Exfoliative Dermatitis

GULIZ KAIUKAVLI. M.U.. CIRANT BECKHAM, M.D.. IDA ORENGO. M.D., and TED ROSEN, M.D.
Baylor Cxillege of Medicine, Houston, Texas

Exfoliative dermatitis, also known as etythroderma, is an uncommon but serious skin

disorder that family physicians must be able to recognize and treat appropriately.
Although the etiology is often unknown, exfoliative dermatitis may be the result of a
drug reaction or an underlying malignancy. The approach to treatment should include
discontinuation of any potentially causative medications and a search for any underlying malignancy. One of the most common malignancies associated with exfoliative
dermatitis is cutaneous T-cell lymphoma, which may not manifest for months or even
years after the onset of the skin condition. Hospitalization is usually necessary for initial evaluation and treatment. In the hospital, special attention must be given to maintaining temperature control, replacing lost fluids and electrolytes, and preventing and
treating infection. The long-term prognosis is good in patients with drug-induced disease, although the course tends to be remitting and relapsing in idiopathic cases. The
prognosis of cases associated with malignancy typically depends on the outcome of
the underlying malignancy.

xfoliative dermatitis is a disease

process in which most, and sometimes all, of the skin is involved in
erythematous inflammation resulting in massive scaling.' A
variety of diseases and other exogenous factors may cause exfoliative dermatitis. Unfortunately, the clinical picture does not contribute to an understanding of the underlying
cause. Therefore, it is important to identify
and treat any underlying disease whenever
possible and to remove any contributing
external factors.-^
Incidence

Most published studies of exfoliative dermatitis have been retrospective and thus do
not address the issue of overall incidence.
Exfoliative dermatitis accounts for about 1
percent of all hospital admissions for dermatologic conditions.'
Although the disease affects both men and
women, it is more common in men, with an
average male-to-female ratio of 2.3:1. The

Known causes of exfoliative dermatitis include preexisting

dermatoses, drug reactions and malignancies.

FEBRUARY 1, 1999 / VOLUME 59, NUMBER 3

average age at onset is 55 years, although exfoliative dermatitis may occur at any time.^
Pathogenesis

Exfoliative dermatitis is the result of a dramatic increase in the epidermal turnover rate.
In patients with this disorder, the mitotic rate
and the absolute number of germinative skin
cells are higher than normal. Moreover, the
time necessary for cells to mature and travel
through the epidermis is decreased. This compressed maturation process results in an overall greater loss of epidermal material, which is
manifested clinically as severe scaling and shedding. Normal epidermis undergoes some extbliation every day, but the scales that are lost
contain little, if any, important viable material,
such as nucleic acids, soluble proteins and
amino acids.** In exfoliative dermatitis, however, protein and folate losses may be high.^
The pathogenesis of exfoliative dermatitis is
a matter of debate. In recent years, clinicians
have come to believe that this condition is secondary to a complicated interaction of cytokines and cellular adhesion molecules. Interleukin (IL)-l, IL-2, IL-8, intercellular adhesion
molecule 1 (ICAM-1), tumor necrosis factor
and interferon gamma are the cytokines that
may have roles in the pathogenensis of exfoliative dermatitis.^

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625

Etiology
The most common causes of exfoliative
dermatitis are preexisting dermatoses, drug
reactions, malignancies and other misceUaneous or idiopathic disorders.
PRIMARY DERMATOLOGIC DISORDERS

Dermatologic disorders occasionally present as exfotiative dermatitis. The most common of these are psoriasis, atopic dermatitis,
seborrheic dermatitis, contact dermatitis and
pityriasis rubra pilaris. Other dermatoses
associated with erythroderma are listed in
Table

}.'''->'

MEDICATIONS

TABLE 1

Dermatoses Associated with Erythroderma

Atopic dermatitis
Candidiasis
Contact dermatitis
Dermatophytosis
Ichthyosts
Lichen planus
Mastocytosis
Nummular eaema
Pemphigus
Photosensitive eczema
Pityriasis rubra pilarts
Prurigo
Psoriasis
Reiter's syndrome
Scabies
Seborrheic dermatitis
Staphylococcus scalded skin syndrome
Stasis with autoeczematization
Subacute cutaneous lupus erythematosus
Vitamin deficiency

Since the earliest descriptions of exfoliative

dermatitis, medications have heen known to
be important causative agents. Hence, the
apparent increase in cases of exfoliative dermatitis may be related to the introduction of
Information from reference 2. 3 and 6 thrxjugh 8.
many new drugs. Drug eruptions that initially present as morbilliform, lichenoid or
urticarial rashes may progress to generalized
exfoliative dermatitis. Antiepileptic medicaA pseudolymphoma reaction with fever,
tions, antihypertensive medications, antibiarthralgias, fymphadenopathy, hepatosplenootics, calcium channel blockers and a variety
megaly, anemia and erythroderma may
of topical agents (Table 2f'^-*-''^ can cause develop as a result of hypersensitivity to dapexfoliative dermatitis, but theoretically, any
sone or antiepileptic drugs. If cutaneous
drug may cause exfoliative dermatitis. Therepathology also mimics cutaneous T-cell lymfore, the clinician should always consider
phoma, it can be very difficult to differentiate
drugs as a possible cause.
a drug-induced skin condition from exfoliative dermatitis associated with a malignancy.^'

The Authors
GULIZ KARAKAYLl, M,D., is 3 visiting professor at the Baylor College of Medicine,
Houston. Dr. Karakayli received a medical degree in Turkey.
GRANT BECKHAM, M.D., is a physician at Baylor Senior Health, Dallas. He received a
medical degree and served a residency in internal medicine at Baylor College of Medicine.
IDA ORENGO, M.D., is an associate professor at the Baylor College of Medicine, where
she received a medical degree and served a residency in dermatology.
TED ROSEN, M.D., is a professor at the Baylor College of Medicine, He received a medical degree from the University of Michigan Medical Schooi, Ann Arbor, and served a
residency in dermatology at Bayiof College of Medicine.
Address correspondence to Ida Orengo, M.D., Department of Dermatology. F840,
One Baylor f^aza. Houston, JX 77030. Reprints are not available from the authors.

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AMKHICAN FAMILY PHYSICIAN

MALIGNANCIES

Malignancies are a major cause of exfoliative dermatitis. Reticuloendotheliai neoplasms, as well as internal visceral malignancies, can produce erythroderma, with the
former being the more predominant cause.
The cutaneous T-cell lymphomas are the
lymphomas most commonly associated with
exfoliative dermatitis. The most notable member of this group is mycosis fungoides. Studies
indicate that mycosis fimgoides may cause 25
to 40 percent of all cases of malignancy-related

VOLUME 59, NUMBER 3 / FEBRUARY 1, 1999

Exfoliative Dermatitis

erythroderma.*'' The erythroderma may arise

as a progression from a previous cutaneous Tcell lymphoma lesion or appear simultaneously with the cutaneous T-cell lymphoma, or
it may precede the appearance of the cutaneous T-cell lymphoma lesion. When it precedes cutaneous T-cell lymphoma lesions,
exfoliative dermatitis becomes the presenting
sign of the underlying malignancy.
The time interval between the appearance
of exfoliative dermatitis and the appearance of
cutaneous T-cell lymphoma lesions can vary
from months to years or even decades. S^zary
syndrome, the leukemic variant of mycosis
fungoides, is also associated with exfoliative
dermatitis. The erythrodermic form of mycosis fungoides and the S^zary syndrome may
also be difficult to distinguish from benign
erythroderma. Immunophenotypic studies
with the use of advanced antibody panels may
be useful in the differential diagnosis of these
two forms.'" Reticulum cell sarcoma is
another form of cutaneous T-cell lymphoma
that may cause exfoliative dermatitis.
Acute and chronic leukemia may also cause
exfoliative dermatitis. The relative risk of
leukemia inducing erythroderma is highly
variable, ranging from 11 to 50 percent."
Internal (visceral) malignancies cause
about 1 percent of all cases of exfoliative dermatitis.' ' Frequently, erythroderma is the presenting sign of the malignancy. Patients with
carcinoma of the colon, lung, prostate and
thyroid have presented with erythroderma.
More recently, carcinomas of the fallopian
tube,'^ larynx'^ and esophagus''' have been
reported as causes of exfoliative dermatitis.
Insidious development of the erythroderma,
progressive debilitation of the patient, absence
of previous skin disease and resistance to
standard therapy are features that may suggest
an underlying malignancy.^"
OTHER ASSOCIATED DISORDERS

Erythroderma is also associated with disorders that cannot easily be classified into groups.
Exfoliative dermatitis has been reported in
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/ VOLUME 59, NUMBER 3

association with hepatitis, acquired immunodeficiency syndrome, congenital immunodeficiency syndrome (Omenn's syndrome) and
graft-versus-host disease.^'^"'''
In reviews of erythroderma, a significant
percentage of patients (about 25 percent) do
not receive a specific etiologic diagnosis.

TABLE 2

Drugs Associated with Erythroderma

Acetaminophen
Actinomycin D (Cosmegan)
Allopurind (Zyloprim)
Aminoglycosides
Aminophylline
Amiodarone (Cordarone)
Arsenic
Aztreonam (Azactam)
Barbiturates
Calcium channel blockers
Captopril (Capoten)
Carbamazepine (Tegretol)
Cephabsporins
Chinese herbs
Chloroquine (Aralen)
Chlorothiazide (Diuril)
Chlorpromazine (Thorazine)
Chlorpropamide (Diabinese)
Cimetidine (Tagamet)
Cisplatin (Platinol)
Clofazimine (Lamprene)
Clotrimazole (Lotritnin)
Codeine
Cyclobenzaprine (Flexeril)
Dapsone
Dimercaprol (BAL in Oil)
Ethylenediamines
Gold
Hydantoins
Hydroxychloroquine (Plaquenil)
lnter!eukin-2 (Proleukin)
Interferon alfa {Roferon-A, Intron A,
Alferon N)
Interferon beta (Avonex, Betaseron)
Iodine (Pima syrup)
Isoniazid (Laniazid, Nydraztd; also in
Rifamate, Rimactane)
Isosorbide dinitrate (Isordil, Sorbitrate)

Isotretinoin (Accutane)
Lithium (Eskalith, Lithobid)
Mefloquine (Larium)
Mephyntoin (Mesantoin)
Mercurials
Mercury
Mexilitene (MexittI)
Minocycline (Dynacin, Minodn, Vectrin)
Mitomycin-C (Mutamycin)
Neomycin (Neosporin)
Nitrofurantoin (Furadantin,
Macrodantin)
Omeprazoie (Prilosec)
Para-amino salicylic add (Sodium PA.S,)
Penicillins
Phenolphthalein (Agoral, Alophen,
Modane)
Phenothiazines
Phenobarbital (Donnatal, Bellatal)
Phenytoin (Dilantin)
Quinacrine
Quinidine (Quinidex)
Ranttidine {Zantac}
Rifampin (Rifadin. Rimactane; also in
Rifamate)
Streptomycin
Sulfadiazine
Sulfonamides
Sulfonylureas
Terbutaline (Brethine, Bricanyl)
Tetrachloroethylene
Tetracyclines
Thalidomide (Synovir)
Thiazide diuretics
Trimethoprim (Trimpex; also in Bactrim,
Septra)
Tolbutamide (Orinase)
Vancomycin (Vancocin)

Information from references 2, 3 and 6 through 9.

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627

Erythematous, pruritic patches tend to spread over a period

of days to weeks and are followed by scaling.

Some of these patients undergo spontaneous

resolution. Other cases are ultimately classifiable as another dermatosis. A significant
number of these patients eventually progress
to cutaneous T-ceU lymphoma.*
CLINICAL MANIFESTATIONS

Clinically, the first stage of exfoliative dermatitis is erythema, often begimiing as single
or multiple pruritic patches, involving especially the head, trunk and genital region.
These patches tend to spread until, after a
matter of days or weeks, most of the skin surface is covered witli an erythematous, pruritic
eruption. Usually, but not always, the palms
of the hands, the soles of the feet and the
mucous membranes are spared. In some
studies, the nose and paranasal area are
spared. This has been called the "nose sign."'*
Once the erythema is well established, scaling inevitably follows {Figure I). The scales
may be small or large, superficial or deep.
Acute processes usually favor large scales,
whereas chronic processes produce smaller
ones. The exfoliative process also may involve
the scalp, with 25 percent of patients developing alopecia.^ Nails can often become dystrophic, particularly in patients with preexisting psoriasis.^'*'
The most fi-equently noted symptoms in
patients with exfoliative dermatitis include
malaise, pruritis and a chilly sensation. Both
hyperthermia and hypothermia are reported.
Other clinical findings include lymphadenopathy, hepatomegaly, splenomegaly, edema
of the foot or ankle^* and gynecomastia.'**
The scaling that occurs in exfoliative dermatitis can have severe metabolic consequences, depending on the intensity and the
duration of the scaling. Since cutaneous
fijnction as a multiprotective barrier is so dis-

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AMERICAN FANHLY PHYSICIAN

FIGURE 1. Elderly man with exfoliative dermatitis of the face caused by psoriasis.

rupted in exfoliative dermatitis, the body

loses heat, water, protein and electrolytes, and
renders itself much more vulnerable to infection. Exfoliative dermatitis is also a risk factor
for epidemic spread of methicillin-resistant
Staphylococcus aureus.'"-"

Heat loss is another major concern that

accompanies a defective skin barrier in
patients with exfoliative dermatitis. Loss of
normal vasoconstriaive function in the dermis, decreased sensitivity to the shivering
reflex and extra cooling that comesfromevaporation of the fluids leaking out of the weeping skin lesions all result in thermoregulatory
dysfunction that can cause hypothermia or
hyperthermia.** The basal metabolic rate also is
increased in patients with exfoliative dermatitis. A catabolic state thus ensues, which Is often
responsible for significant weight loss.
Each of these physiologic disruptions is
potentially life-threatening. Hypothermia can
result in ventricular flutter, decreased heart
rate and hypotension. Increased peripheral
blood flow can result in high-output cardiac
failure. Hypervolemia can also occur in
patients with exfoUative dermatitis, contributing to the likelihood of cardiac
HISTOPATHOLOGY

In most patients with erythroderma, skin

biopsies show nonspecific histopathologic
features, such as hyperkeratosis, parakerato-

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Exfoliative Dermatitis

sis, acanthosis and a chronic perivascular

inflammatory infiltrate, with or without
eosinophils. Even patients with clear histories
of preexisting dermatoses tend to have biopsies that are not diagnostic when they present
with erythroderma/
Laboratory Findings

Lahoratory evaluation of patients with

erythroderma is generally not very helpful in
determining a specific diagnosis. Typical laboratory values include mild anemia, leukocytosis, eosinophilia, elevated erythrocyte sedimentation rate, abnormal serum protein
electrophoresis with a polyclonal elevation in
the gamma globulin region, and elevated igE
levels.'-'""
Blood counts and bone marrow studies
may reveal an underlying leukemia. Analysis
for circulating Sezary cells may he helpful,
but only if the cells are identified in unequivocally large numbers.
Treatment

Hospitalization and dermatologic consultation are indicated in most cases to ensure

that all of the necessary cutaneous, laboratory and radiologic investigations and monitoring are performed. The balance of fluids
and electrolytes should be closely monitored,
since dehydration or hypervolemia can be
problems. Also, physicians should be vigilant
about possible secondary infection, whether
cutaneous, pulmonary or systemic.
In the acute phase, before determination of
the etiology, treatment consists of measures
to soothe the inflamed skin. These measures
include bed rest, lukewarm soaks or baths,
bland emollients and oral antihistamines.^^^'
In patients with chronic idiopathic erythroderma, emollients and topical steroids may
be effective. Other patients may warrant
PUVA (psoralen plus ultraviolet A) phototherapy, systemic steroids (if psoriasis has
been ruled out), retinoids (for exfoliative dermatitis secondary to psoriasis and pityriasis
rubra pilaris), or immunosuppressive agents

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/ VOLUME 59, NUMBER 3

Acute treatment should be aimed at soothing the inflamed

skin with bed rest, lukewarm soaks, bland emollients and
oral antihistamines.

such as methotrexate (Rheumatrex) and azathioprine (Imuran)."'^^

When used as adjunctive therapy, behavior
modification designed to eliminate persistent
scratching has been successfiil in reducing the
rate of excoriation and increasing the rate of
healing.^"
No uniformity of opinion exists concerning the best treatment for cutaneous T-cell
lymphoma. Options include use of PUVA
light therapy, total-body electron beam irradiation, topical nitrogen mustard, systemic
chemotherapy and extracorporeal photopheresis. Consultation with an oncologist
who is well-versed in treatment of cutaneous
T-cell lymphoma is advisable once the disease
progresses to the tumor stage.
Clinical Course, Prognosis
and Sequelae

Even though exfoliative dermatitis is a

complex disorder involving many factors, the
underlying disease is usually the key determinant of the course and prognosis. Druginduced exfoliative dermatitis is usually
short-lived once the inciting medication is
withdrawn and appropriate therapy is
administered. Patients with underlying skin
disorders may respond much more slowly to
therapy, but clearing almost always occurs
eventually. The clinical course of patients
with malignancies depends on the type of
malignancy and the response to appropriate
therapy. Patients who have exfoliative dermatitis of unknown cause tend to have an
unpredictable course, usually replete with
multiple remissions and exacerbations.*
In patients who develop complications
(i.e., infection, fluid and electrolyte abnormalities, cardiac failure), the rate of mortality
AMERICAN FAMII Y PHYSICIAN

629

is often higb. The most common causes of

death in patients with exfoliative dermatitis
are pneumonia, septicemia and heart failure.
Sequelae of exfoliative dermatitis are not
Vk'idely reported. However, patchy, diffuse
areas of postinflammatory hyperpigmentation and hypopigmentation may occur, especially in patients with darker skin.'-^ One case
of posterythrodermic generalized vitiligo
beginning six weeks after the onset of exfoliative dermatitis has been reported.^"*-"* Residual eruptive nevi and keloid formation are
rare sequelae. Mild to severe alopecia and
transient or permanent nail dystrophy also
may be encountered.
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