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Clinical-Epidemiological Features of Nickel Hypersensitivity Adone Baroni2*, Marco Adriano Chessa2, Vincenzo Piccolo2, Giovanna Donnarumma1 and Brunella Perfetto1 1
Dipartimento di Medicina Sperimentale: Sezione di Microbiologia, II University of Naples; Dipartimento Multidisciplinare di Specialità Medico-Chirurgiche e Odontoiatriche” II University of Naples 2
Abstract: Nickel is a chemical element found ubiquitously in the environment and is used with a high frequency worldwide. Nickel hypersensitivity could give rise both to contact dermatitis and to systemic contact dermatitis, the latter, as expression of ingestion or other systemic exposure to a contact allergen. The common clinical presentation of nickel allergic contact dermatitis (ACD) is more often a vesicular pruritic dermatitis in sites of prolonged skin contact with nickel-containing items. Patients can develop acute (bright red rash, edema and vesicle), subacute (less erythematous and edematous lesions, minimal vesiculation, and excoriation) and chronic manifestations (fissuring, scaling, excoriation and mild form of erythema). Systemic contact dermatitis is induced in sensitized individuals when they are exposed to a hapten systemically. In the detection of contact allergy, and in the diagnosis of ACD, patch test is the generally accepted method of choice and the “gold standard”. Their execution increases the probability of correct diagnosis, shortens the time lapse between first visit and final diagnosis, increases the chance for full remission, and reduces therapy costs. Management of nickel allergy is still complex for dermatologists. Between 1994 and 2009, nickel allergy showed a decreased in morbidity; however, after 2000, there was no significant decrease. Exposure to nickelcontaining products exceeding the permitted limit may explain the high persistence of nickel contact allergy in population. In 2001 the European Union, to reduce the exposure to nickel, introduced standards for the productions of tools intended for prolonged skin contact.
Keywords: Allergy, hypersensitivity, metal ions, nickel, nickel dermatitis, secondary eruption, RCLM. INTRODUCTION During the 20th century, due to human activity in consumer products and industrialization, incidence of skin dermatitis related to metals has been increasing. Metal compounds are usually divided by chemical experts as soluble or insoluble. Their solubility in sweat, however, is generally not specified but it has great importance for developing of an allergic contact dermatitis [1]. A few metals, such as nickel, cobalt and chromium, are clinically relevant allergens causing allergic contact dermatitis. *Address correspondence to this author at the Dipartimento Multidisciplinare di Specialità Medico-Chirurgiche e Odontoiatriche, Faculty of Medicine and Surgery, II University of Naples, Via Pansini 5, Naples, Italy; Tel: +39-0815666833; Fax: +39-0815468759; E-mail:
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Nickel is a very common metal that occurs in soil, water, air and in the biosphere. Nickel was discovered in 1751 by Baron Axel Frederik Cronstedt in mineral niccolite and since then it has been widely used in many fields because of its excellent resistance to oxidation. In 1889 nickel allergy was correlated, for the first time, with occupational exposure [2]. In 1925, patch testing to diagnose contact hypersensitivity to nickel was first performed by Schittenhelm and Stockinger [3]. Contact dermatitis to nickel ranks among the most common causes for patients to visit a dermatologist, for this reason nickel was named the ‘‘Contact Allergen of the Year’’ in 2008 by the American Contact Dermatitis Society [4]. Human exposure to nickel can occur through contact with the skin due to occupational or consumer exposure, via inhalation and also ingestion. Significant amounts of nickel may everyday inter© 2014 Bentham Science Publishers
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act with the human body causing adverse health effects [5]. Two types of dermatitis, caused by substances coming in contact with the skin, can appear: irritant contact dermatitis and allergic contact dermatitis. Irritant contact dermatitis is a nonspecific response of the skin to direct chemical damage and may be induced in any person if a sufficiently high concentration is used; the effect, usually, is evident within minutes, and previous exposure is not necessary. Conversely allergic contact dermatitis results when an allergen comes into contact with previously sensitized skin and it is due to type IV hypersensitivity also called delayed type hypersensitivity. In addition when a sensitized individual is exposed to the nickel systemically (per os, respiratory, or parental) it could be observed a systemic contact dermatitis, caracterized by a generalized eczematous skin reactions, dyshidrotic hand eczema or the “baboon syndrome”. The possibility of the metal ions to induce an allergic reaction depends upon their concentration, the extention of the exposed skin area and the duration of the exposure [6]. The concentration of ions developed is dependent on the rate of the alloy reaction, the geometric configuration, the supply of sweat and its composition [6]. Moreover the sensitization and induction nickel hypersensitivity is related to the amount of nickel per unit area present in the epidermis and the unit used for the quantification of the exposure is μg/cm2 [1]. The opportunity of nickel to be released from consumer products has been reported in numerous studies [7, 8]. Several laboratory tests of different materials containing nickel have been realized and nickel release rates have been assessed [9]. Based on this researches, a nickel release limit of 0.5 mg/cm2/week was proposed as a opportune safe practical compromise. In sensitized individuals alloys releasing less than this amount will therefore only rarely cause dermatitis, whereas alloys releasing more than 0.5 mg/cm2/ week are prone to elicit allergic cutaneous reactions [10, 11]. EPIDEMIOLOGY Nickel hypersensitivity is very frequent, and its prevalence continues to increase [12]. The prevalence of patients with nickel dermatitis, previously, was derived from number of patients receiving medical treatment, but the clinical cases seen by
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clinical practioners only represent the most severe and problematic cases. In addition the prevalence of nickel allergy is generally between 15 and 25% while contact allergy to most other allergens is between 2 and 4% [1]. Nickel allergy is more frequent in women than in men and it is the most usual cause of contact dermatitis in women and children [13-16]. Even if all age groups are affected, the prevalence of nickel sensitivity among females tends to rise from 10 years of age onwards [17]. This difference is due, probably, to the use of nickel-containing items in younger people, as well as ear piercing and jewelry [18]. The prevalence of nickel allergy had a significant increase between the 1966s and 2007s [19]. In 2001, the EU, to reduce prevalence of nickel contact dermatitis, according to Menne et al. imposed limits on the amount of nickel up to 0.5 μg/cm2 per week from items intended for prolonged skin contact [20]. Northen European governments introduced this restriction 10 years before the EU nickel directive, and a decrease in nickel allergy has been just observed in young Danish women from the general population [21]. Despite the new legislation, the prevalence of nickel allergy has remained high in Europe and Italy, in particular, is a leading country in Europe for the prevalence of individuals suffering from nickel allergy (32.1%) [22]. Thyssen et al. identified the probable explanation for this phenomenon: infraction and lack of supervision by the governaments, and also a sensitization before the EU directive. RISK FACTORS INFLUENZING THE DEVELOPMENT OF NICKEL CONTACT DERMATITIS The cutaneous barrier modification in atopic dermatitis promotes an increase penetration of chemical agents favoring contact dermatitis [23, 24]. Mutations in the filaggrin gene could facilitate sensitization to nickel [25]. Presence of heterozygous nonfunctional filaggrin mutations may contribute to a particular subtype of chronic hand eczema which is characterized by a combination of irritant and allergic aspects [26]. Beyond atopy, stasis dermatitis secondary to venous insufficiency has been correlated with development of nickel hypersensitivity [27]. Genetic factors may play a limited role in the development of nickel allergy,
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whereas environmental factors are more important [28]. Jewelry and ear piercing are the most common inducers of nickel allergy. In several studies, a clear relationship between ear piercing and nickel sensitization has been found [29-31]. In northern Norway it was showed the prevalence of nickel allergy in women was 27.5% and in men 5.1%, with a clear relationship in women to the number of earlobe piercings [15]. Recently, piercing has gained increasing popularity worldwide, through all social classes. Besides pierced ear lobes, piercing of lip, tongue, nasal, umbilicus, teat and genitalia, are quite common, especially among adolescents and young adults [12, 32]. Ehrlich et al. recently showed metal sensitization in 4% of males without piercing compared with 11.1% in males with 1 piercing and 14.6% of men with more than piercing [33]. Nickel exposure today is primarily related to the individual job rather than to exposures in specific industries. The sources of occupational nickel allergy are immense [34]. A multifactorial analysis has shown that metal furnace operators, metal finischers, cosmetologists, electroplaters, construction workers and hairdressers had a prevalence ratio of nickel hypersensitivity greater than 1.0 compared with a reference group of household workers [35, 36]. The North American Contact Dermatitis Group, considering data obtained during 19942000, showed that 8% of hand contact dermatitis to nickel were occupationally relevant [37]. A recent study revealed a significant association between smokers and nickel allergy [38]. In addition nickel inhaled could induce nickel sensitization [39]. Quantitative studies point out that repeated exposure to occluded metal items releasing nickel at a rate greater than 0.5 μg/cm2/week involves a significant risk of nickel sensitization [11]. Transient but potentially frequent and repeated exposure may occur from thimbles, keys, headsets, knitting needles, scissors, scouring pads, mobile phones [40, 41], handling coins, and other metallic tools. Most silver coins, including the new 1 and 2 euro coins, contain nickel [42], but the amount of nickel released from coins during normal handling is not sufficient to provoke a dermatitis [43, 44]. Conversely several studies showed that a substantial
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amount of nickel is deposited onto the skin by handling of the coins, and it may lead to a reaction in nickel-sensitized individuals [45, 46]. The majority of the world’s population live in countries where coins release nickel, as determinated with the colorimetric dimethylglyoximem (DMG) spot test, while other countries only use coins from which no nickel is released [47]. Furthermor risk of nickel allergy varies between different anatomical sites: head, neck and hands are associated with the hightest risk [36]. Systemic exposure may take place from the diet. Nickel in soil and water is taken up by living organisms, plants and animals, that are food sources for humans. Some plants and foods contain much higher concentrations than others, as particular sources of domestic water [48]; however the nickel content in food is strongly influenced by the concentration of nickel in the soil (ranging between 5 and 500 μg/gr) and water (between 5 and 100 μg/litre) which varies from place to place [49]. There are differences from region to region depending on the type of soil, the use of fertilizers and pesticides, soil pollution correlated to industrial and urban waste, and proximity to nickel foundries [50]. The introduction of substantial amounts of nickel with diet in a nickel-sensitive individual can favour dermatitis such as hand eczema [51]. Hypothetically artificial joints, containing metals, could determine nickel allergy hypersensitivity leading to metal joint replacement failure. In several reviews is reported that the prevalence of metal hypersensitivity was almost 25% among patients with a well-functioning hip arthroplastic implant and 60% among patients with a failed implant [52, 53]. In the late 1990 an experimantal study realized in Seattle demostrated that eleven patients who were nickel patch-test negative before surgery became positive after insertion of a metal implant, and four who were positive initially were patchtest negative postoperatively [54]. In addition other dermatitis temporally associated with joint replacement have been reported [55, 56]. The more relevant question is whether metal allergy screening should be performed prior to device implantation [57]. In Europe individuals without a reported history of metal allergy are not screened routinely conversely in the United States
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some patch testers consider pre-implant patch testing helpful [58, 59]. Percutaneous coronary revascularization procedures, realized with intracoronary stents mostly made from 316L stainless steel which contains metal nickel, chromium, molybdenum and manganese, are performed annually world wide [12]. Recently, Koster et al. supposed that a delayed hypersensitivity reaction to nickel and molybdenum might be part of the inflammatory process and one of the triggering factors in the development of instent restenosis at 6 months [60]. Currently, it is still not clear how nickel or other metal allergy contributes to in-stent restenosis [61]. CLINICAL FEATURES Nickel allergy can appear with typically cutaneous signes, localized or systemic, but also extracutaneus. The anatomical location of primary sensitization, also called “primary eruption”, appears, usually, as eczematous area and it is related to metal contact sites with the skin such as the face and scalp from cell phones and hair clasps, the ears from earrings, the neck from necklaces, the wrists from watches and bracelets, the central back and upper chest from bra components, the central abdomen from studs and zips in trousers, and the dorsa of the feet from shoe buckles [17]. Patients can develop acute (bright red rash, edema and vesicle), subacute (less erythematous and edematous lesions, minimal vesiculation, and excoriation) and chronic manifestations (fissuring, scaling, excoriation and mild form of erythema). “Secondary eruption” or nickel systemic contact dermatitis (SCD) can lead to clinical variants, including eruptions at previous skin areas of contact dermatitis, vesicular hand eczema, and the “baboon syndrome” [62-64]. The SCD would appear in contact-sensitized individuals when they come into contact with haptens systematically (orally, intravenously, by inhalation, or by implants). Baboon syndrome is a generalized skin rash with peculiar involvement of the gluteal areas, the ano-genital region, eyelids, the upper inner surfaces of the thighs and the flexor surfaces. The peculiar involveent of the buttocks and the ano-genital area, likewise the colour, from dark purple to pink, give a similar appearance to the typical buttocks of
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baboons. The acronym SDRIFE (Symmetrical Drug Related Intertriginous and Flexural Exanthema) has also been proposed for this syndrome [65]. Maculopapular lesions and vasculitic skin rash can also appear, often in association with systemic symptoms such as diarrhea, fever, arthralgia, headache, and malaise [24, 26]. In addition pustular and erythema multiforme-like lesions have been described after nickel exposition [24]. In patients with nickel allergy a systemic allergic contact dermatitis was for the first time experimentally induced by Christensen and Möller [67]. Furthermore it is currently accepted that the number of reacting nickel-sensitive persons and the severity of the reaction after exposure increase with higher exposure doses. In order to determine the best possible threshold values for oral nickel exposure, which would elicit allergic contact dermatitis in nickel-sensitive individuals, a modified meta-analysis has been realized combining the data from published oral exposure studies. Its main results showed that 1% of patients with allergy to nickel would get a SCD to the nickel content of a normal diet (i.e., 0.22-0.35 mg nickel), whereas 10% of patients would react to an exposure of 0.55 to 1.33 mg nickel, which could be obtained consuming food with high level of nickel [68]. Undoubtedly the severity of nickel dermatitis is related to how early the condition is diagnosed, whether quickly direct and prolonged skin contact from metal items is avoided, and furthermore whether occupational nickel contact can be minimized. PATHOGENESIS The dermatologist Stephan Rothman has first been described in 1930 a case report on an allergic contact hypersensitivity to metal ions [69]. He deduced that the metal ions itself were the trigger factor for the reaction and stated “obviously only those soluble metal amounts in contact with the skin are allergenic”. They are the metal ions solubilized by body fluids such as sweat that cause nickel allergy [70]. The immunological pathogenesis of contact allergies is represented by activation of antigen-specific T lymphocytes that characterize type IV hypersensitivity reaction resulting clinically in a cutaneous inflammation [70].
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Contact allergens usually could be haptens or half antigens, which can activate the immune system when bound by endogenous proteins [70]. ACD can be subdivided into two consecutive steps: the sensitization phase and the elicitation phase. During the sensitizing contact, the hapten binds to proteins in the skin, altering their antigenic specificity, and the newly created antigens, through their proinflammatory properties, are able to induce the recruitment, migration and maturation of cutaneous dendritic cells (DCs) [71]. Hapten-bearing DCs from the skin migrates in the para-cortical area and activates specific CD8+ and CD4+ T lymphocytes [72]. T cells proliferate and emigrate out of the lymph nodes (LNs) to the blood where they re-circulate between the lymphoid organs and the skin. This first step has no clinical consequence in the majority of cases. Upon re-exposure, the elicitation phase, characterized by diffusion of haptens into the skin where thay are taken up by skin cells, commences and specific T lymphocytes are activated in the dermis and the epidermis [73]. Subsequently T cells, together with neutrophils, macrophages, and skin cells, infiltrating at sites of contact, elicit the cutaneous inflammation characterized by erythema, tissue edema, vesicles, scaling and excoriation. Ni2+ between more than 3,000 known contact allergens [74], is considered the prime example of contact allergen that is capable of activating directly both innate immune responses and adaptive Tcell responses and thereby deliver activation signal which mediate the recruitment, migration and maturation of Langerhans cells (LCs) and DCs. [75]. Further experiments revealed that Ni2+ induces the activation of a conserved proinflammatory pathways in endothelial cells, such as expression of the surface adhesion molecules VCAM1, ICAM1, and E-selectin, and elicits global gene expression patterns overlapping with those triggered by the proinflammatory cytokine TNF-α [70]. Otherwise weak allergens are not enable alone to stimulate activate innate immune response and it is due to their small size, but, by binding to proteins, they form a hapten-carrier complex which is immunogenic [76]. A recent study demostrated that expression of Toll-like receptor (TLR) 2 or TLR4 on DC and IL-12 signaling were involved for generation of allergen-specific T cells [77]. Moreover was also found that lipopolysaccharide (LPS) activates innate immunity via (TLR)
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4, and promotes Ni allergy during both the sensitization step and the elicitation step. For instance a bacterial infection through LPS+ can induce Ni2+ allergy with a lower concentration of Ni2+ [78]. It is also imaginable that genetic polymorphisms might be present in the (TLR) 4 gene that regulate its activity and/or the binding efficiency for Ni2+ therewith influencing the susceptibility of certain persons for Ni2+-induced ACD [70]. TLR signaling, Ni2+ itself and LCs can act coordinately to promote the release of proinflammatory cytokines including production of TNFa and IL-1 β from keratinocytes and LCs, respectively [79]. Both these cytokines inhibit expression of certain chemokine receptors such as CCR1 and CCR5 on the LC cell membrane and they play a decisive role for the migration of LCs to the dLN during sensitization [80]. In addition keratinocytes and LCs, activated by IL-1 β and TNFα, secrete matrix metallo-proteinase (MMP) 3 and 9 that cleave certain proteins at the dermoepidermal junction [81, 82]. Finally signals from TNFα and IL-1 β change immature LCs to professional APCs by inducing up-regulation of expression MHC class II and I and down-regulation of Fc-receptors, and blocking the intracellular machinery which controls macropinocytosis and phagocytosis [83]. Moreover some differences in intensity inflammatory reaction could be due to rapid up-regulation of IL-1 β, IL-6, and IL-10 by skin cells exposed to strong haptens and to differential production of pro and anti-inflammatory cytokines [84]. All these cytokines, undoubtedly, play a fundamental role in the sensitization, elicitation and resolution phases of experimental contact hypersensitivity reactions [75]. In a recent study the expression of IL-1 β, IL-1R α, IL-36 α, IL-36 β, IL-36 γ and IL-33 was found significantly higher in involved and uninvolved skin of ACD patients than in skin from normal donors. By contrast, the expression of the anti-inflammatory IL36Ra cytokine in involved and uninvolved skin did not differ from that in control skin [85]. In the final step, hapten-induced inflammation recruits activated effector T-cells back to the initial site of antigen, and IL-17, IL-22 and IFN-γ are released by CD4+ T lymphocities that are very important effector cells in the nickel-induced ACD [86]. Although most people come into contact with nickel and are probably sensitized to nickel, only a few persons develop ACD. A controlled balance
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between initiation and down-regulation of the immune response is important to maintain immune homeostasis. When this balance is perturbed by the dysregulation of professional suppressor/regulatory T cells, allergic diseases can develop as an effect of an exaggerated immune response against innocuous non-self antigens. In fact immune response in the skin has regulatory mechanisms to avoid immunopathologic reactions to haptens [1]. Rustemeyer et al. established that in actively tolerized individuals there was a highest nickelspecific IL-10 production [87]. IL-10-producing T regulatory-1 cells play an important role in limiting the immune system and thus the tissue damage [88]. Currently, a subset of CD4+ T reg cells constitutively expressing CD25 (the α-chain IL-2R alpha) has been identified in both mice and humans. They are anergic to stimulation and can control proliferation and cytokine production of CD25- T cells [89]. Thus CD25+ T cells regulate nickel-specific T cell responses in healthy persons [90]. If CD4+ CD25+ regulatory lymphocytes are depleted nickel-specific CD4+CD25– T cells could be strongly increased. Conversely when CD4+CD25+ regulatory cells are present with CD4+CD25– effector cells, nickel-specific response is suppressed [91]. EXPOSURE TO NICKEL AND DIAGNOSIS The process of barrier diffusion by metal is very complex and it is related to exogenous factors, such as dose molecular volume, counter ion, protein reactivity, tissue deposition and time of application, but also to endogenous factors, such as age of skin, anatomical site, homeostatic controls, oxidation and reduction of xenobiotics in the skin [92]. However nickel which is present on the nails and in skin could be a applicable parameter to define the amount of metal exposure. Peters et al. pointed out a substantial difference in the nail concentrations in different occupational groups [93]. Recently Staton and Lidèn developed two new methods to determine level of nickel on the skin. On one hand the Staton method is used for the evaluation of nickel levels in occupational exposure situations: in this procedure workers, handling nickel-releasing coins, dip their fingers
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into tubes of extractant; then it is achieved an assesment of the amount of nickel in the water using inductively coupled plasma-optical emission spectrometry after stabilization with nitric acid [94]. On the other hand Lidén method in patients with occupational hand eczema caused by nickel provides for the use of acid wipe sampling by cellulose wipes with 1% nitric acid to determine nickel deposition [95]. Subsequently, a chemical analysis with inductively coupled plasma mass spectrometry is performed and the expression of results is in terms of μg/cm2 [95]. Additionally, the DMG test result is able to identify items that release an excessive amount of nickel; the DMG test was lately validated and is characterized by a high specificity (98%) but a moderate sensitivity (59%) [96]. Some metals, producing other colours than the pink produced by nickel, may hide a weakly positive result [97]. Epicutaneous patch testing is a deceptively simple office procedure to diagnose metal allergy. Schittenhelm and Stockinger achieved the first patch test with nickel sulfate [98]. Today patch test series are practiced with nickel sulfate 2.5% and nickel sulfate 5% in petrolatum in North America and Europe, respectively. The main benefits of patch tests are that they can be realized without hospital surveillance since adverse events have occurred rarely. More than 3,000 chemicals are known to cause ACD [74] but, thankfully, a small percentage of these accounts for a large percentage of cases of ACD [98]. The clinician, before applying the patch tests, should ask questions about exposures both at home and at work, and try to understand the mechanics of the work environment. The medical history and physical examination of a patient with probable allergic contact dermatitis would suggest the causative allergens; however unsuspected allergens are often responsible of the dermatitis. The Thin-Layer Rapid Use Epicutaneous (TRUE) test system consists of 3 panels containing 29 or more allergens or allergen mixes that are well-known causes of contact dermatitis [98]. The number of allergens of TRUE test are continuing on expanding in order to increase diagnostic sensitivity. Only 25 to 30 percent of patients with ACD are completely diagnosed with the TRUE test and 50 percent of allergens causing occupational dermatitis are missed [99]. For this reason referral centers
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with patch test clinics routinely use an “expanded” series of 60+ allergens such as the North American Contact Dermatitis Group (NACDG) screening series. On the other hand the physicians, to prevent severe irritation such as a burn or ulceration, should be aware of the chemical ingredients of the product and avoid to apply unknown chemical substance [100]. There are helpful guides for determining appropriate patch test concentrations for numerous chemicals [74]. Before testing, the patient should avoid taking oral glucocorticoids topically or systemically, macrolactams and ultraviolet radiation for at least a week because may suppress positive reactions; conversely antihistamines can be prescribed, as they will not affect the outcome of the testing. Each chemical is applied to a disc, about 1cm in diameter and then taped on the back in strips of 10. After allergen selection has been finalized, appropriate technique is necessary to ensure adequate testing. The patches are usually removed after 48 hours, as recommended by the International Contact Dermatitis Research Group, however there is an overall agreement that this reading is insufficient. For this reason an additional reading could be also done 72 and 96 hrs after removal of the strips [101]. In fact one common preventable cause of false-negative reactions is the failure to perform a second reading of the test sites after the initial 48-hour inspection [99]. Any positive reactions are scored according to the International Grading System. Then the positive reactions are compared with current products that the patient uses in his work and home environment in order to divide products into two groups: those that are free of the suspected allergen(s) and are safe to use, and those that contain these chemical(s) and should be avoided [100]. False-negative reactions may also occur because nickel ions penetrate the skin only very slowly [102]. In contrast, patients with atopic dermatitis (AD) may develop false positive reactions with a deep erythema and pustulation. In fact, individuals with AD have an epidermal expression deficiency of filaggrin, which would favor an increase of nickel in the epidermis promoting sensitization to nickel [103]. In cases of doubt, intracutaneous testing with 1 mol/L nickel sulphate in saline could be used to clarify the situation [104]. False-negative reactions can also occur when the allergen is used in too low concentration per unit
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area of skin. For this reason, through experimental studies, the conventional concentration threshold to react is 1.5 mg/cm2 in open testing and 0.5 mg/cm2 in closed applications [105, 106]. The reading of patch tests is closely related to the experience of the observer and their interpretation, particularly for weak positive (+/–) and doubtful reactions, remains difficult. Patch test techniques are simple but must be learnt and mastered properly [107]. Reflectance confocal laser microscopy (RCLM) has been used to image human skin without tissue or destruction of the skin. The measured lateral resolution is 0.5±1 mm and the axial resolution and optical section thickness is 3±5 mm, this values are comparable with that of conventional histology. RCLM creates a virtual window into tissues and the resolution is provided by refractive index differences of organelles and other microstructures from the background [108]. Even if skin reactions to different metal allergens and related abnormalities in epidermal thickness are still not well understood with this diagnostic tool, RCLM could be used to assist in more accurate interpretation of the doubtful reaction to patch test [109]. On the other hand the diagnosis of Systemic Nickel Allergy Syndrome (SNAS), both cutaneous and extra-cutaneous is far more complex than the diagnosis of ACD. In fact to diagnose SNAS are not utilized patch test but provocation tests, such as oral test, that mimicking natural exposure [65]. THERAPY The best way to prevent the flare-up of ACD is the avoidance of exposure. When allergens are identified, the patient should be informated on all of these chemicals. The DMG test is helpful in nickel detection both in the occupational and domestic environment [24]. The sheets should be composed individually or obtained from books or website and copied for patient use [110]; specifically the American Contact Dermatitis Society website is an excellent resource for allergen and product information. The patient should also be instructed on how to read the labels of any new or old products not reviewed, in order to avoid future exposure.
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Barrier creams and gloves, applied before exposure, are also essential in the prevention and treatment of contact dermatitis. Agents like ion exchangers have been often added to creams to increase their protective efficacy, such as barrier creams contacting sodium EDTA or clioquinol [111, 112]. However, the regular, frequent and correct application of a protective cream is necessary to be effective [113]. Polyurethane coating of metal products could avoid direct contact with nickel [114]. Although the emollients and barrier creams are essential in the therapy of the contact dermatitis, topical corticosteroids are the cornerstone to control the predominant symptoms, expecially in patients with hand eczema; treatment with mometasone furoate cream is one of the most effective [115]. Furthermore when a very potent steroid is used such as clobetasol propionate risk of recurrence is reduced compared with a moderately potent preparation. In addition topical steroids may be alternated with topical calcineurin inhibitors such as tacrolimus and pimecrolimus in order to avoid tachyphylaxis [116]. Cyclosporin A, oral corticosteroids, azathioprine and mycophenolate mofetil are also prescribed “off-label” in treating severe hand dermatitis [117]. Moreover in multicenter trial was recently demonstrated that alitretinoin was efficacy in the treatment of severe chronic hand eczema refractory to topical corticosteroids [118]. In nickel-allergic individuals is recommended a selection of food with low nickel concentration to reduce dietary intake of the metal [49]. Metals in cigarettes are transported in tobacco smoke proportionally with their concentrations, increasing nickel intake in organism [119, 120]. Systemic therapy with disodium cromoglycate could be effective reducing nickel intestinal absorption [121]. Finally disulfiram is efficacy on treatment of hand eczema in individuals with nickel allergy. Disulfiram acts chelating nickel from the body tissue and favouring excrection mostly through urine and in small amount in bile and sweat [51]. Recall of dermatitis have been reported during this therapy even if the contactant is avoided, probably it is due to the initial mobilization of nickel [122]. CONFLICT OF INTEREST The author(s) confirm that this article content has no conflict of interest.
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ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9]
[10] [11] [12] [13] [14]
[15]
[16] [17]
[18] [19]
Liden C. Metals. In: Contact dermatitis Fifth edition 2011. Issue 35 pages 643-4 Blascho A. Die Berufsdermatosen der Arbeiter. Das Galvanisierekzem. Dtsch Med Wschr 1889; 15: 92527. Schittenhelm A, Stockinger W. Über die Idiosynkrasiegegen Nickel (Nickel krätze) und ihre Beziehung zur Anaphylaxie Z Ges Exp Med 1925; 45: 58-74. Kornik R, Zug KA. Nickel. Dermatitis 2008; 19: 3-8. Denkhaus E, Salnikow K. Nickel essentiality, toxicity, and carcinogenicity. Crit Rev Oncol Hematol 2002; 42: 35-56. Flint GN. A metallurgical approach to metal contact dermatitis. Contact Dermatitis 1998; 39: 213-21. Liden C, Carter S. Nickel release from coins. Contact Dermatitis 2001; 44: 160-5. Nestle FO, Speidel H, Speidel MO. High nickel release from 1- and 2-euro coins. Nature 2002; 419: 132. Jensen CS, Lisby S, Baadsgaard O, Byrialsen K, Menne T. Release of nickel ions from stainless steel alloys used in dental braces and their patch reactivity in nickel-sensitive individuals. Contact Dermatitis 2003; 48: 300-4. Haudrechy P, Mantout B, Frappaz A, et al. Nickel release from stainless steels. Contact Dermatitis 1997; 37: 113-7. Lidén C, Menné T, Burrows D. Nickel-containing alloys and platings and their ability to cause dermatitis. Br J Dermatol 1996; 134: 193-8. Schram SE, Warshaw EM, Laumann A. Nickel hypersensitivity: a clinical review and call to action. Int J Dermatol 2010; 49: 115-25. Peltonen L. Nickel sensitivity in the general population. Contact Dermatitis 1979; 5: 27-32. Nielsen NH, Menne T. Allergic contact sensitization in an unselected Danish population. The Glostrup Allergy Study, Denmark. Acta Derm Venereol 1992; 72: 456-60. Dotterud LK, Smith-Sivertsen T. Allergic contact sensitization in the general adult population: a population-based study from Northern Norway. Contact Dermatitis 2007; 56: 10-5. Sharma VK, Asati DP. Pediatric contact dermatitis. Indian J Dermatol Venereol Leprol 2010; 76: 514-520. Beck MH, Wilkinson SM. Contact Dermatitis. In: Burns T, Breathnach S, Cox N, Griffiths C, eds.Rook’s Textbook of Dermatology 7th edn. Oxford: Blackwell Publishing; 2004. 20.37- 20.41. Brandao MH, Gontijo B, Girundi MA, de Castro MC. Ear piercing as a risk factor for contact allergy to nickel. J Pediatr (Rio J) 2010; 86: 149-54. Thyssen JP, Linneberg A, Menné T, et al. The epidemiology of contact allergy in the general population–prevalence and main findings. Contact Dermatitis 2007; 57: 287-9.
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[20]
[21]
[22]
[23]
[24] [25]
[26]
[27]
[28] [29] [30] [31]
[32]
[33] [34] [35]
Clinical Immunology, Endocrine & Metabolic Drugs, 2014, Vol. 1, No. 2
Thyssen JP, Uter W, McFadden J, et al. The EU Nickel Directive revisited – future steps towards better protection against nickel allergy. Contact Dermatitis 2011; 64: 121-5. Thyssen JP, Linneberg A, Menne T, Nielsen NH, Johansen JD. The association between hand eczema and nickel allergy has weakened among young women in the general population following the Danish nickel regulation: results from two cross-sectional studies. Contact Dermatitis 2009; 61: 342-8. Uter W, Ramsch C, Aberer W, et al. The European baseline series in 10 European Countries, 2005/2006 – results of the European Surveillance System on Contact Allergies (ESSCA). Contact Dermatitis 2009; 61: 31-8. Baroni A, Buommino E, De Gregorio V, Ruocco E, Ruocco V, Wolf R. Structure and function of the epidermis related to barrier properties. Clin Dermatol 2012; 30(3): 257-62. Darlenski R, Kazandjieva J, Pramatarov K. The many faces of nickel allergy. Int J Dermatol 2012; 51(5): 523-30. doi: 10.1111/j.1365-4632.2011.05233.x. Novak N, Baurecht H, Schafer T, et al. Loss-offunction mutations in the filaggrin gene and allergic contact sensitization to nickel. J Invest Dermatol 2008; 128(6): 1430-5. Molin S, Vollmer S, Weiss EH, et al. Filaggrin mutations may confer susceptibility to chronic hand eczema characterized by combined allergic and irritant contact dermatitis. Br J Dermatol 2009; 161: 801-7. Jindal R, Sharma NL, Mahajan VK, Tegta GR. Contact sensitization in venous eczema: preliminary results of patch testing with Indian standard series and topical medicaments. Indian J Dermatol Venereol Leprol 2009; 75: 136-41. Schram SE, Warshaw EM. Genetics of nickel allergic contact dermatitis. Dermatitis 2007; 18: 125-33. Laumann AE, Derick AJ. Tattoos and body piercings in the United States: a national data set. J Am Acad Dermatol 2006; 55: 413-21. Mattila L, Kilpelainen M, Terho EO, et al. Prevalence of nickel allergy among Finnish university students in 1995. Contact Dermatitis 2001; 44: 218-23. Mayers LB, Chiffriller SH. Body art (body piercing and tattooing) among undergraduate university students: ‘‘then and now’’. J Adolesc Health 2008; 42: 201-3. Kaatz M, Elsner P, Bauer A. Body-modifying concepts and dermatologic problems: tattooing and piercing. Clin Dermatol 2008; 26(1): 35-44. doi: 10.1016/j.clindermatol.2007.10.004. Ehrlich A, Kucenic M, Belsito DV. Role of body piercing in the induction of metal allergies. Am J Contact Dermat 2001; 12: 151-5. Liden C. Nickel. In Kanerva L, Elsner P, Wahberg JE, Maibach HI, eds. Handbook of Occupational Dermatitis. Berlin: Springer, 2000: 524-33. Lidén C, Röndell E, Skare L, et al. Nickel release from tools on the Swedish market. Contact Dermatitis 1998; 39: 127-31.
[36] [37]
[38]
[39] [40]
[41] [42] [43] [44] [45]
[46]
[47]
[48] [49] [50] [51] [52] [53]
71
Uter W, Pfahlberg A, Gefeller O, et al. Risk factors for contact allergy to nickel – results of a multifactorial analysis. Contact Dermatitis 2003; 48: 33-8. Warshaw EM, Ahmed RL, Belsito DV, et al. Contact dermatitis of the hands: cross-sectional analyses of North American Contact Dermatitis Group Data, 1994-2004. J Am Acad Dermatol 2007; 57: 301-14. Thyssen JP, Johansen JD, Menne T, et al. Effect of tobacco smoking and alcohol consumption on the prevalence of nickel sensitization and contact sensitization. Acta Derm Venereol 2010; 90: 27-33. Mann E, Ranft U, Eberwein G, et al. Does airborne nickel exposure induce nickel sensitization? Contact Dermatitis 2010; 62: 355-362. Thyssen JP, Johansen JD, Zachariae C, et al. The outcome of dimethylglyoxime testing in a sample of cell phones in Denmark. Contact Dermatitis 2008; 59: 38-42. Jensen P, Johansen UB, Johansen JD, Thyssen JP. Nickel may be released from iPhone(®) 5. G Ital Med Lav Ergon 2012; 34(3 Suppl): 147-9. Jellesen MS, Hilbert LR, Menné T, Möller H. Nickelcontaining coins: a health risk for nickel-sensitive individuals? Br J Dermatol 2006; 155: 1301-2. Fournier PG, Govers TR Contamination by nickel, copper and zinc during the handling of euro coins. Contact Dermatitis 2003; 48: 181-8. Zhai H, Chew AL, Bashir SJ et al. Provocative use test of nickel coins in nickel-sensitized subjects and controls. Br J Dermatol 2003; 149: 311-7. Lidén C, Skare L, Vahter M. Release of nickel from coins and deposition onto skin from coin handling– comparing euro coins and SEK. Contact Dermatitis 2008; 59: 31-7. Thyssen JP, Gawkrodger DJ, White IR, Julander A, Menn´e T, Lid´en C. Coin exposure may cause allergic nickel dermatitis: a review. Contact Dermatitis 2013; 68: 3-14. Hamann CR, Hamann D, Hamann C, Thyssen JP, Lidén C. The cost of nickel allergy: a global investigation of coin composition and nickel and cobalt release. Contact Dermatitis 2013; 68(1): 15-22. doi: 10.1111/cod.12008. Lee AY, Lee YS. A case of allergic contact dermatitis due to nickel in underground water. Contact Dermatitis 1990; 22: 141-3. Sharma AD. Relationship between nickel allergy and diet. Indian J Dermatol Venereol Leprol 2007; 73: 307-12. Pecegueiro M. Contact dermatitis due to nickel in fertilizers. Contact Dermatitis 1990; 22: 114-5. Sharma AD. Disulfiram and low nickel diet in the management of hand eczema: A clinical study. Indian J Dermatol Venereol Leprol 2006; 72: 113-8. Basko-Plluska JL, Thyssen JP, Schalock PC. Cutaneous and systemic hypersensitivity reactions to metallic implants. Dermatitis 2011; 22: 65-79. Hallab N, Merritt K, Jacobs JJ. Metal sensitivity in patients with orthopaedic implants. J Bone Joint Surg Am 2001; 83-A: 428-36.
72
[54] [55] [56] [57]
[58]
[59] [60] [61]
[62] [63] [64]
[65] [66]
[67] [68]
[69] [70]
[71]
[72]
Clinical Immunology, Endocrine & Metabolic Drugs, 2014, Vol. 1, No. 2
Swiontkowski MF, Agel J, Schwappach J, et al. Cutaneous metal sensitivity in patients with orthopaedic injuries. J Orthop Trauma 2001; 15: 86-9. Kanerva L, Forstrom L. Allergic nickel and chromate hand dermatitis induced by orthopaedic metal implant. Contact Dermatitis 2001; 44: 103-4. Kubba R, Taylor JS, Marks KE. Cutaneous complications of orthopedic implants. A two-year prospective study. Arch Dermatol 1981; 117: 554-60. Wolf R, Orion E, Ruocco E, Baroni A, Ruocco V. Contact dermatitis: facts and controversies. Clin Dermatol 2013; 31(4): 467-78. doi: 10.1016/ j.clindermatol.2013.01.014. Schalock PC, Menne T, Johansen JD, et al. Hypersensitivity reactions to metallic implants - diagnostic algorithm and suggested patch test series for clinical use. Contact Dermatitis 2012; 66: 4-19. Bruze M. Thoughts on implants and contact allergy. Arch Dermatol 2008; 144: 1042-4. Koster R, Vieluf D, Kiehn M, et al. Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis. Lancet 2000; 356: 1895-7. Iijima R, Ikari Y, Amiya E, et al. The impact of metallic allergy on stent implantation: metal allergy and recurrence of in-stent restenosis. Int J Cardiol 2005; 104: 319-25. Sànchez-Morillas L, Reano MM, Rodriguez MM, et al. Baboon syndrome. Allergol Immunopathol (madr) 2004; 32(1): 43-5. Kolodziej T, Szepietowki JC, Sikora J, BialynickBirula R. The baboon syndrome due to nikel. Acta Dermatovenerol Croat 2003; 11(1): 29-31. Häusermann P, Harr TH, Bircher AJ. Baboon syndrome resulting from systemic drugs: is there strife between SDRIFE and allergic contact dermatitis syndrome? Contact Dermatitis 2004; 51(5-6): 297-310. Pizzutelli S. Systemic nickel hypersensitivity and diet: myth or reality? Eur Ann Allergy Clin Immunol 2011; 43(1): 5-18. Thyssen JP, Menne T. Metal allergy – a review on exposures, penetration, genetics, prevalence, and clinical implications. Chem Res Toxicol 2010; 23: 30918. Christensen OB, Möller H External and internal exposure to the antigen in the hand eczema of nickel allergy. Contact Dermatitis 1975; 1: 136-41. Jensen CS, Menne T, Johansen JD. Systemic contact dermatitis after oral exposure to nickel: a review with a modified meta-analysis. Contact Dermatitis 2006; 54: 79-86. Rothman S. Überempfindlichkeit gegen Hartgeld. Dermatol Wochenschr 1930; 2: 98-9. Schmidt M, Goebeler M. Nickel allergies: paying the Toll for innate immunity. J Mol Med (Berl). 2011 Oct; 89(10): 961-70. doi: 10.1007/s00109-011-07800. Epub 2011 Jun 23. Furio L, Guezennec A, Ducarre B, Guesnet J, PeguetNavarro J. Differential effects of allergens and irritants on early differentiating monocyte-derived dendritic cells. Eur J Dermatol 2008; 18: 141-47. Xu H, DiIulio NA, Fairchild RL. T cell populations primed by hapten sensitization in contact sensitivity
[73] [74] [75] [76]
[77]
[78]
[79] [80]
[81]
[82]
[83]
[84]
[85]
[86]
Baroni et al.
are distinguished by polarized patterns of cytokine production: interferon gamma- producing (Tc1) effector CD8+ T cells and interleukin (Il) 4/Il-10producing (Th2) negative regulatory CD4+ T cells. J Exp Med 1996; 183: 1001-12. Vocanson M, Hennino A, Rozieres A, Poyet G, Nicolas JF. Effector and regulatory mechanisms in allergic contact dermatitis. Allergy 2009; 64: 1699-714. de Groot A. Patch testing: test concentrations and vehicles for 4350 allergens. Patch Testing 3rd edition Acdegroot Publishing, Wapserveen, 2009. Christensen AD, Haase C. Immunological mechanisms of contact hypersensitivity in mice. APMIS 2012; 120: 1-27. Martin SF, Esser PR, Weber FC, et al. Mechanisms of chemical induced innate immunity in allergic contact dermatitis. Allergy 2011; doi:10.1111/j.13989995.2011.02652.x. Martin SF, Dudda JC, Bachtanian E, et al. Toll like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J Exp Med 2008; 205: 215162. Kinbara M, Sato N, Kuroishi T, Takano-Yamamoto T, Sugawara S, Endo Y. Allergy-inducing nickel concentration is lowered by lipopolysaccharide at both the sensitization and elicitation steps in a murine model. Br J Dermatol 2011; 164: 356-62. Kaplan DH, Igyártó BZ, Gaspari AA. Early immune events in the induction of allergic contact dermatitis. Nat Rev Immunol 2012; 12(2): 114-24. Cumberbatch M, Dearman RJ, Kimber I. Langerhans cells require signals from both tumour necrosis factor-alpha and interleukin-1 beta for migration. Immunology 1997; 92: 388-95. Lamberti M, Perfetto B, Costabile T, et al. In vitro evaluation of matrix metalloproteinases as predictive testing for nickel, a model sensitizing agent. Toxicol Appl Pharmacol 2004; 195(3): 321-30. Perfetto B, Lamberti M, Giuliano MT, Canozo N, Cammarota M, Baroni A. Analysis of the signal transduction pathway of nickel-induced matrix metalloproteinase-2 expression in the human keratinocytes in vitro: preliminary findings. J Cutan Pathol 2007; 34(6): 441-7. Kimber I, Cumberbatch M, Dearman RJ, Bhushan M, Griffiths CE. Cytokines and chemokines in the initiation and regulation of epidermal Langerhans cell mobilization. Br J Dermatol 2000; 142: 401-12. Bonneville M, Chavagnac C, Vocanson M, et al. Skin contact irritation conditions the development and severity of allergic contact dermatitis. J Invest Dermatol 2007; 127: 1430-5. Mattii M, Ayala F, Balato N, et al. The balance between pro- and anti-inflammatory cytokines is crucial in human allergic contact dermatitis pathogenesis: the role of IL-1 family members. Exp Dermatol 2013; 22(12): 813-9. doi: 10.1111/exd.12272. Dyring-Andersen B, Skov L, Løvendorf MB, et al. CD4(+) T cells producing interleukin (IL)-17, IL-22 and interferon-γ are major effector T cells in nickel allergy. Contact Dermatitis 2013; 68(6): 339-47. doi: 10.1111/cod.12043.
Clinical-Epidemiological Features of Nickel
[87]
Clinical Immunology, Endocrine & Metabolic Drugs, 2014, Vol. 1, No. 2
Rustemeyer T, Blomberg BME, Hoogstraten IMW, Bruynzeel DP, Scheper RJ. Analysis of effector and regulatory immune reactivity to nickel. Clin Exp Immunol 2004; 34: 1458-66. [88] Cavani A, Nasorri F, Prezzi C, et al. Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses. J Invest Dermatol 2000; 114: 295-302. [89] Taams LS, Smith J, Rustin MH, Salmon M, Poulter LW, Akbar AN. Human anergic/suppressive CD4(+) CD25(+) T cells: a highly differentiated and apoptosis-prone population. Eur J Immunol 2001; 31: 11221131. [90] Cavani A, Nasorri F, Ottaviani C, et al. Human CD25+ regulatory T cells maintain immune tolerance to nickel in healthy, nonallergic individuals. J Immunol 2003; 171: 5760-8. [91] Moed H, Von Blomberg BM, Bruynzeel DP, et al. Regulation of nickel-induced T-cell responsiveness by CD4+CD25+ cells in contact allergic patients and healthy individuals. Contact Dermatitis 2005; 53: 71-4. [92] Hostynek JJ. Factors determining percutaneous metal absorption. Food Chem Toxicol 2003; 41: 327-45. [93] Peters K, Gammelgaard B, Menné T. Nickel concentrations in fingernails as a measure of occupational exposure to nickel. Contact Dermatitis 1991; 25: 23741. [94] Staton I, Ma R, Evans N, et al. Dermal nickel exposure associated with coin handling and in various occupational settings: assessment using a newly developed finger immersion method. Br J Dermatol 2006; 154: 658-64. [95] Lidén C, Skare L, Lind B, et al. Assessment of skin exposure to nickel, chromium and cobalt by acid wipe sampling and ICP-MS. Contact Dermatitis 2006; 54: 233-8. [96] Thyssen JP, Skare L, Lundgren L, et al. Sensitivity and specificity of the nickel spot (dimethylglyoxime) test. Contact Dermatitis 2010; 62: 279-88. [97] Biesterbos J, Yazar K, Lid´en C. Nickel on the Swedish market: follow-up 10 years after entry into force of the EU nickel directive. Contact Dermatitis 2010; 63: 333-9. [98] James WD, Rosenthal LE, Brancaccio RR, Marks JG Jr. American Academy of Dermatology patch testing survey: use and effectiveness of this procedure. J Am Acad Dermatol 1992; 26: 991-4. [99] Belsito DV. Patch testing with a standard allergen (“screening”) tray: rewards and risks. Dermatologic Therapy 2004; 17: 231-9. [100] Jean L. Bolognia, Joseph L. Jorizzo, Julie V. Schaffer. Allergic contact dermatitis. In Dermatology 3rd Edition. Issue 14 pages 236-9. [101] Wolf R, Orion E, Ruocco V, Baroni A, Ruocco E. Patch testing: facts and controversies. Clin Dermatol 2013; 31(4): 479-86. doi: 10.1016/ j.clindermatol.2013.01.015. [102] Fullerton A, Anderson JR, Hoelgaard A, et al. Permeation of nickel salts through human skin in vitro. Contact Dermatitis 1986; 15: 173-7.
73
[103] Thyssen JP, Carlsen BC, Menné T. Nickel sensitization, hand eczema, and loss-of-function mutations in the filaggrin gene. Dermatitis 2008; 19: 303-7. [104] Möller H. Intradermal testing in doubtful cases of contact allergy to metals. Contact Dermatitis 1989; 20: 120-3. [105] Menné T, Calvin G. Concentration threshold of nonoccluded nickel exposure in nickel-sensitive individuals and controls with and without surfactant. Contact Dermatitis 1993; 29: 180-4. [106] Andersen KE, Lidén C, Hansen J, et al. Doseresponse testing with nickel sulphate using the TRUE test in nickelsensitive individuals. Multiple nickel sulphate patch-test reactions do not cause an ‘angry back’. Br J Dermatol 1993; 129: 50-6. [107] Nosbaum A, Vocanson M, Rozieres A, Hennino A, Nicolas JF. Allergic and irritant contact dermatitis. Pathophysiology and immunological diagnosis. Eur J Dermatol 2009; 19: 325-32. [108] Huzaira M, Rius F, Rajadhyaksha M, Anderson RR, Gonzalez S. Topographic variations in normal skin, as viewed by in vivo reflectance confocal microcopy. J Invest Dermatol 2001; 116: 846-52. [109] Sakanashi EN, Matsumura M, Kikuchi K, Ikeda M, Miura H. A comparative study of allergic contact dermatitis by patch test versus reflectance confocal laser microscopy, with nickel and cobalt. Eur J Dermatol 2010; 20: 705-11. [110] Marks JGJr, Elsner P, DeLeo VA. Standard allergens. In: Contact and Occupational Dermatology, 3rd edn. Philadelphia: Mosby, 2002, 139. [111] Wohrl S, Kriechbaumer N, Hemmer W, et al. A cream containing the chelator DTPA (diethylenetriaminepenta-acetic acid) can prevent contact allergic reactions to metals. Contact Dermatitis 2001; 44: 224-8. [112] Memon AA, Molokhia MM, Friedmann PS. The inhibitory effects of topical chelating agents and antioxidants on nickel-induced hypersensitivity reactions. J Am Acad Dermatol 1994; 30: 560–5. [113] Berndt U, Wigger-Alberti W, Gabard B, Elsner P. Efficacy of a barrier cream and its vehicle as protective measures against occupational irritant contact dermatitis. Contact Dermatitis 2000: 42: 77-80. [114] Moseley JC, Allen HJJr. Polyurethane coating in the prevention of nickel dermatitis. Arch Dermatol 1971; 103: 58-60. [115] English J, Aldridge R, Gawkrodger DJ, et al. Consensus statement on the management of chronic hand eczema. Clin Exp Dermatol 2009; 34(7): 761-9. [116] Sehgal VN, Srivastava G, Aggarwal AK, Sharma AD. Hand dermatitis/eczema: current management strategy. J Dermatol 2010; 37(7): 593-610. [117] English JS, Wootton CI. Recent advances in the management of hand dermatitis: does alitretinoin work? Clin Dermatol 2011; 29(3): 273-7. [118] Bissonnette R, Varjonen E, Holló P, et al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial. Br J Dermatol 2008; 158(4): 808-17.
74
Clinical Immunology, Endocrine & Metabolic Drugs, 2014, Vol. 1, No. 2
[119] Afridi HI, Kazi TG, Talpur FN, Brabazon D, Naher S. Estimation of toxic elements in the samples of different cigarettes and their impact on human health of Irish hypertensive consumers. Clin Chim Acta 2013; 426: 51-7. doi: 10.1016/j.cca.2013.08.023. [120] Fresquez MR, Pappas RS, Watson CH. Establishment of toxic metal reference range in tobacco from US cigarettes. J Anal Toxicol 2013; 37(5): 298-304. doi: 10.1093/jat/bkt021. Epub 2013 Apr 2.
Received: December 02, 2014
Revised: January 15, 2015
Accepted: January 30, 2015
Baroni et al.
[121] Pigatto PD, Gibelli E, Fumagalli M, et al. Disodium cromoglycate versus diet in the treatment and prevention of nickel-positive pompholyx. Contact Dermatitis 1990; 22: 27-31. [122] Zawar V, Nerlikar S. Dermatitis recall during disulfiram therapy. Indian J Dermatol Venereol Leprol 2004; 70: 33-5.
