopsy'.)

Routine staining — The histopathology of erythroderma may reflect the underlying etiology. However, histology is more often unrevealing or nonspecific. Frequent findings on routine staining include:

●Hyperkeratosis

●Acanthosis

●Spongiosis

●Perivascular, inflammatory infiltrate

The relative prominence of these features may vary with the stage of the disease and the severity of inflammation (table 3) [29-31]. Alternating orthokeratosis and parakeratosis may be observed in pityriasis rubra pilaris. More specific histopathologic changes may become apparent later in the course of the disease. Therefore, repeated skin biopsies over time may be needed to establish the diagnosis. However, in approximately 30 percent of cases, the histologic features of erythroderma remain nonspecific throughout its course, and a precise diagnosis of the underlying condition cannot be made. (See 'Etiology' above.)

As an example, in the initial phase of Sézary syndrome histology may show a nonspecific perivascular lymphocytic infiltrate without atypical lymphocytes and an overlying hyperplastic and parakeratotic epidermis (picture 9) [29]. At a later stage, the infiltrate may become increasingly pleomorphic and acquire specific diagnostic features, such as atypical cerebriform mononuclear cells and Pautrier microabscesses (picture 9). (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Skin pathology'.)

Immunohistochemistry and immunophenotyping — Immunohistochemistry and T cell receptor gene rearrangement studies should be performed if atypical lymphocytes are identified in the inflammatory infiltrate by routine histologic examination. The demonstration of an immunophenotype of T cells lacking mature T cell antigens (CD3⁺, CD4⁺, CD7^-) and the clonality of the T cell receptor gene rearrangement support the diagnosis of Sézary syndrome. The expression of the programmed death-1 (PD-1) may also be helpful in differentiating Sézary syndrome from erythroderma associated with inflammatory skin diseases. In one study PD-1 was expressed by over 50 percent of neoplastic CD4⁺ T cells in 23 of 25 biopsies from patients with Sézary syndrome and only in 4 of 30 biopsies from patients with erythroderma associated with inflammatory skin diseases [32]. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Skin pathology'.)

A predominance of CD8⁺ lymphocytes in the dermal infiltrate suggests chronic actinic dermatitis (actinic reticuloid). (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Chronic actinic dermatitis'.)

Direct immunofluorescence should be performed if an immunobullous disease is suspected based upon the presence of intraepidermal bullae or subepidermal bullae or an urticarial appearance of the erythroderma. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Direct immunofluorescence' and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Direct immunofluorescence'.)

Laboratory and imaging tests — Laboratory testing is based upon the patient's medical history, clinical presentation, and suspected cause of erythroderma. The initial laboratory evaluation includes:

●Complete blood cell count and differential. Leukocytosis is common in all types of erythroderma. Eosinophilia >700/microL may be found in drug reaction with eosinophilia and systemic symptoms (DRESS). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Systemic symptoms and laboratory abnormalities'.)

●Routine biochemistry tests including electrolytes, glucose, serum albumin, LDH, liver and kidney function tests. (See 'Complications' above.)

●Examination of a peripheral blood smear for the presence of Sézary cells (atypical lymphocytes with cerebriform nuclei). Counts of Sézary cells >20 percent of examined lymphocytes suggest Sézary syndrome. Counts <10 percent can be found in erythrodermas of different etiologies and are considered nonspecific. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Blood assessment'.)

●Bacterial cultures and assessment of antimicrobial susceptibilities, fungal cultures, and swabs for polymerase chain reaction tests for herpes simplex virus and varicella zoster virus should be performed if superinfection of skin lesions is suspected. (See "Diagnosis of varicella-zoster virus infection", section on 'Polymerase chain reaction' and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Polymerase chain reaction'.)

In patients presenting to a tertiary referral center, a wide differential diagnosis is entertained, and the following specific tests are considered:

●Peripheral blood flow cytometry and T cell clonality – In patients with suspected cutaneous T cell lymphoma, immunophenotyping and T cell receptor gene rearrangement studies should be performed to confirm or to rule out the diagnosis of Sézary syndrome. Findings that support the diagnosis of Sézary syndrome include absolute Sézary cell count ≥1000/microL; CD4:CD8 ratio greater than 10; aberrant expression of pan-T cell markers including CD2, CD3, CD7; deficient expression of CD26 and CD7 (CD4⁺CD26^- ≥30 percent and CD4⁺CD7^- ≥40 percent); and evidence of a circulating T cell clone [33]. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Blood assessment'.)

●Studies for immunobullous and autoimmune disease – In patients with an urticarial eruption or blisters, immunobullous disease should be considered. Direct immunofluorescence studies of skin biopsy specimens are essential for the diagnosis of immunobullous disease. Biopsies should be taken in perilesional skin (erythematous areas close to bullae or erosions). The detection of circulating autoantibodies anti-desmoglein 1 and 3 or anti-bullous pemphigoid antigens BP180 or BP230 confirms the diagnosis of pemphigus or bullous pemphigoid, respectively. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'Serology' and "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Enzyme-linked immunosorbent assay'.)

In patients with a photosensitive eruption, connective tissue disease should be considered. The presence of antinuclear antibodies (ANA) and antibodies against extractable nuclear antigens (ENA) suggests the diagnosis of lupus erythematosus or other autoimmune disease. (See "Overview of cutaneous lupus erythematosus", section on 'Diagnosis'.)

In patients with associated muscle weakness, raised ANA and increased serum levels of muscle enzymes (creatine kinase, aldolase) can confirm a clinical suspicion of dermatomyositis. Myositis-specific antibodies (eg, Jo-1 and other antisynthetases, anti-Mi-2, SRP, PM-Scl) may be helpful in identifying subsets of dermatomyositis (picture 10). (See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Laboratory findings'.)

●Skin scrapings – In all patients with erythroderma, particularly if there is associated crusting, the possibility of scabies should be considered. Scrapings of burrows for mites should be performed and examined under a microscope in patients with suspected crusted scabies. Potassium hydroxide (KOH) preparations may be useful to identify hyphae and arthrospores if a generalized dermatophyte infection is suspected. (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Scabies preparation' and "Dermatophyte (tinea) infections", section on 'Diagnosis'.)

●Imaging studies – Because erythroderma may be a skin manifestation of underlying malignancy, age- and sex-appropriate screening for underlying malignancy should be performed. Additionally, work-up should be guided by any symptoms or signs that might indicate possible underlying malignancy (eg, weight loss, shortness of breath, change in bowel habit). Radiologic work-up may include chest radiograph, computed tomography (CT) or magnetic resonance imaging (MRI) (or, alternatively, positron emission tomography/computed tomography [PET/CT]) of the abdomen and pelvis, colonoscopy, mammography in females, or ultrasonography of the prostate in males.

TREATMENT

Initial management — Patients with symptomatic erythroderma and patients who are in any way unstable (particularly patients who are hemodynamically unstable) may require hospitalization for initial evaluation and treatment. Regardless of the specific etiology, the initial management involves:

●Assessment, active management, and ongoing monitoring of the hemodynamic status

●Replacement of fluid and electrolytes

●Assessment and management of skin

●Assessment and management of oral mucosa, eyes, genitourinary tract

●Monitoring of body temperature

●Nutritional support

●Treatment of cutaneous superinfections

●Symptomatic treatment of skin inflammation and pruritus

Patients should be placed in a warm (30 to 32°C) and humid environment to prevent hypothermia. Symptomatic relief of skin pain and itching may include intensive skin care with emollients and wet dressings.

For the symptomatic treatment of skin inflammation and pruritus, we also suggest low- to mid-potency topical corticosteroids. We generally use low-potency topical corticosteroids (groups six and seven (table 4)) for the face and body folds and mid-potency corticosteroids (groups four and five) for other body areas two to three times per day until improvement.

Oral antihistamines may be helpful in reducing itching in some patients. We prefer first-generation antihistamines for their sedating effect, especially at night to help with sleep (eg, diphenhydramine [25 to 50 mg orally every four to six hours for adults and children ≥12 years] or hydroxyzine [25 mg orally three to four times per day for adults and children ≥6 years]).

Cutaneous infection from S. aureus, including methicillin-resistant Staphylococcus aureus (MRSA), is common and requires prompt institution of systemic antibiotic therapy. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections", section on 'Antibiotic selection'.)

Cutaneous infection with herpes simplex virus requires treatment with antiviral medications such as acyclovir, valacyclovir, or famciclovir. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults", section on 'Dosing of antiviral therapy'.)

If eyes appear involved, ophthalmologic assessment is appropriate.

If oral involvement precludes eating and drinking, consideration can be given to placement of a nasogastric tube or intravenous fluids.

If genitourinary involvement is present, consideration can be given to placement of a urinary catheter.

Treatment of underlying conditions — After the underlying etiology of erythroderma has been determined, appropriate treatment of the underlying condition should be added to the initial management measures (see 'Initial management' above):

●Drug hypersensitivity reaction – If a drug hypersensitivity reaction is suspected, all medications that are not essential should be withdrawn. For these patients, a short course of moderate/high-dose systemic corticosteroids (eg, prednisone 0.5 to 1 mg/kg per day) may be beneficial. (See "Exanthematous (maculopapular) drug eruption", section on 'Management' and "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Management'.)

●Stevens-Johnson syndrome/toxic epidermal necrolysis – If a patient has Stevens-Johnson syndrome/toxic epidermal necrolysis, consideration should be given to moving the patient to an environment where expert skin care can be appropriately provided (eg, burn unit, intensive care unit with expert nursing). (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

●Erythrodermic psoriasis – Patients with erythrodermic psoriasis require systemic therapies including methotrexate, cyclosporine, acitretin, or biologics [34,35]. (See "Treatment of psoriasis in adults", section on 'Erythrodermic psoriasis'.)

●Erythrodermic atopic dermatitis – Patients with erythrodermic atopic dermatitis may benefit from systemic corticosteroids or other immunosuppressant/immunomodulatory medications, such as dupilumab, cyclosporine, methotrexate, or azathioprine, although most patients respond to intensive topical treatments alone in the short term [36]. (See "Treatment of atopic dermatitis (eczema)".)

●Sézary syndrome – Patients with Sézary syndrome may require systemic and skin-directed therapies that target the circulating Sézary cells and control the skin manifestations. These treatments, which include extracorporeal photochemotherapy, systemic retinoids, methotrexate, histone deacetylase (HDAC) inhibitors (romidepsin, vorinostat, belinostat), and mogamulizumab, are discussed separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

●Pityriasis rubra pilaris – For patients with pityriasis rubra pilaris, treatment options include interleukin (IL) 17 or IL-23 pathway inhibitors (eg, ixekizumab, secukinumab, ustekinumab, guselkumab), systemic retinoids, and methotrexate. (See "Pityriasis rubra pilaris: Prognosis and management".)

Management of patients with idiopathic erythroderma — There are no specific treatments for idiopathic erythroderma. In the short-term, most patients respond to skin care measures (eg, wet dressings) and symptomatic treatment of skin inflammation with low- to mid-potency topical corticosteroids and oral antihistamines. (See 'Initial management' above.)

Patients who fail to respond to topical treatments are often empirically treated with systemic corticosteroids or other immunosuppressants (eg, methotrexate, cyclosporine). However, evidence for efficacy of systemic corticosteroids or other immunosuppressant therapy for patients with erythroderma is scant and limited to small case series and their use in the absence of a precise diagnosis remains controversial [2,4,14,37]. (See 'Initial management' above.)

For patients with idiopathic erythroderma that does not respond to topical therapy, systemic agents may be considered if symptoms are severe. We suggest initial treatment with systemic corticosteroids rather than other immunosuppressant treatments because they have a more rapid onset of action (usually within days rather than weeks). We generally use prednisone 0.5 to 1 mg/kg per day for 7 to 10 days up to a maximum dose of 60 mg per day; prednisone is then slowly tapered over several weeks to minimize the chances of rebound. During this time other immunosuppressive agents, such as methotrexate, azathioprine, or mycophenolate mofetil, can be introduced.

A frequent problem with the use of systemic corticosteroids is that patients have a great difficulty in weaning from systemic corticosteroids because of the high chance of rebound after the interruption of treatment. Patients should be monitored for potential adverse effects from systemic corticosteroids (in particular, fluid retention, hypertension, hyperglycemia, increased risk of infection). (See "Major adverse effects of systemic glucocorticoids".)

Cyclosporine (4 to 5 mg/kg per day) or methotrexate (10 to 20 mg weekly) may be alternative initial therapies for patients for whom systemic corticosteroids are contraindicated. However, these agents have a slower onset of action and a less predictable anti-inflammatory effect than systemic corticosteroids. Cyclosporine or methotrexate may be continued until the erythroderma is under control and then gradually weaned to the lowest dose that satisfactorily controls the skin inflammation. It is generally recommended that cyclosporine be used for less than one year to avoid renal damage. (See "Cyclosporine and tacrolimus nephrotoxicity".)

Monitoring — It is important that patients with idiopathic erythroderma be re-evaluated periodically, at least every six months. Over time, repeated skin biopsies and other laboratory or imaging studies may reveal the underlying cause of erythroderma.

PREVENTION — Relapses of erythroderma may be prevented by controlling the underlying cause and avoiding triggers. Known triggers of erythroderma in patients with psoriasis or atopic dermatitis include the abrupt discontinuation of corticosteroids or other immunosuppressants; topical application of irritants; medications (eg, lithium salts and antimalarials in patients with psoriasis); and phototherapy burns. Patients with a history of erythrodermic drug eruption must avoid re-exposure to the culprit drug.

PROGNOSIS — Erythroderma is a serious disorder associated with both increased morbidity and mortality. The mortality rate for erythroderma ranges from 4 to 64 percent, with higher rates reported in older case series. Advanced age, comorbidities, and need for hospitalization are associated with unfavorable prognosis. In a population-based cohort study from Denmark, 31 and 40 percent of patients with erythrodermic psoriasis and exfoliative erythroderma, respectively, died within the first three years following hospital admission, compared with 14 percent of patients hospitalized for severe psoriasis vulgaris [38].

The prognosis may vary depending upon the underlying condition:

●Erythroderma secondary to psoriasis or atopic dermatitis usually improves within several weeks to several months after starting appropriate treatment. However, chronic or recurrent erythroderma is not uncommon in these patients [39].

●Erythroderma due to drug reactions usually resolves in two to six weeks after stopping the culprit drug but can last for longer.

●Erythroderma in Sézary syndrome and paraneoplastic erythroderma are often refractory to therapy and have a poor prognosis [40,41].

●Most patients with idiopathic erythroderma have a favorable prognosis. However, they require clinical monitoring because the underlying diagnosis may become apparent over months to years (see 'Monitoring' above). In some of these patients, erythroderma may represent a prelymphomatous condition. In a study of 28 patients with idiopathic erythroderma observed over a mean period of 33 months, 15 improved, 10 went into remission, and 2 patients developed a cutaneous T cell lymphoma [13]. In another study, 4 of 38 patients with erythroderma of unknown etiology followed up for a median of 30 months developed mycosis fungoides [14].

SUMMARY AND RECOMMENDATIONS

●Definition – Erythroderma (exfoliative dermatitis) is a severe and potentially life-threatening condition that presents with diffuse erythema and scaling involving ≥90 percent of the skin surface area.

●Etiology – The most common causes of erythroderma include exacerbation of a pre-existing inflammatory dermatosis, hypersensitivity reactions to drugs, and cutaneous T cell lymphomas. Less common causes of erythroderma are summarized in the table (table 1). In approximately one-third of patients, the cause of erythroderma remains undetermined (idiopathic erythroderma). (See 'Etiology' above.)

●Clinical presentation and clinical course – Erythroderma may develop acutely over hours or days or evolve gradually over weeks to months. Patients typically present with erythematous patches that increase in size and coalesce into a generalized erythroderma (picture 1A-B). In skin of color, the erythema may be subtle and appear brown or black. Patients appear uncomfortable, shiver, and complain of feeling cold. Scaling begins two to six days after the onset of erythema and may become prominent. Extracutaneous symptoms include fever or hypothermia, peripheral edema, and tachycardia. (See 'Clinical manifestations' above and 'Clinical course' above.)

●Complications – Erythroderma is relatively well tolerated by many patients. However, patients at the extremes of age and patients with comorbidities may experience complications, including high-output heart failure, fluid and electrolytic imbalance, heat loss, hypothermia, compensatory hypermetabolism, protein loss and negative nitrogen balance, hypoalbuminemia, edema, muscle wasting, and secondary skin infection. (See 'Complications' above.)

●Diagnosis – The diagnosis of erythroderma is straightforward. However, determining the cause of erythroderma is often difficult and involves a detailed history, physical examination, skin biopsy, and laboratory/imaging studies. In some cases histology reveals the underlying etiology (table 3), but it is more often nonspecific, and repeated skin biopsies may be necessary. (See 'Diagnosis' above and 'Determining the underlying cause' above.)

●Initial in-hospital management – Patients who are hemodynamically unstable or those with severe symptoms may require hospitalization. Regardless of the specific etiology, the initial management involves:

•Assessment, active management, and ongoing monitoring of the hemodynamic status

•Replacement of fluid and electrolytes

•Assessment and management of skin

•Assessment and management of oral mucosa, eyes, genitourinary tract

•Monitoring of body temperature

•Nutritional support

•Treatment of cutaneous superinfections

•Symptomatic treatment of skin inflammation and pruritus

For the symptomatic treatment of skin inflammation and pruritus, we suggest topical corticosteroids and oral antihistamines (Grade 2C). We generally use low-potency to mid-potency topical corticosteroids (groups 4 to 7 (table 4)) two to three times per day until improvement. (See 'Initial management' above.)

●Patients with idiopathic erythroderma – For patients with idiopathic erythroderma that does not respond to topical therapy, we suggest initial use of systemic corticosteroids rather than other immunosuppressive treatments (Grade 2C). We generally use prednisone 0.5 to 1 mg/kg per day for 7 to 10 days. Prednisone is then slowly tapered over several weeks to avoid rebound while introducing other immunosuppressive treatments, such as methotrexate or cyclosporine. If systemic corticosteroids are contraindicated, cyclosporine may be used initially. (See 'Management of patients with idiopathic erythroderma' above.)