Are You Confident of the Diagnosis?

What you should be alert for in the history

The most critical factor in the history is the temporal relationship between the exposure to allergens and the development of symptoms. Exposure to the allergen can occur via multiple routes including ingestion, inhalation, injection (intramuscular, intravenous, subcutaneously), or transepidermally. Systemic contact dermatitis (SCD) can have varied latency from the time of exposure from a few hours to a few days after exposure. By definition there should be a first episode at some point in the past to a well-defined contact allergen which could have occurred weeks to years before the episode of SCD. Associated systemic symptoms including headache, nausea, vomiting, arthralgias, and diarrhea can accompany the cutaneous findings.

Characteristic findings on physical examination

Physical examination is highly variable, as SCD may present with a wide spectrum of physical findings (Figure 1). The classic presentation is a polymorphous eruption with macules, papules, and vesicles localized to the antecubital fossae, axillae, eyelids, lateral aspect of the neck, and genitalia. The presentation with diffuse erythema of the anogenital region has been referred to as the baboon syndrome.

Figure

Urticarial and eczematous reaction in a woman taking propolis tablets after demonstrating a local reaction to a topical agent containing propolis.

SCD can present in a more localized fashion as deep-seated vesicles and erythema of the palms and fingers or with generalized exfoliative erythroderma. Exposure to the allergen can frequently result in a dermatitis at the initial area of sensitization and at previous positive patch test reactions to the antigen.

Patch testing may be valuable in determining the cause of SCD. It may also serve as a reminder that systemic administration of a particular drug or agent may result in a SCD. An initial screening series such as the TRUE test can be performed by most dermatologists. Additional patch test series to consider might include the following: medicaments, metals, fragrances, plants, and corticosteroids.

Expected results of diagnostic studies

Histopathology is not specific for SCD. There is a range of histologic findings that include an acute or chronic spongiotic dermatitis versus a more nonspecific hypersensitivity reaction with a superficial and deep component of perivascular inflammation including eosinophils.

Diagnosis confirmation

When SCD is more localized to the hands it resembles chronic vesicular hand dermatitis (formerly dyshidrotic eczema) and can usually only be differentiated by a combination of history, patch testing, and avoidance trials. Widely disseminated SCD can easily be mistaken for a maculopapular drug reaction. The more flexural variants can be mistaken for severe seborrheic dermatitis, inverse psoriasis, and nutritional deficiencies (glucagonoma syndrome). Erythrodermic variants can be difficult to distinguish from other forms of erythroderma including psoriasis, atopic dermatitis, and cutaneous T-cell lymphoma.

Who is at Risk for Developing this Disease?

Patients at particular risk include those that have been previouly sensitized to allergens. The more common allergens that have been associated with SCD include nickel, Balsam of Peru, and medications or their cross-reactors that are systemically administered.

What is the Cause of the Disease?
Etiology

The following table lists many of the reported agents responsible for eliciting SCD.

Table I.

Table I.
Metals that Cause SCD Drugs that Cause SCD Flavorings, Botanicals, and Preservatives that Cause SCD
Nickel Penicillin, Amoxicillin, Ampicillin Balsam of Peru
Cobalt Neomycin Garlic
Gold Streptomycin Sorbic acid
Copper Sulfonamides (cross reacts with saccharin) Propylene glycol (cases of SCD from foods and medicaments)
Mercury Bacitracin (also anaphylaxis) Cinnamon oil
Zinc 5-Fluoruracil Chamomile
Aluminum Allopurinol Echinacea
Benzocaine Feverfew
Corticosteroids (inhaled and systemic) Marigold
Erythromycin Vanilla oil
Ethylenediamine (cross reacts with aminophylline and hydroxyzine) Parabens
Mesalazine (5-amino ASA) Cashew nut oil (cross reacts with toxicodendron)
Acyclovir Propolis (cross reacts with Balsam of Peru)
Terbinafine
Intravenous Immune Globulin

Similar to classic allergic contact dermatitis, SCD requires initial sensitization usually to a well-defined contact allergen. This initial reaction could take place weeks or years prior to repeat exposure.

Pathophysiology

In SCD, the second phase or elicitation phase occurs hematogenously rather than by direct cutaneous exposure. After systemic exposure the antigen is delivered to the epidermis and taken up by antigen presenting cells in the epidermis where it is presented to memory T cells. These activated T-cells initiate a cascade of inflammation which results in the dermatitis. While this is a type IV immunologic reaction it has also been suggested that a type III response is involved in SCD. In a type III reaction antigen-antibody complexes are deposited in the skin leading to inflammation.

Systemic Implications and Complications

Associated systemic symptoms including headache, nausea, vomiting, arthralgias, and diarrhea can accompany the cutaneous findings.

More specifically, drug-induced SCD may present as the baboon syndrome with gluteal and intertriginous involvement. Commonly implicated agents responsible for the baboon syndrome include medications and in particular beta-lactam antibiotics. SCD to nickel can be suspected in nickel allergic patients with refractory vesicular hand dermatitis. Formaldehyde has been implicated in systemic reactions including migraine headaches, asthma, and generalized eczema.,

Treatment Options

Table II summarizes treatment options for systemic contact dermatitis.

Table II.
Medical Treatments Physical Modalities
Topical corticosteroids
Oral corticosteroids
Avoidance protocols based on patch testing (must have intimate knowledge of cross reactors) Phototherapy
Narrow band UVB
Topical PUVA (photochemotherapy) especially in the case of SCD of the hands associated with nickel
Disulfiram with nickel SCD (rarely used with risk of hepatoxicity and antabuse-like reaction with alcohol)

Optimal Therapeutic Approach for this Disease

The highest priority in treating SCD is to identify and avoid causative allergens.

Topical corticosteroids, including desoximetasone 0.25% ointment (preferred due to low allergenicity), can be used to manage acute episodes of SCD. Since SCD often involves intertriginous areas the use of topical corticosteroids, especially in those locations, should be weighed against the risk of cutaneous atrophy, including striae.

Oral corticosteroids are a mainstay in the acute phase of SCD. Similar to other cases of acute contact dermatitis, patients typically require at least a 2-week course to prevent rebound phenomenon. Most adults require an initial dosage of 40 to 60mg/day.

SCD of the hands can behave in a more chronic fashion and avoidance of the offending allergen may result in some degree of improvement. In more chronic cases, consideration should be given to the use of psoralen plus ultraviolet A (PUVA), either topical or systemic.

Below are examples of practical measures for avoidance of the following common or more ubiquitous allergens involved in SCD.

Nickel

When nickel is the cause of SCD, a low nickel diet can be considered. This can be achieved by the following measures:

Avoidance of foods high in nickel including shellfish, chocolate, legumes, grains, nuts, canned foods, leafy green vegetables, vitamin supplements/beverages, and margarine.

Eating of animal meats (other than shellfish), eggs, dairy, refined grains, vegetables (that are not green), citrus fruits, and high iron (prevents absorption of nickel).

Running tap water prior to drinking to flush out nickel leached into the water from the pipes.

Avoidance of stainless steel cookware and use of glass or ceramic cookware as an alternative.

Balsam of Peru

When Balsam of Peru is suspected as a cause of SCD, avoidance of flavoring and spices should be considered. This includes cloves, vanillin, and cinnamon. Balsam of Peru can be found in cola drinks, vermouth, throat lozenges, orange marmalade, and chutney.

Sorbic acid

When sorbic acid is the suspected cause of SCD, a low sorbic acid diet should be considered and should restrict the following:

Fruits – chestnuts, plums, prunes, strawberries, currants, cranberries

Candies

Dairy – including margarine, butter, cheese, spreads, fruit yogurt

Flavored drinks

Other- refrigerated salads with meats or shellfish

Propylene glycol

Propylene glycol (PG) can be used in foods as a thickening agent and when suspected of causing SCD the following foods should be restricted

Cake mixes

Salad dressings

Popcorn

Soda beverages

Certain medications that contain PG in the inactive filler

Patient Management

As with any allergy, it is important to educate the patient and the family on avoidance measures specific to the allergen. It is also important to review any potential cross-reacting substances.

Consider a medical alert bracelet, as would be used in a more classic drug allergy. In cases of SCD due to foods, consider consultation with a nutritionist, since many of the avoidance diets may be limiting.

Unusual Clinical Scenarios to Consider in Patient Management

Aspartame, an artificial sweetener, may be a relevant cause of SCD in formaldehyde-sensitive patients. Belsito described a case of SCD of the eyelids associated with formaldehyde. A known formaldehyde sensitive patient noted improvement of her eyelid dermatitis upon withdrawal of aspartame and worsening upon re-challenge.

Aspartame, an l-aspartyl-l-phenylalanine methyl ester, is converted in the intestine to phenylalanine (50%), aspartic acid (40%), and aspartic acid methyl ester (10%).

The methyl ester is then converted to methyl alcohol (methanol) and carried to the liver. Methanol is then converted to formaldehyde. This occurs not only in the liver but also in other organs containing high levels of these enzymes, including the eye. Aspartame is a commonly used artificial sweetener found in many diet beverages and artificially sweetened chewable vitamins for children.

What is the Evidence?

Thyssen , JP, Maibach , HI. “Drug-elicited systemic allergic (contact) dermatitis–update and possible pathomechanisms”. Contact Dermatitis . vol. 59. 2008. pp. 195-202. (Reviews drug-induced SCD and illustrates potential mechanisms.)

Scheper , RJ, von Blomberg , M, Boerrigter , GH. “Induction of immunological memory in the skin”. Role of local T cell retention. Clin Exp Immunol . vol. 51. 1983. pp. 141-8. (This article reviews SCD due to drugs and discusses possible pathomechanisms.)

Andersen , KE, Hjorth , N, Menné , T. “The baboon syndrome: systemically-induced allergic contact dermatitis”. Contact Dermatitis . vol. 10. 1984. pp. 97-100. (Demonstrates three case reports of baboon syndrome variant of SCD to ampicillin, nickel, and mercury.)

Menne , T, Weismann , K. “Hematogenous contact eczema following oral administration of neomycin”. Hautzart . vol. 35. 1997. pp. 547-55. (A case report of pompholyx type of SCD after systemic oral ingestion of neomycin in a previously sensitized individual.)

Lachapelle , JM, Maibach , HI. “Patch testing and prick testing; A practical guide”. 2009. pp. 7-32. (Overview of the spectrum of the three stages of allergic contact dermatitis including local reactions, lymphatic spread, and hematogenous dissemination.)

Hausermann , P, Harr , TH, Bircher , AJ. “Baboon syndrome resulting from systemic drugs; is there strife between SDRIFE and allergic contact dermatitis syndrome?”. Contact Dermatitis. vol. 51. 2004. pp. 297-310. (Compares the allergic contact dermatitis and SDRIFE both clinically and mechanistically.)

Nijhawan , RI, Molenda , M, Zirwas , MJ, Jacob , SE. “Systemic contact dermatitis”. Derm Clin . vol. 27. 2009. pp. 355-64. (A review of systemic contact dermatitis with a focus on nickel and balsam of Peru.)

Sharma , AD. “Relationship between nickel allergy and diet”. Indian J Dermatol Venerol . vol. 73. 2007. pp. 307-312. (Reviews the sources of nickel in the environment in foods in the context of influencing dermatitis in the nickel sensitive individual.)

Hill , AM, Belsito , DV. “Systemic contact dermatitis of the eyelids caused by formaldehyde derived from aspartame”. Contact Dermatitis. . vol. 49. 2003. pp. 258-259. (A case report of a formaldehyde-sensitized patient with eyelid dermatitis associated with the ingestion of aspartame.)

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