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Exacerbation of pustulosis palmaris et plantaris after topical application of metals accompanied by elevated levels of leukotriene B4 in pustules
Exacerbation of pustulosis palmaris et plantaris after topical application of metals accompanied by elevated levels of leukotriene B4 in pustules Koichiro Nakamura, MD, PhD,a Sumihisa Imakado, MD, PhD,b Mitsuhisa Takizawa, MD,a Makoto Adachi, MD,a Makoto Sugaya, MD,a Motoshi Wakugawa, MD,a Akihiko Asahina, MD, PhD,a and Kunihiko Tamaki, MD, PhDa Tokyo, Japan Background: Pustulosis palmaris et plantaris (PPP) is a chronic inflammatory disease consisting of polymorphonuclear leukocyte infiltration, and is often exacerbated by focal infections such as tonsillitis. In some cases, metal allergy has been reported. Objective: The purpose of this study was to evaluate (1) the significance of metal allergy in the formation of pustules, and (2) the participation of leukotriene (LT) B4 in the formation of pustules of PPP. Methods: Patch tests with metals were performed on 7 patients with PPP, and both pustular and plasma levels of LTB4 were measured in these 7 patients before and 48 hours after metal patch tests. Results: Palmoplantar pustules were exacerbated after the metal patch tests in all 7 patients. The mean levels of LTB4 in plasma and pustules of the volar surface at 48 hours after the metal patch tests were significantly higher than those before the metal patch tests. Conclusion: Metals can be important in the pathogenesis of PPP by contributing to the induction of high LTB4 concentration in the pustules. (J Am Acad Dermatol 2000;42:1021-5.)
P
ustulosis palmaris et plantaris (PPP) is a chronic, relapsing inflammatory disease characterized by multiple pustules and erythematous plaques on the palms and soles.1,2 In the very early lesions, erythema appears, and then vesicles and pustules occur in the erythematous patches. Histologically, 3 steps are evident during the exacerbation of PPP: first vesicles, then vesiculopustules, and finally pustules.3 Early lesions of the vesicles histologically show basal epidermal spongiosis around the tip of the dermal papillae, then pustules show subcorneal blisters, and finally the contents of the pustules consist of polymorphonuclear leukocyte
From the Department of Dermatology, University of Tokyo,a and the Department of Dermatology, University of Tsukuba.b Supported by grants from the Ministry of Education, Science and Culture Ministry of Health and Welfare, and grants from Ono Pharmaceutical Company. Accepted for publication Nov 1, 1999. Reprint requests: K. Nakamura, Department of Dermatology, the University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan 113-0033. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/104305 doi:10.1067/mjd.2000.104305
(PMN) infiltrations.4 The origin of PPP has not yet been well elucidated; however, Andrews and Machacek1 as well as other authors5 have noted that the eruptions of patients with PPP were exacerbated after focal infections such as tonsillitis or tooth infection. It is well known that metal allergens are another exacerbating factor of PPP in Japan.6 It has been reported that the topical application of metal allergens in patients with PPP who have metal allergy sometimes leads to formation of pustules at the application sites of metal patch tests, and these palmoplantar pustules are histologically sterile subcorneal spongiform pustules composed of PMN.6 These findings indicate that metal allergens may be another exacerbating factor of PPP. Several chemoattractant mediators, including interleukin 8 (IL-8) and C5a, are involved in the pathogenesis of psoriasis and PPP.7-9 Leukotriene B4 (LTB4) is a lipoxygenase product of arachidonate metabolites and has a highly potent leukocyte chemotactic activity.10-13 In vivo topical application of LTB4 produces intraepidermal microabscesses composed of PMNs.14 Also, intradermal injection of LTB4 in the skin of human volunteers causes accumulation of PMNs.15 Furthermore, elevated levels of 1021
1022 Nakamura et al
J AM ACAD DERMATOL JUNE 2000
Table I. Material series in the patch test Metal
Fig 1. Case 1. Multiple pustules under site of nickel patch test.
LTB4 have been demonstrated in scale extracts from patients with psoriasis vulgaris as well as synovial fluids of patients with pustular psoriasis who also have recurrent arthritis.16-19 However, little is known about LTB4 in the pathogenesis of PPP. We show that patients with PPP showed positivity to certain metals in patch tests with metals and that both plasma level and pustular levels of LTB4 were significantly elevated after metal patch tests in patients with PPP. Pustular formation was observed at the application sites of metal patch tests, accompanied by increased numbers of palmoplantar pustules in these patients with metal allergy.
PATIENTS Seven patients with PPP, 3 men and 4 women ranging in age from 46 to 62 years (average, 53 years), were included in this study. The patients were treated with several topical corticosteroid ointments or anti-inflammatory medications (eg, loxoprofen, naproxen) from 1 month through 7 years. The average duration after the onset of the disease ranged from 1 to 10 years (mean: 6.2 years). A closed patch test was performed for these patients using the metal standard patch test series (Torii Co, Tokyo, Japan). The metals examined in the experiment are listed in Table I. The result was scored at 48 hours after the application according to the criteria of the International Contact Dermatitis Research Group Organization (ICDRG). Reactions + to +++ were recorded in all patients.
METHODS Measurement of immunoreactive LTB4 in pustules and plasma of patients with PPP Immunoreactive LTB4 in pustules and plasma was measured before and after the metal patch tests. The
Aluminum chloride Chromium sulfate Cobalt chloride Copper sulfate Ferric chloride Gold chloride Indium trichloride Iridium tetrachloride Manganese chloride Mercury bichloride Nickel sulfate Platinum chloride Palladium chloride Potassium dichromate Stannous chloride Silver bromide Zinc chloride
%
Base
2 2 2 1 2 0.2 1 1 2 0.05 5 0.5 1 0.5 1 2 2
Aq Aq Aq Aq Aq Aq Aq Aq Pet Aq Aq Aq Aq Aq Aq Pet Pet
Aq, Aqueous; pet, petrolatum.
pustular contents and plasma of the patients were individually collected before and at 48 hours after the metal patch tests, and each sample was mixed with 4 volumes of ethanol. After the mixtures were centrifuged twice at 15,000 rpm for 45 minutes, the samples were collected and applied onto Sep-pak C18. Extraction of LTB4 was performed with water, ether, and methanol. The LTB4 concentration was measured with a radioimmunoassay kit (Amersham, UK).19 The detectable range was 16 to 2000 pg/mL. Appropriate dilution was performed with ethanol in the measurement of the pustules. Statistical analysis To assess the difference of LTB4 concentration in pustules or plasma before and after the metal patch tests, the Wilcoxon signed-rank test was performed by means of Stat View 4.0 (Abacus Concepts Inc, Berkeley, Calif).
RESULTS Positive metal patch test reactions were detected for metals such as nickel, cobalt, platinum, tin, iron, and palladium in all 7 patients with PPP (Table I). Pustules were newly formed at the application sites of the metal patch test in 3 patients with PPP (Fig 1). The palmoplantar pustules were exacerbated at 48 hours after the metal patch test in all 7 patients (Fig 2). No bacterial or fungal agents were cultured from the palmoplantar pustules and pustules that newly appeared at the sites of the metal patch tests. No pustule formation occurred in normal controls (data
Nakamura et al 1023
J AM ACAD DERMATOL VOLUME 42, NUMBER 6
A
B Fig 2. Case 1. A, Volar eruption before metal patch test. B, Volar eruption at 48 hours after metal patch test.
Table II. Pustular and plasma levels of LTB4 concentration and the number of pustules in patients with PPP LTB4 in pustule (pg/mL)† Patient No.
1 2 3 4 4 5 6 7
Age (y)
Sex
46 57 52 62
M F F F
50 53 51
F M M
LTB4 in plasma (pg/mL)†
No. of pustules‡
Patch test (ICDRG)
Positive*
Before
After
Before
After
Before
After
++ ++ + + + + ++ +
Ni, Pt, Pd, Sn Fe, Sn Ni, Co, Pd Co Co Co Ni, Sn Fe
22,000 13,650 2310 –§ nd 30,000 24,000 12,000
80,000 42,600 4730 9820 nd 31,500 43,800 18,000
nd 170 50 206 42 150 110 118
nd 260 158 289 123 162 156 138
90 59 67 68 nd 55 64 46
157 109 92 99 nd 63 122 87
Co, Cobalt; Fe, iron; nd, not done; Ni, nickel; Pd, palladium; Pt, platinum; Sn, stannum. *Metals that showed positive reactions in the metal patch tests. †LTB concentration in palmoplantar pustules and plasma in patients with PPP before and at 48 hours after metal patch tests. 4 ‡Total numbers of palmoplantar pustules of patients with PPP before and at 48 hours after metal patch tests. §There were no pustules, and LTB was unmeasurable. 4
not shown). The average pustular levels of LTB4 obtained from palms and soles was 36,771 ± 10,581 pg/mL (mean ± SEM) after the metal patch tests, and 12,827 ± 3731 pg/mL before the metal patch tests (Table II). These pustular levels of LTB4 after the metal patch tests were significantly higher than those before the metal patch tests (P<.05). The average plasma level of LTB4 was 171 ± 25 pg/mL after the metal patch tests and 121 ± 20 pg/mL before the metal patch tests. These plasma levels of LTB4 after the metal patch tests were also significantly elevated compared with those before the metal patch tests (P<.05).
DISCUSSION PPP is a chronic relapsing disorder in which aseptic pustules and vesicles form in palmoplantar areas, consisting of PMN infiltration. Focal infec-
tion, such as tooth infection or tonsillitis, is a wellknown exacerbating factor of PPP.1,5 In addition, certain metal allergens are recognized as inducers of the exacerbation of palmoplantar eruptions of patients with PPP in Japan, but this is not widely accepted in the English-language literature.6 Thus in this study we examined the involvement of metal allergy in PPP. For this, we performed the patch tests in 7 patients with PPP. Interestingly, all 7 patients showed positivity for metals. Three of them showed grouped pustules at the sites of patch tests. Furthermore, all 7 patients showed exacerbation of the lesions and increases in the number of pustules after metal patch tests. We also observed the improvement of palmoplantar eruptions after the removal of an artificial tooth in 2 of our cases as previously described.6 These data indicate that metals may be important in the patho-
1024 Nakamura et al
genesis of PPP, as in other dermatitides such as hand eczema or oral lichen planus.20-22 It has been reported that pustules are often newly formed at the sites of metal patch tests in patients with metal allergies. Several mechanisms of pustular formation at the sites of metal patch tests in these patients have been considered. Stone and Johnson23 mentioned pustular formation under the site of nickel attachment at the sites injected with heat-inactivated bacteria. They suggested that this phenomenon was not merely irritant dermatitis. The histology of these pustules that appear at the lesions of metal patch tests indicates subcorneal microabscesses of PMNs, similar to the histology of palmoplantar pustules of PPP, and not that of contact dermatitis.24 Thus it is suggested that the formation of pustules in the applied lesions after metal patch tests in patients with PPP is not the result of simple irritant reactions. Chemotactic cytokines (IL-8 and gro-α), and complement (C5a) are known to be important for accumulation of PMNs in inflammatory skin diseases such as psoriasis.7,8 In addition to these factors, arachidonic acid metabolites such as LTB4, LTC4, and LTD4 are reported to act as chemoattractants and to activate PMN in inflammatory skin diseases.15-19 It has been reported that high levels of LTB4 are present in the tissues of inflammatory skin diseases like psoriasis vulgaris.16-19 Furthermore, high levels of LTB4 were identified in the synovial fluids of joints of 2 patients with pustular psoriasis who had severe complications of aseptic purulent arthritis.19 Thus it is suggested that LTB4 may be associated with the pathogenesis of PMN infiltration in the lesional skin of psoriasis vulgaris. However, little is known about LTB4 in the pathogenesis of PPP. Recently, a slight but not significant increase of the plasma level of LTB4 in PPP was reported.25 Thus we decided to examine the plasma and pustular levels of LTB4 in pustules of the palmoplantar area. Furthermore, the LTB4 levels were also examined after the metal patch tests. Our data demonstrated that the plasma level of LTB4 in PPP patients ranged from 42 to 206 pg/mL, which was higher than that in normal volunteers (<46 pg/mL). The levels of plasma LTB4 increased at 48 hours after the metal patch tests. The levels of LTB4 in pustules ranged from 2310 to 30,000 pg/mL before the metal patch tests, and the LTB4 levels increased from 4730 to 80,000 pg/mL at 48 hours after the metal patch tests. The increased plasma and pustular LTB4 levels after the metal patch tests were shown to be associated with the exacerbation of pustules of PPP. Thus it was suggested that the increased LTB4 level in the pustules was linked with the pustule formation of metal-allergen–exacerbated PPP, although we cannot exclude the possibility that
J AM ACAD DERMATOL JUNE 2000
other chemotactic factors such as IL-8 may also be important in the formation of pustules of PPP. The mechanism by which certain metals induce high levels of LTB4 in plasma and pustules of PPP is not fully understood. However, there is a possibility that metal allergens may cause production of cytokines such as granulocyte colony-stimulating factor, and this may activate PMNs. Another possibility is that, because topical application of certain metals is reported to enhance expression of adhesion molecules like intercellular adhesion molecule 1 or vascular cell adhesion molecule 1 on endothelial cells,26 this enhancement of adhesion molecules on endothelial cells may accelerate migration of PMNs through blood vessel walls in the dermis. Because the expression of intercellular adhesion molecule 1 on keratinocytes has been demonstrated in the lesional skin of PPP,27 the alteration of adhesion molecule expression on endothelial cells, induced by metals, may cause activated PMNs to enter the epidermis. Although the precise mechanisms of the effects of metals in PPP are not yet clear, our data demonstrate that certain metals activate PMNs, and this results in the exacerbation of PPP, along with the induction of high levels of LTB4 in the pustules. Recently, the structure and function of the LTB4 receptor has been reported. Further investigations will elucidate the effects of LTB4–LTB4 receptor interactions on PMNs in PPP.28 This understanding will lead to future therapy in the PMN-accumulating skin diseases such as PPP and psoriasis vulgaris. REFERENCES 1. Andrews GC, Machacek GF. Pustular bacterids of the hands and feet. Arch Dermatol Syphiol 1935;32:837-47. 2. Christophers E. Pustular eruptions of palms and soles. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in general medicine. 4th ed. New York: McGraw-Hill; 1993. p. 648-54. 3. Toussaint S, Kamino H. Noninfectious erythematous, papular, and squamous diseases. 7th ed. In: Lever WF, Lever GS, editors. Histopathology of the skin. Philadelphia: Lippincott; 1997. p. 163-4. 4. Uehara M, Ofuji S. The morphogenesis of pustulosis palmaris et plantaris. Arch Dermatol 1974;109:518-20. 5. Yamazaki Y, Saito S, Ogawa H. Tonsil and pustulosis palmaris et plantaris. Acta Oto-Laryngol 1981;suppl 401:43-50. 6. Nakayama H, Nogi N, Kasahara N, Matsuo S. Allergen control: an indispensable treatment for allergic contact dermatitis. Dermatol Clin 1990;8:197-204. 7. Schroder JM. Chemotactic cytokines in the epidermis. Exp Dermatol 1992;1:12-9. 8. Tagami H, Ofuji S. Characterization of a leukocytic factor derived from psoriatic scales. Br J Dermatol 1977;97:509-18. 9. Tagami H, Ofuji S. A leukotactic factor in the stratum corneum of pustulosis palmaris et plantaris. Acta Derm Venereol (Stockh) 1978;58:401-5. 10. Palmar EM, Stepney PJ, Higgs GA, Eakins KE. Chemokinetic
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11. 12.
13.
14.
15.
16.
17.
18. 19.
activity of arachidonic acid lipoxygenase products in leukocytes of different species. Prostaglandins 1980;20:411-8. Bray MA, Ford-Huchinson AW, Smith MJ. Leukotriene B4: an inflammatory mediator in vivo. Prostaglandins 1981;22:213-22. Ford-Hutchinson AW, Bray MA, Doig MV, Shipley ME, Smith MJ. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature 1980;286:264-5. Kishikawa K,Tateishi N, Maruyama T, Seo R,Toda M, Miyamoto T. Ono-4057, a novel, orally active leukotriene B4 antagonist: effects on LTB4-induced neutrophil functions. Prostaglandins 1992;44:261-75. Camp R, Derm FF, Jones RR, Brain S, Woollard P, Greaves M. Production of intraepidermal microabscesses by topical application of leukotriene B4. J Invest Dermatol 1984;82:202-4. Camp R, Coutts AA, Greaves MD, Kay AB, Walport MJ. Responses of human skin to intradermal injection of leukotriene C4, D4, and B4. Br J Pharmacol 1983;80:497-502. Grabbe J, Czarnetzki BM, Rosenbach T, Mardin M. Identification of chemotactic lipoxygenase products of arachidonate metabolism in psoriatic skin. J Invest Dermatol 1984;82:477-9. Brainy SD, Camp RD, Cunningham FM, Dowd PM, Greaves MW, Black AK. Leukotriene B4-like material in scale of psoriatic skin lesions. Br J Pharmacol 1984;83:313-7. Grabbe J, Czarnetzki BM, Mardin M. Chemotactic leukotrienes in psoriasis [letter]. Lancet 1982;2:1464. Kawana S, Nishiyama S. Pustular psoriasis and aseptic purulent arthritis: possible role of leukotrienes B4 and C4 in a flare of synovitis. Dermatology 1995;190:35-8.
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20. Veien NK, Menne T. Nickel contact allergy and nickel-restricted diet. Semin Dermatol 1990;9:197-205. 21. Thomson J, Russel JA. Dermatitis due to mercury following amalgam dental restorations. Br J Dermatol 1970;82:292-7. 22. Frykholm KO, Frithiof L, Fernstrom AI, Moberger G, Blohm SG, Bjorn E. Allergy to copper derived from dental alloys as a possible cause of oral lesions of lichen planus. Acta Derm Venereol (Stockh) 1969;49:268-81. 23. Stone OJ, Johnson DA. Pustular patch test—experimentally induced. Arch Dermatol 1967;95:618-9. 24. Fisher AA, Chargin L, Fleischmajer R, Hyman A. Pustular patch test reactions. Arch Dermatol 1959;80:742-52. 25. Izaki S, Yamamoto T, Goto Y, Ishimaru S, Yudate F, Kitamura K, et al. Platelet-activating factor and arachidonic acid metabolites in psoriatic inflammation. Br J Dermatol 1996;134:1060-4. 26. Goebeler M, Meinardsu-Hager G, Roth J, Goerdt S, Sorg C. Nickel chloride and cobalt chloride, two common contact sensitizers, directly induce expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1) by endothelial cells. J Invest Dermatol 1993;100:759-65. 27. Yokochi K, Tamada Y, Takama H, Ikeya T, Ohashi M. Role of adhesion molecules in the development of pustular lesions in patients with pustulosis palmaris et plantaris. Acta Derm Venereol (Stockh) 1996;76:118-22. 28. Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T. A G-protein–coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 1997;387:620-4.
P
ustulosis palmaris et plantaris (PPP) is a chronic, relapsing inflammatory disease characterized by multiple pustules and erythematous plaques on the palms and soles.1,2 In the very early lesions, erythema appears, and then vesicles and pustules occur in the erythematous patches. Histologically, 3 steps are evident during the exacerbation of PPP: first vesicles, then vesiculopustules, and finally pustules.3 Early lesions of the vesicles histologically show basal epidermal spongiosis around the tip of the dermal papillae, then pustules show subcorneal blisters, and finally the contents of the pustules consist of polymorphonuclear leukocyte
From the Department of Dermatology, University of Tokyo,a and the Department of Dermatology, University of Tsukuba.b Supported by grants from the Ministry of Education, Science and Culture Ministry of Health and Welfare, and grants from Ono Pharmaceutical Company. Accepted for publication Nov 1, 1999. Reprint requests: K. Nakamura, Department of Dermatology, the University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan 113-0033. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/104305 doi:10.1067/mjd.2000.104305
(PMN) infiltrations.4 The origin of PPP has not yet been well elucidated; however, Andrews and Machacek1 as well as other authors5 have noted that the eruptions of patients with PPP were exacerbated after focal infections such as tonsillitis or tooth infection. It is well known that metal allergens are another exacerbating factor of PPP in Japan.6 It has been reported that the topical application of metal allergens in patients with PPP who have metal allergy sometimes leads to formation of pustules at the application sites of metal patch tests, and these palmoplantar pustules are histologically sterile subcorneal spongiform pustules composed of PMN.6 These findings indicate that metal allergens may be another exacerbating factor of PPP. Several chemoattractant mediators, including interleukin 8 (IL-8) and C5a, are involved in the pathogenesis of psoriasis and PPP.7-9 Leukotriene B4 (LTB4) is a lipoxygenase product of arachidonate metabolites and has a highly potent leukocyte chemotactic activity.10-13 In vivo topical application of LTB4 produces intraepidermal microabscesses composed of PMNs.14 Also, intradermal injection of LTB4 in the skin of human volunteers causes accumulation of PMNs.15 Furthermore, elevated levels of 1021
1022 Nakamura et al
J AM ACAD DERMATOL JUNE 2000
Table I. Material series in the patch test Metal
Fig 1. Case 1. Multiple pustules under site of nickel patch test.
LTB4 have been demonstrated in scale extracts from patients with psoriasis vulgaris as well as synovial fluids of patients with pustular psoriasis who also have recurrent arthritis.16-19 However, little is known about LTB4 in the pathogenesis of PPP. We show that patients with PPP showed positivity to certain metals in patch tests with metals and that both plasma level and pustular levels of LTB4 were significantly elevated after metal patch tests in patients with PPP. Pustular formation was observed at the application sites of metal patch tests, accompanied by increased numbers of palmoplantar pustules in these patients with metal allergy.
PATIENTS Seven patients with PPP, 3 men and 4 women ranging in age from 46 to 62 years (average, 53 years), were included in this study. The patients were treated with several topical corticosteroid ointments or anti-inflammatory medications (eg, loxoprofen, naproxen) from 1 month through 7 years. The average duration after the onset of the disease ranged from 1 to 10 years (mean: 6.2 years). A closed patch test was performed for these patients using the metal standard patch test series (Torii Co, Tokyo, Japan). The metals examined in the experiment are listed in Table I. The result was scored at 48 hours after the application according to the criteria of the International Contact Dermatitis Research Group Organization (ICDRG). Reactions + to +++ were recorded in all patients.
METHODS Measurement of immunoreactive LTB4 in pustules and plasma of patients with PPP Immunoreactive LTB4 in pustules and plasma was measured before and after the metal patch tests. The
Aluminum chloride Chromium sulfate Cobalt chloride Copper sulfate Ferric chloride Gold chloride Indium trichloride Iridium tetrachloride Manganese chloride Mercury bichloride Nickel sulfate Platinum chloride Palladium chloride Potassium dichromate Stannous chloride Silver bromide Zinc chloride
%
Base
2 2 2 1 2 0.2 1 1 2 0.05 5 0.5 1 0.5 1 2 2
Aq Aq Aq Aq Aq Aq Aq Aq Pet Aq Aq Aq Aq Aq Aq Pet Pet
Aq, Aqueous; pet, petrolatum.
pustular contents and plasma of the patients were individually collected before and at 48 hours after the metal patch tests, and each sample was mixed with 4 volumes of ethanol. After the mixtures were centrifuged twice at 15,000 rpm for 45 minutes, the samples were collected and applied onto Sep-pak C18. Extraction of LTB4 was performed with water, ether, and methanol. The LTB4 concentration was measured with a radioimmunoassay kit (Amersham, UK).19 The detectable range was 16 to 2000 pg/mL. Appropriate dilution was performed with ethanol in the measurement of the pustules. Statistical analysis To assess the difference of LTB4 concentration in pustules or plasma before and after the metal patch tests, the Wilcoxon signed-rank test was performed by means of Stat View 4.0 (Abacus Concepts Inc, Berkeley, Calif).
RESULTS Positive metal patch test reactions were detected for metals such as nickel, cobalt, platinum, tin, iron, and palladium in all 7 patients with PPP (Table I). Pustules were newly formed at the application sites of the metal patch test in 3 patients with PPP (Fig 1). The palmoplantar pustules were exacerbated at 48 hours after the metal patch test in all 7 patients (Fig 2). No bacterial or fungal agents were cultured from the palmoplantar pustules and pustules that newly appeared at the sites of the metal patch tests. No pustule formation occurred in normal controls (data
Nakamura et al 1023
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A
B Fig 2. Case 1. A, Volar eruption before metal patch test. B, Volar eruption at 48 hours after metal patch test.
Table II. Pustular and plasma levels of LTB4 concentration and the number of pustules in patients with PPP LTB4 in pustule (pg/mL)† Patient No.
1 2 3 4 4 5 6 7
Age (y)
Sex
46 57 52 62
M F F F
50 53 51
F M M
LTB4 in plasma (pg/mL)†
No. of pustules‡
Patch test (ICDRG)
Positive*
Before
After
Before
After
Before
After
++ ++ + + + + ++ +
Ni, Pt, Pd, Sn Fe, Sn Ni, Co, Pd Co Co Co Ni, Sn Fe
22,000 13,650 2310 –§ nd 30,000 24,000 12,000
80,000 42,600 4730 9820 nd 31,500 43,800 18,000
nd 170 50 206 42 150 110 118
nd 260 158 289 123 162 156 138
90 59 67 68 nd 55 64 46
157 109 92 99 nd 63 122 87
Co, Cobalt; Fe, iron; nd, not done; Ni, nickel; Pd, palladium; Pt, platinum; Sn, stannum. *Metals that showed positive reactions in the metal patch tests. †LTB concentration in palmoplantar pustules and plasma in patients with PPP before and at 48 hours after metal patch tests. 4 ‡Total numbers of palmoplantar pustules of patients with PPP before and at 48 hours after metal patch tests. §There were no pustules, and LTB was unmeasurable. 4
not shown). The average pustular levels of LTB4 obtained from palms and soles was 36,771 ± 10,581 pg/mL (mean ± SEM) after the metal patch tests, and 12,827 ± 3731 pg/mL before the metal patch tests (Table II). These pustular levels of LTB4 after the metal patch tests were significantly higher than those before the metal patch tests (P<.05). The average plasma level of LTB4 was 171 ± 25 pg/mL after the metal patch tests and 121 ± 20 pg/mL before the metal patch tests. These plasma levels of LTB4 after the metal patch tests were also significantly elevated compared with those before the metal patch tests (P<.05).
DISCUSSION PPP is a chronic relapsing disorder in which aseptic pustules and vesicles form in palmoplantar areas, consisting of PMN infiltration. Focal infec-
tion, such as tooth infection or tonsillitis, is a wellknown exacerbating factor of PPP.1,5 In addition, certain metal allergens are recognized as inducers of the exacerbation of palmoplantar eruptions of patients with PPP in Japan, but this is not widely accepted in the English-language literature.6 Thus in this study we examined the involvement of metal allergy in PPP. For this, we performed the patch tests in 7 patients with PPP. Interestingly, all 7 patients showed positivity for metals. Three of them showed grouped pustules at the sites of patch tests. Furthermore, all 7 patients showed exacerbation of the lesions and increases in the number of pustules after metal patch tests. We also observed the improvement of palmoplantar eruptions after the removal of an artificial tooth in 2 of our cases as previously described.6 These data indicate that metals may be important in the patho-
1024 Nakamura et al
genesis of PPP, as in other dermatitides such as hand eczema or oral lichen planus.20-22 It has been reported that pustules are often newly formed at the sites of metal patch tests in patients with metal allergies. Several mechanisms of pustular formation at the sites of metal patch tests in these patients have been considered. Stone and Johnson23 mentioned pustular formation under the site of nickel attachment at the sites injected with heat-inactivated bacteria. They suggested that this phenomenon was not merely irritant dermatitis. The histology of these pustules that appear at the lesions of metal patch tests indicates subcorneal microabscesses of PMNs, similar to the histology of palmoplantar pustules of PPP, and not that of contact dermatitis.24 Thus it is suggested that the formation of pustules in the applied lesions after metal patch tests in patients with PPP is not the result of simple irritant reactions. Chemotactic cytokines (IL-8 and gro-α), and complement (C5a) are known to be important for accumulation of PMNs in inflammatory skin diseases such as psoriasis.7,8 In addition to these factors, arachidonic acid metabolites such as LTB4, LTC4, and LTD4 are reported to act as chemoattractants and to activate PMN in inflammatory skin diseases.15-19 It has been reported that high levels of LTB4 are present in the tissues of inflammatory skin diseases like psoriasis vulgaris.16-19 Furthermore, high levels of LTB4 were identified in the synovial fluids of joints of 2 patients with pustular psoriasis who had severe complications of aseptic purulent arthritis.19 Thus it is suggested that LTB4 may be associated with the pathogenesis of PMN infiltration in the lesional skin of psoriasis vulgaris. However, little is known about LTB4 in the pathogenesis of PPP. Recently, a slight but not significant increase of the plasma level of LTB4 in PPP was reported.25 Thus we decided to examine the plasma and pustular levels of LTB4 in pustules of the palmoplantar area. Furthermore, the LTB4 levels were also examined after the metal patch tests. Our data demonstrated that the plasma level of LTB4 in PPP patients ranged from 42 to 206 pg/mL, which was higher than that in normal volunteers (<46 pg/mL). The levels of plasma LTB4 increased at 48 hours after the metal patch tests. The levels of LTB4 in pustules ranged from 2310 to 30,000 pg/mL before the metal patch tests, and the LTB4 levels increased from 4730 to 80,000 pg/mL at 48 hours after the metal patch tests. The increased plasma and pustular LTB4 levels after the metal patch tests were shown to be associated with the exacerbation of pustules of PPP. Thus it was suggested that the increased LTB4 level in the pustules was linked with the pustule formation of metal-allergen–exacerbated PPP, although we cannot exclude the possibility that
J AM ACAD DERMATOL JUNE 2000
other chemotactic factors such as IL-8 may also be important in the formation of pustules of PPP. The mechanism by which certain metals induce high levels of LTB4 in plasma and pustules of PPP is not fully understood. However, there is a possibility that metal allergens may cause production of cytokines such as granulocyte colony-stimulating factor, and this may activate PMNs. Another possibility is that, because topical application of certain metals is reported to enhance expression of adhesion molecules like intercellular adhesion molecule 1 or vascular cell adhesion molecule 1 on endothelial cells,26 this enhancement of adhesion molecules on endothelial cells may accelerate migration of PMNs through blood vessel walls in the dermis. Because the expression of intercellular adhesion molecule 1 on keratinocytes has been demonstrated in the lesional skin of PPP,27 the alteration of adhesion molecule expression on endothelial cells, induced by metals, may cause activated PMNs to enter the epidermis. Although the precise mechanisms of the effects of metals in PPP are not yet clear, our data demonstrate that certain metals activate PMNs, and this results in the exacerbation of PPP, along with the induction of high levels of LTB4 in the pustules. Recently, the structure and function of the LTB4 receptor has been reported. Further investigations will elucidate the effects of LTB4–LTB4 receptor interactions on PMNs in PPP.28 This understanding will lead to future therapy in the PMN-accumulating skin diseases such as PPP and psoriasis vulgaris. REFERENCES 1. Andrews GC, Machacek GF. Pustular bacterids of the hands and feet. Arch Dermatol Syphiol 1935;32:837-47. 2. Christophers E. Pustular eruptions of palms and soles. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in general medicine. 4th ed. New York: McGraw-Hill; 1993. p. 648-54. 3. Toussaint S, Kamino H. Noninfectious erythematous, papular, and squamous diseases. 7th ed. In: Lever WF, Lever GS, editors. Histopathology of the skin. Philadelphia: Lippincott; 1997. p. 163-4. 4. Uehara M, Ofuji S. The morphogenesis of pustulosis palmaris et plantaris. Arch Dermatol 1974;109:518-20. 5. Yamazaki Y, Saito S, Ogawa H. Tonsil and pustulosis palmaris et plantaris. Acta Oto-Laryngol 1981;suppl 401:43-50. 6. Nakayama H, Nogi N, Kasahara N, Matsuo S. Allergen control: an indispensable treatment for allergic contact dermatitis. Dermatol Clin 1990;8:197-204. 7. Schroder JM. Chemotactic cytokines in the epidermis. Exp Dermatol 1992;1:12-9. 8. Tagami H, Ofuji S. Characterization of a leukocytic factor derived from psoriatic scales. Br J Dermatol 1977;97:509-18. 9. Tagami H, Ofuji S. A leukotactic factor in the stratum corneum of pustulosis palmaris et plantaris. Acta Derm Venereol (Stockh) 1978;58:401-5. 10. Palmar EM, Stepney PJ, Higgs GA, Eakins KE. Chemokinetic
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