16 Systemic Contact Dermatitis

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Contents

16.1 Introduction . . . . 295

16.2 Clinical Features . . . . 295

16.3 Mechanism . . . . 297

16.4 Medicaments . . . . 298

16.5 Metals . . . . 298

16.5.1 Nickel . . . . 298

16.5.2 Chromium and Cobalt . . . . 300

16.5.3 Gold . . . . 301

16.5.4 Mercury . . . . 301

16.6 Other Contact Allergens . . . . 301

16.7 Risk-Assessment-Oriented Studies . . . . 302

16.8 Diagnosis . . . . 303

16.9 Case Reports . . . . 303

References . . . . 305

16.1 Introduction

Systemic contact dermatitis may occur in persons with contact sensitivity when these persons are exposed to the hapten orally, transcutaneously, intrave- nously or by inhalation. The entity can present with clinically characteristic features or be clinically indistinguishable from other types of contact dermatitis. Contact sensitization to ubiquitous haptens is common. In a Danish population-based study, 15.2%

reacted to one or more of the haptens in the Euro- pean standard patch test series [1]. Many of these haptens can be presented to the immune system by a systemic route. The total number of individuals at risk of developing systemic contact dermatitis is therefore large.

The first description of systemic contact dermatitis can probably be ascribed to the pioneering Brit- ish dermatologist, Thomas Bateman [2]. His description of the mercury dermatitis called eczema rubrum is similar to what we today describe as the “baboon syndrome”: “Eczema rubrum is preceded by a sense

of stiffness, burning, heat and itching in the part where it commences, most frequently the upper and inner surface of the thighs and about the scrotum in men, but sometimes it appears first in the groin, axil- lae or in the bends of the arms, on the wrists and hands or on the neck.”

In the 20th century, the systemic spread of nickel dermatitis to areas other than the sites of contact was described by Schittenhelm and Stockinger in Kiel in 1925 [3]. After patch testing nickel-sensitive workers with nickel sulfate, they observed dermatitis and flares in former areas of contact dermatitis even when there was no current contact with nickel items in these areas. The literature on systemic contact dermatitis is now comprehensive. Reviews include Cro- nin [4], Fisher [5], Menné et al. [6] and Veien et al. [7].

쐽 Systemic contact dermatitis may occur after the systemic administration of a hapten in persons with contact sensitivity to the hapten. Systemic contact dermatitis may be indistinguishable from other types of contact dermatitis.

16.2 Clinical Features

The clinical features of systemic contact dermatitis are summarized in Table 1.

A causal relationship between systemic administration of the hapten and these clinical manifestations is most easily documented in persons sensitized to medicaments. For such persons, the exposure to the hapten can be controlled. This is less feasible for persons sensitized to, for example, ubiquitous metals.

Flare-up reactions at former sites of dermatitis or previously positive patch test sites raise a suspicion of systemic contact dermatitis [8–10]. A flare at a

Systemic Contact Dermatitis

Niels K. Veien, Torkil Menné 16

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previously positive patch test site following ingestion of the hapten is a fascinating and specific sign of systemic contact dermatitis. Such reactions may be caused by medicaments and are also sometimes seen in experimental oral provocation studies. This symptom is hapten specific and can be seen years after the original patch testing [11, 12].

Vesicular hand eczema (Fig. 1) [13] is a pruritic eruption on the palms, volar aspects and sides of the fingers, around the nails and occasionally on the plantar aspects of the feet with deep-seated vesicles and sparse or no erythema. If the periungual area is involved, transverse ridging of the fingernails can be a consequence. Vesicular hand eczema is a common disease, often with unknown etiology. It may have the

appearance of chronic hand eczema if frequent vesicular eruptions occur, and the dermatitis does not clear completely between eruptions. Crops of vesicles may be seen at the periphery of an area of dermatitis.

This type of hand eczema may be a symptom of systemic contact dermatitis.

A flare-up of dermatitis in the elbow and the knee flexures is a common symptom of systemic contact dermatitis. Such flares are difficult to distinguish from the early lesions of atopic dermatitis [14].

The “baboon syndrome” (Fig. 2) [15] is a characteristic, although rare, clinical manifestation of systemic contact dermatitis. It is a well-demarcated eruption on the buttocks, in the genital area and in a V-shape on the inner thighs, of a color ranging from dark-violet to pink. It may occupy the whole area or only part of it. Nakayama et al. [16] described the same clinical features as mercury exanthema. In mercury-sensitive patients, the baboon syndrome may also be seen in connection with acute generalized ex- anthematous pustulosis [17].

A nonspecific, maculopapular rash (toxicoderma) is often seen in systemic contact dermatitis. General symptoms such as headache and malaise are rarely seen in sensitized individuals following oral provocation with gold and medicaments. In patients sensitive to neomycin [8] and chromate [18], oral provocation with the hapten can cause nausea, vomiting, and diarrhea. A few patients have complained of arthralgia. Systemic administration of gold to gold-sensitized individuals has led to toxicoderma and slight fever [19, 20]. Malaise, leukocytosis, and pyrexia have also been seen in patients with systemic contact dermatitis from mercury [21].

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Fig. 1.

Vesicular eruption in the thenar region after oral challenge with 4 mg nickel

Table 1.Clinical aspects of systemic contact dermatitis Dermatitis in areas Flare-up of previous dermatitis of previous exposure Flare-up of previously positive

patch test sites Dermatitis on previously Vesicular hand eczema unaffected skin Flexural dermatitis

Baboon syndrome Maculopapular rash (toxicoderma) Vasculitis-like lesions General symptoms Headache

Malaise Arthralgia

Diarrhea and vomiting Fever

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쐽 The clinical features of systemic contact dermatitis include flare-up of previous dermatitis or previously positive patch test sites, vesicular palmar and/or plantar dermatitis, flexural dermatitis, and the baboon syndrome.

16.3 Mechanism

Based on human and animal experiments, it appears that both the humoral and the cellular immune sys- tems are activated in systemic contact dermatitis.

The histopathology of flare-up reactions is similar to that seen in ordinary contact dermatitis, while the ac- cumulation of neutrophils in the baboon syndrome

suggests that circulating immune complexes play a role [7].

Flares at sites of previous dermatitis or previously positive patch test sites are probably caused by specifically sensitized T-cells, either resting at the site or homing to the area after specific hapten exposure [12, 22, 23]. A reduction of CD4+ cells, CD4+ CD45Ro+

and CD8+ cells was seen in the peripheral blood of nickel-sensitive women after oral challenge with nickel. The oral challenge induced maturation of naive T-cells into memory cells. Memory cells were seen particularly in the intestinal mucosa [24].

A reduction of the number of CLA+ CD45Ro+

CD3+ and CLA+ CD45Ro+ CD8+ but not CLA+

CD45Ro+ CD4+ cells was seen in the peripheral blood of nickel-sensitive patients after oral challenge with nickel [25].

CD4+ T-cell clones reacted to cobalt but not to nickel in a patient following the removal of a cobalt- containing metal joint prosthesis [26].

Flexural eczema, vesicular hand eczema, the baboon syndrome, and toxicoderma may be caused by nonspecific cytokine release [27]. Möller et al. [19]

recorded a significant increase of cytokines such as IL-ra, interferon-γ (IFN-γ), tumor necrosis factor α (TNF-α), type-1 TNFα receptor (TNF-R1), IL-6 and acute phase reactants during systemic contact reactions to gold. In a patient with systemic contact dermatitis from prednisolone, elevated serum values of the IL-5, IL-6, and IL-10 were seen [28].

Antigen-specific tolerance to nickel has been demonstrated in guinea pigs [29]. Flares of dermatitis are frequently seen in clinical hyposensitization experiments when the hapten is given orally. Of 20 Parthenium-sensitive patients, 6 had to stop oral hy- posensitization therapy due to aggravation of their dermatitis [30].

쐽 The mechanism of systemic contact dermatitis includes both specifically sensitized T-cells and nonspecific cytokine release.

The latter could explain nonspecific symptoms such as flexural dermatitis and the baboon syndrome.

Fig. 2.Baboon syndrome in a patient sensitive to balsam of Pe- ru after the use of suppositories that contained balsam of Peru

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16.4 Medicaments

Most diagnosed cases of systemic contact dermatitis have occurred as a consequence of systemic exposure to medicaments in specifically contact-sensitized individuals. Such cases were common in the early era of the use of antibiotics, when drugs such as streptomy- cin and penicillin were given both topically and systemically.

Medicaments known to cause systemic contact dermatitis are summarized in Chap. 35 and elsewhere [7]. Many case reports are available, and while the list illustrates the wide range of possibilities, it is not complete. Any drug is probably capable of causing systemic contact dermatitis if cutaneous sensitization precedes systemic exposure. In this context, it should be kept in mind, as it is not uncommon that a drug reaction can be diagnosed later by patch testing (Chap. 35).

Table 2 shows how contact sensitization to medicaments may result in systemic contact dermatitis.

Contact sensitization is most commonly caused by the use of topical antibiotics in the treatment of leg ulcers, but the less common exposures outlined in Table 2 should be kept in mind. In a controlled study, Isaksson [31] showed that some budesonide-sensitive patients react to the inhalation of budesonide. Inha- lation of budesonide caused angioedema in one contact-sensitized person [32]. Occupational exposure to drugs is seen in the pharmaceutical industry as well as among health care professionals such as nurses, who administer tablets or give injections. Among those with occupational contact with medicaments, veterinarians have a high frequency of contact allergy to medicaments. Systemic contact dermatitis can be caused by the cross-reactivity of certain medicaments. Corticosteroids can cause anaphylactoid-like reactions [33].

쐽 Drugs used both topically and systemically may cause systemic contact dermatitis either as a flare-up of dermatitis in previous areas of dermatitis or as a widespread rash.

16.5 Metals

16.5.1 Nickel

Schittenhelm and Stockinger [3] observed the spread of nickel dermatitis after cutaneous exposure to nickel. Many patients with severe suspender dermatitis in the 1950s and 1960s had widespread dermatitis, with vesicular hand eczema and flexural dermatitis similar to that seen in systemic contact dermatitis [34, 35]. Systemic exposure from the absorption of nickel in the area of the dermatitis was thought to explain the clinical picture. Recently, it has been documented that avoidance of prolonged skin contact

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Table 2.Routes of sensitization to medicaments Use as a topical medicament (particularly in leg ulcer patients)

Leaking of the medicament to the epidermis from various sites of intravenous injection

Occupational exposure Eye drops

Suppositories

Intravesical installation

Injection of medicaments, middle ear, surgical wounds and intraperitoneal injection

Cross-reactivity

Fig. 3.Edematous eruption of the eyelid and dermatitis where spectacle frames touched the facial skin after oral challenge with 2.5 mg nickel

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with nickel-releasing alloys results in a statistically significant decrease in the frequency of hand eczema in nickel-sensitive individuals [36]. It has also been shown that following the adoption in Denmark of a regulation prohibiting the use of nickel in clothing or jewelry, a previously identified statistical association between nickel sensitivity and hand eczema no long- er exists [37].

The study of orally provoked flare-ups of nickel dermatitis was pioneered by Christensen and Möller [9], followed up by Kaaber et al. [38, 39], and Veien et al. [40]. In a double-blind study, Christensen and Möller [9] provoked 12 nickel-sensitive individuals

with an oral dose of 5.6 mg nickel. Of the 12 patients, 9 reacted with systemic contact dermatitis after an average of 8 h. These patients had the symptoms list- ed in Table 1, in particular, vesicular hand eczema (Fig. 1). The results of this study have been repeated and confirmed by several authors [6, 12]. The evidence for immunological specificity includes flare- up reactions at previous nickel contact sites, for example under metal spectacle frames (Fig. 3). Such a reaction was seen under previous sites of suspender nickel dermatitis in a woman who had not used garter belts containing nickel for over 30 years (Fig. 4).

Vasculitis-like lesions may also be seen (Fig. 5).

Fig. 4.

A plaque of dermatitis on the upper thigh in a 64-year- old woman after oral challenge with 2.5 mg nickel. As a young girl she had suspender dermatitis on the thighs from nickel in garter belts.

She had not worn a garter belt for 30 years

Fig. 5.

Following a placebo-controlled challenge with 2.5 mg nickel, this nickel-sensitive patient developed discrete, very pruritic, vasculitis-like lesions on the forearms and thighs

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The above-mentioned studies illustrate that few patients react to a dose of less than 0.5 mg nickel given as a single oral dose, while the majority of patients react to a dose of 5 mg or more. Dose responsiveness in nickel-sensitive patients has been demonstrated in two studies in which 0.3–4 mg and 1 or 3 mg nickel, respectively, was used for oral challenge [41, 42].

Systemic nickel dermatitis has been seen following accidental intravenous exposure to micrograms of nickel [43–45]. Nickel released from dental braces [46–48] and from older types of orthopedic prostheses can cause systemic nickel dermatitis and/or loos- ening of the prostheses [49, 50].

The daily ingestion of nickel from food varies from 150 to 500µg and depends both on the type of food and the production environment of the individual foodstuff. Foods with high nickel content include whole-grain flour, oats, soybeans, legumes, shellfish, nuts, licorice, and chocolate [51]. Nickel may be leached from cooking utensils [52]. The amount of nickel absorbed depends upon the concurrent intake of other foodstuffs such as proteins and alcohol. Che- lating medicaments can interfere with nickel absorption and metabolism and in that way provoke systemic contact dermatitis. This has been well described for disulfiram (Fig. 6) [39].

Dietary intervention is indicated for nickel-sensitive patients with vesicular hand eczema or more widespread systemic contact dermatitis, if the elimination of nonoccupational as well as occupational nickel exposure does not improve or clear the dermatitis. Dietary restriction following the guidelines by Veien et al. [53] should be followed for 1–2 months, and the outcome at that time should determine

whether dietary restriction should be continued.

Clinical studies suggest that approximately one- quarter of selected patients benefit from prolonged dietary treatment [54, 55].

쐽 A flare-up of dermatitis at a previously positive patch test site or widespread eruptions may be seen after placebo- controlled oral challenge with nickel.

16.5.2 Chromium and Cobalt

Cobalt and chromium salts can provoke systemic contact dermatitis [6, 56]. Dose–response studies with chromium suggest that a range from 0.05 mg to 14.2 mg potassium dichromate given as a single oral dose is appropriate. Chromium picolinate given as a nutritional supplement caused systemic contact dermatitis in one person [57]. Only one study has been made of cobalt-sensitive individuals. Four of six cobalt-sensitive patients with vesicular hand eczema had a flare of the dermatitis after placebo-controlled oral challenge with 1 mg cobalt given as 4.75 mg cobalt chloride [58]. The removal of chromium- and cobalt-releasing dental braces or dietary restrictions may help individual patients.

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Fig. 6.

Symmetrical vesicular dermatitis of the periungual area in a nickel-sensitive person a few days after begin- ning treatment for alcohol dependence with disulfiram

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16.5.3 Gold

Following the introduction of routine testing with gold sodium thiosulfate, a frequency of up to 10%

positive reactions has been seen among consecutive- ly patch-tested patients. Systemic contact dermatitis from gold in patients with rheumatoid arthritis treated with gold salts is probably common, as indicated by both clinical and experimental experience [59–62].

16.5.4 Mercury

Widespread eruptions, erythema-multiforme-like eruptions, and the baboon syndrome have been described in mercury-sensitive patients exposed to systemic mercury. Exposure can be from the vapors released from a broken thermometer, from homeopathic drugs or the drilling of amalgam dental fillings [21, 63–66].

쐽 Mercury-sensitive persons exposed to mercury vapors from a broken thermometer may develop baboon syndrome.

16.6 Other Contact Allergens

Most clinical and experimental studies of systemic contact dermatitis deal with either metals or medicaments, but important anecdotal evidence suggests that systemic contact dermatitis may be caused by certain plants, spices, and preservatives [67].

In a study of 42 patients with systemic contact dermatitis from Rhus, it was suggested that a toxic rather than an immunological reaction caused the symptoms. No information about patch test results was provided [68].

Kligman [69] attempted to hyposensitize persons with Rhus dermatitis by giving increasing oral doses of the allergen. Half of the moderately to severely sensitive patients developed either pruritus or a rash;

10% of the patients experienced flares of their dermatitis at sites of previously healed contact dermatitis. Flare-ups of vesicular hand eczema and erythema multiforme were rare. Perianal pruritus occurred in 10% of the highly sensitive individuals. Severe systemic contact dermatitis has been described in Rhus-sensitive patients who had eaten cashew nuts

[70]. This reaction was explained by an allergen in cashew nut shells that cross-reacts with urushiols in poison ivy [71].

The oral hyposensitization of 20 patients sensitive to Parthenium hysterophorus resulted in such severe flares in 6 of them that hyposensitization had to be stopped. Fourteen other patients successfully com- pleted the hyposensitization procedure [72].

Systemic contact dermatitis has been seen in patients sensitive to balsam of Peru (Myroxylon perei- rae) which contains naturally occurring flavors.

Hjorth [73] observed systemic contact dermatitis in balsam-of-Peru-sensitive patients who had eaten fla- vored ice cream and orange marmalade. Veien et al.

[74] challenged 17 patients sensitive to balsam of Pe- ru with an oral dose of 1 g balsam of Peru. Ten patients reacted to balsam of Peru and one to a placebo (Fig. 7).

Of 102 patients sensitive to balsam of Peru, 8 reacted to coniferous benzoate and benzyl alcohol. All 8 had systemic contact dermatitis. Three had hand eczema, and three had widespread dermatitis [75].

In other studies, reduction of the dietary intake of balsams has been shown to improve the dermatitis of more than half of selected patients who were sensitive to balsam of Peru [76–78].

쐽 Patients with contact sensitivity to balsam of Peru may develop systemic contact dermatitis from spices and other flavorings.

Open studies indicate that diet treatment may be helpful.

Members of the Compositae family of plants commonly cause allergic contact dermatitis. Systemic contact dermatitis in this group of patients is easily overlooked [79]. Sesquiterpene lactones are found in food and herbal remedies containing laurel, chamomile, and goldenrod [80–83]. One of four patients with contact allergy to lettuce had a flare of vesicular hand dermatitis after oral challenge with lettuce, and one of ten reacted to feverfew [79].

쐽 Herbal remedies such as laurel, chamomile, and goldenrod contain sesquiterpene lactones and may cause systemic contact dermatitis in sensitized persons.

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Garlic tablets caused a flare of vesicular hand eczema in a 58-year-old man with a positive patch test to garlic. A double-blind oral challenge was positive, and the dermatitis resolved when the garlic tablets were discontinued [84]. Periorbital and flexural dermatitis were seen in another garlic-sensitive person after the ingestion of garlic [85].

The antioxidant butylated hydroxyanisole (BHA), used both in cosmetics and in foods, can cause systemic contact dermatitis [86] as can the preservative sorbic acid [87–89].

Systemically aggravated contact dermatitis has been caused by aluminum in toothpaste in children sensitized to aluminum in vaccines [90].

16.7 Risk-Assessment-Oriented Studies While the risk of systemic contact dermatitis from drugs can be assessed, it is more difficult to carry out similar studies on ubiquitous contact allergens such as metals and naturally occurring flavors. In spite of intensive research on the significance of orally ingested nickel in nickel-sensitive individuals, we are unable to give firm advice concerning the oral dose that would represent a risk for the wide range of nickel-sensitive individuals. Many variables, such as the route of administration, bioavailability, individual sensitivity to nickel, interaction with naturally occurring amino acids, and interaction with medicaments, must be considered. A number of as yet unknown factors could influence nickel metabolism.

Furthermore, immunological reactivity to nickel can

change with time [12] and can be influenced by sex hormones and the development of tolerance. It is important to recognize that this area of research is ex- tremely complex and that much well-controlled research is still needed.

쐽 Systemic contact dermatitis in nickel- sensitive patients is complex. Reactions may vary with individual sensitivity to nickel, with bioavailability, with interaction with other food items or medicaments.

Reactions may also be influenced by sex hormones and the development of tolerance.

Well-controlled oral challenge studies can be carried out with medicaments in sensitized individuals. The beta-adrenergic blocking agent alprenolol is a potent contact sensitizer. Ekenvall and Forsbeck [91] identified 14 workers employed in the pharmaceutical industry who were contact sensitized to this com- pound. Oral challenge with a therapeutic dose (100 mg) led to a flare-up in one worker who developed pruritus and widespread dermatitis.

The preservative Merthiolate (thimerosal) is wide- ly used in sera and vaccines. Förström et al. [92] in- vestigated 45 thimerosal contact-sensitive persons to evaluate the risk of a single therapeutic dose of 0.5 ml

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Fig. 7.

Facial dermatitis in a baker sensitive to balsam of Peru after oral challenge with 1 g balsam of Peru

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of a 0.01% Merthiolate solution given subcutaneous- ly. Only 1 of the 45 patients developed a systemic contact dermatitis reaction. Aberer [93] did not observe any reactions in a similar study involving 12 patients.

Maibach [94] studied a group of patients who had discontinued the use of transdermal clonidine because of dermatitis. Of 52 patients with positive patch tests to clonidine, 29 were challenged orally with a therapeutic dose of the substance. Only one patient reacted with a flare-up at the site of the original dermatitis.

Propylene glycol is used as a vehicle in topical medications and cosmetics and as a food additive.

Propylene glycol is both a sensitizer and an irritant.

Hannuksela and Förström [95] challenged ten contact-sensitized individuals with 2–15 ml propylene glycol. Eight reacted with exanthema 3–16 h after the ingestion.

The overall impression of these studies is that systemic contact dermatitis in patients sensitized to a particular medicament is rare when the same patients are exposed to a therapeutic systemic dose of the medicament. Gold may constitute an exception to this general impression.

쐽 Although systemic contact dermatitis to medicaments given in therapeutic doses is probably rare in relation to the number of patients treated, there are many case reports of such reactions.

16.8 Diagnosis

Systemic contact dermatitis can occur in patients who are contact sensitized to a particular hapten if these patients are then systemically exposed to the same hapten or to breakdown products such as formaldehyde, a breakdown of aspartame [96].

The number of persons who will actually react to systemic exposure depends on the dose adminis- tered. In the case of nickel, whether a patient reacts to systemic exposure may also depend on the strength of the patch test reaction and the time that has elapsed since patch testing [42].

According to the available literature, particularly from experimental nickel challenge studies and challenge studies with medicaments, a relatively high dose of the hapten is needed to produce systemic contact dermatitis. The number of patients with

systemic contact dermatitis seen in clinical practice is low compared to the number of patients with allergic and irritant contact dermatitis [97]. In spite of the fact that systemic contact dermatitis is relatively rare, it is important to identify this type of reaction to pro- vide optimal management of the individual patient.

The diagnosis rests on the history of the patient, patch testing, and oral challenge and elimination studies. Severe reactions are unusual. Anaphylactic reactions following the administration of corticosteroids have been described [33].

16.9 Case Reports

쐽 A 37-year-old woman had had severe anogenital dermatitis for 3 years (Fig. 8).

She had previously been treated by her gynecologist who had found no explana- tion for the dermatitis.

The result of various topical treatments was unsatisfactory. Patch testing showed a ++ reaction to nickel. She had no memory of rashes under cheap jewelry or other nickel items.

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Fig. 8.Edematous anogenital dermatitis in a nickel-sensitive patient prior to initiation of a low-nickel diet

Case Report 1

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Placebo-controlled oral challenge with 2.5 mg nickel produced a severe flare of her anogenital dermatitis after 2 days. The flare lasted more than a week. She was instructed to follow a low-nickel diet, and after 2 months the dermatitis was quiescent (Fig. 9).

Two years later the woman was seen again. The current problem was very pruritic perianal dermatitis. She was again advised to reduce the nickel intake in food, and after 2 months, the dermatitis had practically cleared. She admitted that on both occasions she had eaten lots of chocolate, known to contain significant amounts of nickel.

쐽 A 43-year-old woman was seen because of an acute eruption of vesicular hand eczema (Fig. 10). She was known to have nickel allergy, and the eruption had occurred after 1 week on a weight-reducing diet.

Many of the foods included in this diet were high in nickel content. She was instructed in how to avoid food items with a high content of nickel, and the dermatitis faded (Fig. 11).

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Fig. 10.

An acute eruption of vesicular hand eczema after a weight-reducing diet that included foods with a high nickel content

Fig. 9.The same patient as in Fig. 8 after 2 months on a low- nickel diet

Case Report 2

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Fig. 11.

The same patient as in Fig. 10. The dermatitis faded after she was instructed to follow a low-nickel diet

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