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Chapter 16 Systemic Contact 16 Niels K. Veien, Torkil Menné

Contents of stiffness, burning, heat and itching in the part 16.1 Introduction ...... 295 where it commences, most frequently the upper and inner surface of the thighs and about the scrotum in 16.2 Clinical Features ...... 295 men, but sometimes it appears first in the groin, axil- 16.3 Mechanism ...... 297 lae or in the bends of the arms, on the wrists and 16.4 Medicaments ...... 298 hands or on the neck.” In the 20th century, the systemic spread of nickel 16.5 Metals ...... 298 dermatitis to areas other than the sites of contact was 16.5.1 Nickel ...... 298 described by Schittenhelm and Stockinger in Kiel in 16.5.2 Chromium and Cobalt ...... 300 1925 [3]. After patch testing nickel-sensitive workers 16.5.3 Gold ...... 301 16.5.4 Mercury ...... 301 with nickel sulfate, they observed dermatitis and flares in former areas of even 16.6 Other Contact ...... 301 when there was no current contact with nickel items 16.7 Risk-Assessment-Oriented Studies ...... 302 in these areas. The literature on systemic contact der- 16.8 Diagnosis ...... 303 matitis is now comprehensive. Reviews include Cro- nin [4], Fisher [5], Menné et al. [6] and Veien et al. [7]. 16.9 Case Reports ...... 303 References ...... 305 Core Message

í Systemic contact dermatitis may occur after the systemic administration of a 16.1 Introduction hapten in persons with contact sensitivity to the hapten. Systemic contact dermatitis Systemic contact dermatitis may occur in persons may be indistinguishable from other types with contact sensitivity when these persons are ex- of contact dermatitis. posed to the hapten orally, transcutaneously, intrave- nously or by inhalation. The entity can present with clinically characteristic features or be clinically in- distinguishable from other types of contact derma- titis. Contact sensitization to ubiquitous haptens is 16.2 Clinical Features common. In a Danish population-based study, 15.2% reacted to one or more of the haptens in the Euro- The clinical features of systemic contact dermatitis pean standard series [1]. Many of these are summarized in Table 1. haptens can be presented to the by a A causal relationship between systemic adminis- systemic route. The total number of individuals at tration of the hapten and these clinical manifesta- risk of developing systemic contact dermatitis is tions is most easily documented in persons sensi- therefore large. tized to medicaments.For such persons,the exposure The first description of systemic contact derma- to the hapten can be controlled. This is less feasible titis can probably be ascribed to the pioneering Brit- for persons sensitized to, for example, ubiquitous ish dermatologist, Thomas Bateman [2]. His descrip- metals. tion of the mercury dermatitis called eczema rubrum Flare-up reactions at former sites of dermatitis or is similar to what we today describe as the “baboon previously positive patch test sites raise a suspicion syndrome”: “Eczema rubrum is preceded by a sense of systemic contact dermatitis [8–10]. A flare at a 16_295_308* 05.11.2005 10:27 Uhr Seite 296

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Table 1. Clinical aspects of systemic contact dermatitis appearance of chronic hand eczema if frequent vesic- ular eruptions occur, and the dermatitis does not Dermatitis in areas Flare-up of previous dermatitis of previous exposure clear completely between eruptions. Crops of vesicles Flare-up of previously positive may be seen at the periphery of an area of dermatitis. patch test sites This type of hand eczema may be a symptom of Dermatitis on previously Vesicular hand eczema systemic contact dermatitis. unaffected skin Flexural dermatitis A flare-up of dermatitis in the elbow and the knee flexures is a common symptom of systemic contact Maculopapular rash dermatitis. Such flares are difficult to distinguish (toxicoderma) from the early lesions of [14]. Vasculitis-like lesions The “baboon syndrome” (Fig. 2) [15] is a charac- General symptoms Headache teristic, although rare, clinical manifestation of Malaise systemic contact dermatitis. It is a well-demarcated eruption on the buttocks, in the genital area and in a Arthralgia V-shape on the inner thighs, of a color ranging from Diarrhea and vomiting dark-violet to pink. It may occupy the whole area or Fever only part of it. Nakayama et al. [16] described the same clinical features as mercury exanthema.In mer- cury-sensitive patients, the baboon syndrome may previously positive patch test site following ingestion also be seen in connection with acute generalized ex- of the hapten is a fascinating and specific sign of anthematous pustulosis [17]. systemic contact dermatitis. Such reactions may be A nonspecific, maculopapular rash (toxicoderma) caused by medicaments and are also sometimes seen is often seen in systemic contact dermatitis. General in experimental oral provocation studies. This symp- symptoms such as headache and malaise are rarely tom is hapten specific and can be seen years after the seen in sensitized individuals following oral provo- original patch testing [11, 12]. cation with gold and medicaments. In patients sensi- Vesicular hand eczema (Fig. 1) [13] is a pruritic tive to neomycin [8] and chromate [18], oral provoca- eruption on the palms, volar aspects and sides of the tion with the hapten can cause nausea, vomiting, and fingers, around the nails and occasionally on the diarrhea. A few patients have complained of arthral- plantar aspects of the feet with deep-seated vesicles gia. Systemic administration of gold to gold-sensi- and sparse or no erythema. If the periungual area is tized individuals has led to toxicoderma and slight involved, transverse ridging of the fingernails can be fever [19, 20]. Malaise, leukocytosis, and pyrexia have a consequence. Vesicular hand eczema is a common also been seen in patients with systemic contact der- disease,often with unknown etiology.It may have the matitis from mercury [21].

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Fig. 1. Vesicular eruption in the thenar region after oral chal- lenge with 4 mg nickel 16_295_308* 05.11.2005 10:27 Uhr Seite 297

Systemic Contact Dermatitis Chapter 16 297

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 spe- cifically 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 ba- boon 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 reac- tions to gold. In a patient with systemic contact der- matitis from prednisolone, elevated serum values of Fig. 2. Baboon syndrome in a patient sensitive to balsam of Pe- the IL-5, IL-6, and IL-10 were seen [28]. ru after the use of suppositories that contained balsam of Peru Antigen-specific tolerance to nickel has been demonstrated in guinea pigs [29]. Flares of derma- titis are frequently seen in clinical hyposensitization experiments when the hapten is given orally. Of 20 Core Message Parthenium-sensitive patients, 6 had to stop oral hy- posensitization therapy due to aggravation of their dermatitis [30]. í The clinical features of systemic contact dermatitis include flare-up of previous dermatitis or previously positive patch test sites, vesicular palmar and/or plantar Core Message dermatitis, flexural dermatitis, and the baboon syndrome. í The mechanism of systemic contact der- matitis includes both specifically sensitized T-cells and nonspecific cytokine release. The latter could explain nonspecific symp- toms such as flexural dermatitis and the 16.3 Mechanism baboon syndrome.

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 16_295_308* 05.11.2005 10:27 Uhr Seite 298

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16.4 Medicaments Core Message

Most diagnosed cases of systemic contact dermatitis í Drugs used both topically and systemically have occurred as a consequence of systemic exposure may cause systemic contact dermatitis to medicaments in specifically contact-sensitized in- either as a flare-up of dermatitis in previ- dividuals.Such cases were common in the early era of ous areas of dermatitis or as a widespread the use of , when drugs such as streptomy- rash. 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 16.5 Metals illustrates the wide range of possibilities, it is not complete. Any drug is probably capable of causing systemic contact dermatitis if cutaneous sensitiza- 16.5.1 Nickel tion precedes systemic exposure. In this context, it should be kept in mind, as it is not uncommon that a Schittenhelm and Stockinger [3] observed the spread drug reaction can be diagnosed later by patch testing of nickel dermatitis after cutaneous exposure to (Chap. 35). nickel. Many patients with severe suspender derma- Table 2 shows how contact sensitization to medic- titis in the 1950s and 1960s had widespread derma- aments may result in systemic contact dermatitis. titis, with vesicular hand eczema and flexural derma- Contact sensitization is most commonly caused by titis similar to that seen in systemic contact derma- the use of topical antibiotics in the treatment of leg titis [34, 35]. Systemic exposure from the absorption ulcers, but the less common exposures outlined in of nickel in the area of the dermatitis was thought to Table 2 should be kept in mind. In a controlled study, explain the clinical picture. Recently, it has been doc- Isaksson [31] showed that some budesonide-sensitive umented that avoidance of prolonged skin contact patients react to the inhalation of budesonide. Inha- lation of budesonide caused angioedema in one con- tact-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 aller- gy to medicaments. Systemic contact dermatitis can be caused by the cross-reactivity of certain medica- ments. Corticosteroids can cause anaphylactoid-like 16 reactions [33].

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 Fig. 3. Edematous eruption of the eyelid and dermatitis where spectacle frames touched the facial skin after oral challenge Cross-reactivity with 2.5 mg nickel 16_295_308* 05.11.2005 10:27 Uhr Seite 299

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with nickel-releasing alloys results in a statistically with an oral dose of 5.6 mg nickel. Of the 12 patients, significant decrease in the frequency of hand eczema 9 reacted with systemic contact dermatitis after an in nickel-sensitive individuals [36]. It has also been average of 8 h. These patients had the symptoms list- shown that following the adoption in Denmark of a ed in Table 1, in particular, vesicular hand eczema regulation prohibiting the use of nickel in clothing or (Fig. 1). The results of this study have been repeated jewelry, a previously identified statistical association and confirmed by several authors [6, 12]. The evi- between nickel sensitivity and hand eczema no long- dence for immunological specificity includes flare- er exists [37]. up reactions at previous nickel contact sites, for ex- The study of orally provoked flare-ups of nickel ample under metal spectacle frames (Fig. 3). Such a dermatitis was pioneered by Christensen and Möller reaction was seen under previous sites of suspender [9], followed up by Kaaber et al. [38, 39], and Veien et nickel dermatitis in a woman who had not used gar- al. [40]. In a double-blind study, Christensen and ter belts containing nickel for over 30 years (Fig. 4). Möller [9] provoked 12 nickel-sensitive individuals 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 chal- lenge 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-con- trolled challenge with 2.5 mg nickel, this nickel-sensitive patient developed discrete, very pruritic, vasculitis-like lesions on the forearms and thighs 16_295_308* 05.11.2005 10:27 Uhr Seite 300

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The above-mentioned studies illustrate that few whether dietary restriction should be continued. patients react to a dose of less than 0.5 mg nickel giv- Clinical studies suggest that approximately one- en as a single oral dose, while the majority of patients quarter of selected patients benefit from prolonged react to a dose of 5 mg or more. Dose responsiveness dietary treatment [54, 55]. 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]. Core Message Systemic nickel dermatitis has been seen following accidental intravenous exposure to micrograms of í A flare-up of dermatitis at a previously nickel [43–45]. Nickel released from dental braces positive patch test site or widespread [46–48] and from older types of orthopedic prosthe- eruptions may be seen after placebo- ses can cause systemic nickel dermatitis and/or loos- controlled oral challenge with nickel. ening of the prostheses [49, 50]. The daily ingestion of nickel from food varies from 150 to 500 µg and depends both on the type of food and the production environment of the individ- ual foodstuff. Foods with high nickel content include 16.5.2 Chromium and Cobalt whole-grain flour, oats, soybeans, legumes, shellfish, nuts, licorice, and chocolate [51]. Nickel may be Cobalt and chromium salts can provoke systemic leached from cooking utensils [52]. The amount of contact dermatitis [6, 56]. Dose–response studies nickel absorbed depends upon the concurrent intake with chromium suggest that a range from 0.05 mg to of other foodstuffs such as proteins and alcohol. Che- 14.2 mg potassium dichromate given as a single oral lating medicaments can interfere with nickel absorp- dose is appropriate. Chromium picolinate given as a tion and metabolism and in that way provoke nutritional supplement caused systemic contact der- systemic contact dermatitis. This has been well de- matitis in one person [57]. Only one study has been scribed for disulfiram (Fig. 6) [39]. made of cobalt-sensitive individuals. Four of six co- Dietary intervention is indicated for nickel-sensi- balt-sensitive patients with vesicular hand eczema tive patients with vesicular hand eczema or more had a flare of the dermatitis after placebo-controlled widespread systemic contact dermatitis, if the elimi- oral challenge with 1 mg cobalt given as 4.75 mg co- nation of nonoccupational as well as occupational balt chloride [58].The removal of chromium- and co- nickel exposure does not improve or clear the derma- balt-releasing dental braces or dietary restrictions titis. Dietary restriction following the guidelines by may help individual patients. Veien et al. [53] should be followed for 1–2 months, and the outcome at that time should determine

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Fig. 6. Symmetrical vesicular der- matitis of the periungual ar- ea in a nickel-sensitive per- son a few days after begin- ning treatment for alcohol dependence with disulfiram 16_295_308* 05.11.2005 10:27 Uhr Seite 301

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16.5.3 Gold [70]. This reaction was explained by an in cashew nut shells that cross-reacts with urushiols in Following the introduction of routine testing with poison ivy [71]. The oral hyposensitization of 20 patients sensitive gold sodium thiosulfate, a frequency of up to 10% Parthenium hysterophorus positive reactions has been seen among consecutive- to resulted in such severe ly patch-tested patients. Systemic contact dermatitis flares in 6 of them that hyposensitization had to be from gold in patients with rheumatoid arthritis treat- stopped. Fourteen other patients successfully com- ed with gold salts is probably common, as indicated pleted the hyposensitization procedure [72]. Systemic contact dermatitis has been seen in pa- by both clinical and experimental experience Myroxylon perei- [59–62]. tients sensitive to balsam of Peru ( rae) which contains naturally occurring flavors. Hjorth [73] observed systemic contact dermatitis in 16.5.4 Mercury balsam-of-Peru-sensitive patients who had eaten fla- vored ice cream and orange marmalade. Veien et al. Widespread eruptions, erythema-multiforme-like [74] challenged 17 patients sensitive to balsam of Pe- eruptions, and the baboon syndrome have been de- ru with an oral dose of 1 g balsam of Peru. Ten pa- scribed in mercury-sensitive patients exposed to tients reacted to balsam of Peru and one to a placebo systemic mercury. Exposure can be from the vapors (Fig. 7). released from a broken thermometer, from ho- Of 102 patients sensitive to balsam of Peru,8 react- meopathic drugs or the drilling of amalgam dental ed to coniferous benzoate and benzyl alcohol. All 8 fillings [21, 63–66]. had systemic contact dermatitis. Three had hand ec- zema, and three had widespread dermatitis [75]. In other studies, reduction of the dietary intake of Core Message balsams has been shown to improve the dermatitis of more than half of selected patients who were sensi- í Mercury-sensitive persons exposed to mer- tive to balsam of Peru [76–78]. cury vapors from a broken thermometer may develop baboon syndrome. Core Message

í Patients with contact sensitivity to balsam of Peru may develop systemic contact der- matitis from spices and other flavorings. 16.6 Other Contact Allergens Open studies indicate that diet treatment may be helpful. Most clinical and experimental studies of systemic contact dermatitis deal with either metals or medica- ments, but important anecdotal evidence suggests that systemic contact dermatitis may be caused by Members of the Compositae family of plants com- certain plants, spices, and preservatives [67]. monly cause allergic contact dermatitis. Systemic In a study of 42 patients with systemic contact contact dermatitis in this group of patients is easily dermatitis from Rhus, it was suggested that a toxic overlooked [79]. Sesquiterpene lactones are found in rather than an immunological reaction caused the food and herbal remedies containing laurel, chamo- symptoms. No information about patch test results mile, and goldenrod [80–83]. One of four patients was provided [68]. with contact allergy to lettuce had a flare of vesicular Kligman [69] attempted to hyposensitize persons hand dermatitis after oral challenge with lettuce, and with Rhus dermatitis by giving increasing oral doses one of ten reacted to feverfew [79]. of the allergen. Half of the moderately to severely sensitive patients developed either pruritus or a rash; Core Message 10% of the patients experienced flares of their der- matitis at sites of previously healed contact derma- titis. Flare-ups of vesicular hand eczema and erythe- í Herbal remedies such as laurel, chamomile, ma multiforme were rare. Perianal pruritus occurred and goldenrod contain sesquiterpene in 10% of the highly sensitive individuals. Severe lactones and may cause systemic contact systemic contact dermatitis has been described in dermatitis in sensitized persons. Rhus-sensitive patients who had eaten cashew nuts 16_295_308* 05.11.2005 10:27 Uhr Seite 302

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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

Garlic tablets caused a flare of vesicular hand eczema change with time [12] and can be influenced by sex in a 58-year-old man with a positive patch test to gar- hormones and the development of tolerance. It is im- lic. A double-blind oral challenge was positive, and portant to recognize that this area of research is ex- the dermatitis resolved when the garlic tablets were tremely complex and that much well-controlled re- discontinued [84]. Periorbital and flexural dermatitis search is still needed. were seen in another garlic-sensitive person after the ingestion of garlic [85]. Core Message The antioxidant butylated hydroxyanisole (BHA), used both in cosmetics and in foods, can cause systemic contact dermatitis [86] as can the preserva- í Systemic contact dermatitis in nickel- tive sorbic acid [87–89]. sensitive patients is complex. Reactions Systemically aggravated contact dermatitis has may vary with individual sensitivity to been caused by aluminum in toothpaste in children nickel, with bioavailability, with interaction sensitized to aluminum in vaccines [90]. with other food items or medicaments. Reactions may also be influenced by sex hormones and the development 16 16.7 Risk-Assessment-Oriented Studies of tolerance.

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 Well-controlled oral challenge studies can be carried as metals and naturally occurring flavors. In spite of out with medicaments in sensitized individuals. The intensive research on the significance of orally in- beta-adrenergic blocking agent alprenolol is a potent gested nickel in nickel-sensitive individuals, we are contact sensitizer. Ekenvall and Forsbeck [91] identi- unable to give firm advice concerning the oral dose fied 14 workers employed in the pharmaceutical in- that would represent a risk for the wide range of dustry who were contact sensitized to this com- nickel-sensitive individuals. Many variables, such as pound. Oral challenge with a therapeutic dose the route of administration, bioavailability, individu- (100 mg) led to a flare-up in one worker who devel- al sensitivity to nickel, interaction with naturally oc- oped pruritus and widespread dermatitis. curring amino acids, and interaction with medica- The preservative Merthiolate (thimerosal) is wide- ments, must be considered. A number of as yet un- ly used in sera and vaccines. Förström et al. [92] in- known factors could influence nickel metabolism. vestigated 45 thimerosal contact-sensitive persons to Furthermore, immunological reactivity to nickel can evaluate the risk of a single therapeutic dose of 0.5 ml 16_295_308* 05.11.2005 10:27 Uhr Seite 303

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of a 0.01% Merthiolate solution given subcutaneous- systemic contact dermatitis seen in clinical practice ly. Only 1 of the 45 patients developed a systemic con- is low compared to the number of patients with aller- tact dermatitis reaction. Aberer [93] did not observe gic and irritant contact dermatitis [97]. In spite of the any reactions in a similar study involving 12 patients. fact that systemic contact dermatitis is relatively rare, Maibach [94] studied a group of patients who had it is important to identify this type of reaction to pro- discontinued the use of transdermal clonidine be- vide optimal management of the individual patient. cause of dermatitis.Of 52 patients with positive patch The diagnosis rests on the history of the patient, tests to clonidine, 29 were challenged orally with a patch testing, and oral challenge and elimination therapeutic dose of the substance. Only one patient studies. Severe reactions are unusual. Anaphylactic reacted with a flare-up at the site of the original der- reactions following the administration of corticos- matitis. teroids have been described [33]. 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 con- 16.9 Case Reports tact-sensitized individuals with 2–15 ml propylene glycol. Eight reacted with exanthema 3–16 h after the ingestion. Case Report 1 The overall impression of these studies is that systemic contact dermatitis in patients sensitized to a particular medicament is rare when the same pa- í A 37-year-old woman had had severe tients are exposed to a therapeutic systemic dose of anogenital dermatitis for 3 years (Fig. 8). the medicament.Gold may constitute an exception to She had previously been treated by her this general impression. gynecologist who had found no explana- tion for the dermatitis. The result of various topical treatments Core Message was unsatisfactory. Patch testing showed a ++ reaction to nickel. She had no memory í Although systemic contact dermatitis of rashes under cheap jewelry or other to medicaments given in therapeutic doses nickel items. 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 for- maldehyde, 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 chal- lenge studies with medicaments, a relatively high dose of the hapten is needed to produce systemic Fig. 8. Edematous anogenital dermatitis in a nickel-sensitive contact dermatitis. The number of patients with patient prior to initiation of a low-nickel diet 16_295_308* 05.11.2005 10:28 Uhr Seite 304

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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 instruct- ed 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 choco- late, known to contain significant amounts of nickel.

Case Report 2

í Fig. 9. The same patient as in Fig. 8 after 2 months on a low- A 43-year-old woman was seen because of nickel diet 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 in- structed 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 vesicu- lar hand eczema after a weight-reducing diet that in- cluded foods with a high nickel content 16_295_308* 05.11.2005 10:28 Uhr Seite 305

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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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