Erythema is defined as redness of the skin, resulting from congestion of the capillaries. There are many causes and manifestations of erythema; some examples include photosensitivity, erythema multiforme and erythema nodosum. Erythema multiforme is a an acute inflammatory eruption of the skin and/or mucosal membranes. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been historically considered severe forms of erythema multiforme, although some people view them as separate but related conditions. Erythema nodosum (also called subacute migratory panniculitis) is a nodular erythematous eruption that is typically limited to the extremities. The following sections address background and treatment information about erythema multiforme and erythema nodosum; the complementary and alternative therapies section also covers approach for adjunctive treatment of erythema in general, particularly photosensitivity.

Erythema multiforme

• Idiopathic—50% of cases
• Infectious—primarily herpes simplex virus (HSV) and mycoplasma pneumonia, but numerous others (e.g., Epstein-Barr virus, hepatitis B, influenza A, Salmonella, Streptococcus pyogenes, Trichomonas vaginalis)
• Drugs—including sulfonamides, anticonvulsants, penicillin, poliomyelitis vaccine, 5-fluorouracil
• Radiation therapy
• Malignancies
• Serum sickness
• Erythema infectiosum (fifth disease)—human parvovirus B19
• Chemicals

Erythema nodosum

• Idiopathic—50% of cases
• Tuberculosis
• Streptococcal infection
• Sarcoidosis
• Systemic lupus erythematosus (SLE)
• Ulcerative colitis
• Pregnancy
• Drugs—especially oral contraceptives, sulfonamides, bromides
• HSV
• Leprosy (usually after initiation of antimicrobial therapy)

Erythema multiforme

• Previous history
• Males at greater risk than females
• Sun exposure

Erythema nodosum

• Familial
• Females at greater risk than males

Erythema multiforme

• Prodromal symptoms—malaise, fever, sore throat, cough, and itching or burning at impending site
• Sudden onset
• Target lesions and papules—central erythema surrounded by normal skin, which is surrounded by erythematous ring; central portion dusky red, 1 to 3 cm circumference, may become cyanotic, purpuric, or vesicular; heal without scarring; hyperpigmentation or hypopigmentation common
• Knees, elbows, palms, soles; oral lesions appear in 25% of cases; trunk in severe cases
• Lesions recur in crops
• Erythema infectiosum—facial "slapped cheek" rash; reticulated rash (upper extremities) lasting about 2 weeks
• SJS—upper respiratory infection; flat atypical targets on trunk; mucosal involvement (oral blisters, conjunctivitis, nares, anorectal junction, vulvovaginal region); hacking cough; fever
• TEN—initial SJS-type symptoms progress to generalized detachment of the epidermis; sepsis, fluid loss; death

Erythema nodosum

• Prodromal symptoms—fatigue, malaise, upper respiratory infection; low-grade fever, flu-like symptoms
• Tender nodules—2 to 6 cm in diameter; resolve without scarring or joint damage
• Lesions change from red, hard, and painful to fluctuant and bluish, fading to yellowish or brown
• Arthralgias
• Arthritis
• Typically in crops, may be solitary
• Shins, forearms, thighs, trunk
• Leprosy—severe and systemic

Erythema multiforme

• Kawasaki disease
• Behcet's syndrome
• Urticaria
• HSV
• Stomatitis

Erythema nodosum

• Nodular nonsuppurative panniculitis (Weber-Christian disease)
• Thrombophlebitis
• Erysipelas
• Cellulitis
• Arteriosclerosis obliterans

Clinical appearance helps to identify the type of erythema. Physical examination may identify underlying disease. A thorough history can reveal agents.

Erythema multiforme

• Skin biopsy—may reveal HSV-specific DNA
• Immunoglobulin (IgM) antibody to B19—fifth disease
• Immunofluorescence—SJS
• Test for lymphopenia—TEN

Erythema nodosum

• Elevated erythrocyte sedimentation rate
• Mild leukocytosis
• For differential diagnosis: throat culture, stool culture, tuberculin skin test

Erythema multiforme

• Circulating immune complexes and mononuclear and T lymphocyte-rich cell infiltrates around upper dermal blood vessels
• Increased expression of intracellular adhesion molecule 1 (ICAM-1)
• TEN—keratinocyte necrosis

Erythema nodosum

• Lymphohistiocytic infiltrate
• Granulomatous inflammation
• Fibrosis in the septa of subcutaneous fat

X ray—bilateral hilar adenopathy with erythema nodosum, related to a particular disease or may be nonspecific reaction

• Excisional biopsy

Underlying disease is treated and causative drugs stopped. Measures to control symptoms are instigated. While mild cases need not be treated, bed rest and medication are used for moderate or severe cases.

Erythema multiforme

• Prednisone—high dose for 1 to 3 weeks until controlled, then taper quickly; prevents recurrence; use is controversial
• Acyclovir (400 mg bid for 6 months)—continual use prevents HSV-related lesions
• Valacyclovir (500 mg/day) or famciclovir (250 mg bid)—newer antiviral agents
• Azathioprine (100 to 150 mg/day)—anecdotal reports of efficacy; however, recurs upon discontinuation
• Thalidomide (100 mg/day, then titrate to effective level)—for refractory cases; severely teratogenic
• Levamisole hydrochloride (150 mg/day for 3 days)—for oral lesions
• Antihistamines—control pruritus
• Burrow's compresses—for cutaneous blisters
• Analgesics—preferably not NSAIDs
• Topical steroids—for papules and plaques
• Antibiotics—for secondary infection, avoiding drugs associated with erythema
• Human intravenous immunoglobulin—promising experimental treatment for SJS and TEN

Erythema nodosum

• Intralesional triamcinolone acetonide (2.5 to 5 mg/mL)—for symptom relief
• Corticosteroids—reduces symptoms; masks underlying disease; recurs on discontinuation
• Antibiotics—for underlying infections
• Thalidomide (200 mg bid for 2 to 3 days, then reduce)—for leprosy; severely teratogenic

Treatment of any type of erythema is dependent upon the underlying cause. Certain CAM therapies may:

• Reduce inflammation
• Support the immune system
• Help prevent secondary infections

Antioxidant compounds, for example, have demonstrated protective effects for the skin against ultraviolet-induced damage in clinical trials. Therefore, the question raised is whether antioxidants may confer protection to the skin from other sources of damage. In addition, because sun exposure is one of the risk factors for erythema multiforme, photoprotective antioxidants may, theoretically, confer some protection against this disease process.

According to scientific studies, dietary supplementation or topical administration of antioxidants provides some protection against damage to the skin, such as that which ultraviolet radiation may cause. The mechanism of action is not entirely understood but antioxidants are scavengers of ROS (reactive oxygen species). ROS and oxygen-derived free radicals cause damage to the skin by depleting it of important protective antioxidants. These reactive substances also interact with lipids, proteins, and other biomolecules and, in the process, make the skin tissue more susceptible to damage (Dreher et al. 1998).

The studies described in the following subsections suggest that supplementation with antioxidants may provide at least modest photoprotective benefit when used prior to exposure. It is not clear from the data whether topical or oral antioxidants confer protection to the skin from other types of damage leading to erythema multiforme, erythema nodosum, or other forms of erythema; such protection, though, seems plausible. Supplements with antioxidant properties that have been investigated include:

• Carotenoids
• Vitamin C
• Vitamin E
• Melatonin
• Zinc

Caution should be exercised when considering supplementation with megadoses of vitamins. Although they may provide photoprotection, the impact of long term supplementation is unknown. In addition, the results are not yet conclusive and more research is needed.

Carotenoids

Carotenoids are highly effective natural scavengers of ROS. Several small studies have investigated whether carotenoids help to protect against UV-light-induced erythema and have reported positive results. In one study, for example, twenty healthy subjects, ages 20 to 57, were randomly assigned to two groups:

• Group one received 25 mg of carotenoids (primarily beta-carotene) daily for 12 weeks
• Group two received the same oral carotenoid supplementation together with 500 IU alpha-tocopherol (vitamin E)

Subjects were categorized by skin type:

• Type I (fair, white skin; red or blonde hair; green or blue eyes; extremely sensitive to sun exposure; absence of tanning) 
• Type II (white skin, blonde or light brown hair, blue eyes; sensitive to sun exposure; and minimal tanning).

In both groups, participants' unprotected skin response prior to supplementation was used as the control. Both groups experienced greater protection against erythema formation during supplementation, as indicated by higher MED (minimal erythema dose) levels than baseline values. Group two showed less erythema formation than group one, indicating a possible additional protection from vitamin E, although this difference was not statistically significant (Stahl et al. 2000).

Vitamins C and E

A few small studies suggest that vitamins C and E, taken in combination, may have photoprotective properties. In one double-blind, placebo-controlled study, for example, 10 subjects took the following for eight days:

• Ascorbic acid 2 g
• d-alpha-tocopherol 1,000 IU

MEDs were assessed before and after the trial. In the vitamin group, MED level increased in eight subjects following eight days compared to no change in the placebo group (Eberlein-König et al. 1998).

These synergistic effects were further examined in a prospective, randomized, placebo-controlled study of 40 healthy volunteers. Results showed that oral supplementation with megadoses of vitamins C and E (3 grams and almost 3,000 IU respectively), in combination, achieved greater photoprotective effects than supplementation with either vitamin alone (Fuchs and Kern 1998). As stated earlier, though, caution must be exercised when using megadoses of vitamins because of lack of knowledge regarding long term safety.

Melatonin

A small scale study suggests that topical melatonin may confer added photoprotection when combined with both vitamin C and vitamin E in topical form (Dreher et al. 1998). In this study by Dreher et al (1998), significant differences were also seen when vitamin E was combined with either melatonin or vitamin C. Even melatonin alone achieved significant dose-dependent effects compared to placebo. Vitamin C or vitamin E alone, however, demonstrated only modest to no effect.

Given the size of the melatonin, vitamin C and vitamin E studies to date, more research is required before drawing conclusions about efficacy or even safety of these substances for skin protection from the sun or other damaging processes.

If there are benefits to topical antioxidants in protecting against sun damage to the skin, it seems that these free radical scavengers should be used prophylactically rather than as treatment. Six volunteers applied topical vitamin C, vitamin E, melatonin, or placebo cream alone or in combination following UV-light irradiation. (An unexposed and untreated skin area served as a negative control for each subject.) Significant reductions in erythema response were not observed with single antioxidants or combinations, nor with single or multiple applications. The authors concluded that the benefits of topical antioxidants in erythema suppression appear to be limited to preparations applied prior to, not following, UV exposure. The authors suggest that oxidative skin damage is a rapid event and that antioxidants can help prevent such damage only when present in UV-exposed skin prior to and during exposure (Dreher et al. 1999).

Zinc Sulfate

A review article describes seven known cases of necrolytic acral erythema (NAE; a condition akin to TEN as described earlier) and adds an eighth case. Dosages of oral zinc sulfate (60 to 440 mg/day), administered alone or in combination with interferon, were reported to be effective for five of the eight patients (Sinclair and Reynolds 1997).

Flavonoids

In theory, flavonoids confer a benefit for erythematous skin conditions such as erythema multiforme and erythema nodosum because they act as anti-inflammatories and strengthen connective tissue. Examples include (Murray 1996):

• Quercetin 200 to 400 mg tid 20 minutes prior to meals
• Rutin 50 to 250 mg bid to tid
• Hesperidin 250 mg bid to tid

Green Tea

Antioxidant properties in green tea may provide protection against UV-light-induced erythema. Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea (Camellia sinensis), has demonstrated photoprotection in previous animal models. In a human study, volunteers were subjected to UVB radiation equal to a 4 MED dose, delivered to buttock skin with or without topical EGCG applied 30 minutes before exposure. Skin punch biopsies were obtained from the treated areas and nontreated control areas. EGCG significantly (Katiyar et al. 1999):

• Inhibited erythema formation
• Reduced myeloperoxidase and cyclooxygenase
• Protected against leukocyte infiltration 
• Diminished prostaglandin metabolite formation
• Reduced cellular oxidative damage

Other Herbs

Although not studied scientifically, herbs used traditionally to promote dermal healing, stimulate lymphatic circulation, and possibly help treat the underlying cause include the following examples:

• Burdock root (Arctium lappa) can be used topically for skin inflammation and wound healing (Blumenthal et al. 2000)
• Goldenseal (Hydrastis canadensis)—for an infectious etiology
• Lemon balm (Melissa officinalis) cream or wash can be applied to HSV lesions (which may cause erythema multiforme – see section entitled Etiology) (Blumenthal et al. 2000).
• Licorice root (Glycyrrhiza glabra)—in the case of a virus; contraindicated with hypertension (Blumenthal et al. 2000)
• Meadowsweet (Filipendula ulmaria)—for pain, particularly arthralgias (as may be seen with erythema nodosum) (Blumenthal et al. 2000)
• Milk thistle (Silybum marianum)—for a chemical etiology (Blumenthal et al. 2000)
• Slippery elm (Ulmus fulva) may be combined with goldenseal root and applied topically for treatment of an open wound (Blumenthal et al. 2000)
• Yarrow (Achillea millefolium) can be used topically for skin inflammation and wound healing (Blumenthal et al. 2000)

Independent studies published by two groups of researchers have demonstrated positive photoprotective effects of homeopathic treatment with Apis in albino guinea pigs subjected to radiation. Although neither of these studies was methodologically rigorous, both reported positive results (Vickers 1999).

Additional remedies commonly used in clinical practice for skin conditions include:

• Chininum sulphuricum 
• Rhus toxicodendron -- used in the case of blisters and vesicles accompanied by intense itching that worsens at night and improves with the application of heat; the appropriate patient is generally restless and unable to get comfortable at night

Should be avoided in the case of acute erythematous skin conditions

Erythema multiforme

• Burn unit—preferred when 20% of body affected
• Monitor fluid and electrolyte abnormalities, protein loss, organ damage

• Treat underlying disease
• Avoid known triggers
• Acyclovir—with HSV

• SJS—may lead to blindness
• TEN—may lead to death (see Prognosis section below)
• Erythema nodosum—pulmonary hilar adenopathy

Erythema multiforme

• Episodes generally resolve in 4 to 6 weeks

SJS and TEN

• SJS—generally resolves in 1 month without complication; 10% mortality with extensive disease
• TEN—34% to 40% overall mortality; 25% to 100% with full-thickness epidermal loss
• Prompt withdrawal of causative drug decreases mortality

Erythema nodosum

• Recurs for months; may persist for 2 years

• Thalidomide—severely teratogenic
• Precipitating factor with erythema nodosum
• Erythema infectiosum—can lead to fetal infection, causing fetal anemia, heart failure, fetal hydrops, death

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