Expression of nicotinic receptors in the skin of patients with palmoplantar pustulosis

BACKGROUND: A suggested role for nicotine in the pathogenesis of palmoplantar pustulosis (PPP) has been discussed. The target for the inflammation in PPP is the acrosyringium. Nicotine acts as an agonist on nicotinic acetylcholine receptors (nAChRs) and can influence a variety of cellular functions. OBJECTIVES: To study the alpha 3- and alpha 7-nAChR expression in palmar skin of patients with PPP in comparison with that in healthy smoking and non-smoking controls. METHODS: Biopsies from 20 patients with PPP, seven healthy smokers and eight healthy non-smokers were studied by immunohistochemistry with a monoclonal anti-alpha 3 and a polyclonal anti-alpha 7 antibody. RESULTS: In healthy controls both nAChR subtypes showed stronger immunoreactivity in the eccrine glands and ducts than in the epidermis. The papillary endothelium was positive for both subtypes. Epidermal alpha 3 staining was stronger and that of the coil and dermal ducts weaker in healthy smokers than in healthy non-smokers. In involved PPP skin, granulocytes displayed strong alpha 3 immunoreactivity. The normal epidermal alpha 7 staining pattern was abolished in PPP skin and was replaced by strong mesh-like surface staining, most markedly adjacent to the acrosyringium, which in controls was intensely alpha 7 positive at this level. Endothelial alpha 7 staining was stronger in PPP skin than in the controls. CONCLUSIONS: Smoking can influence nAChR expression. The altered nAChR staining pattern in PPP skin may indicate a possible role for nicotine in the pathogenesis of PPP. We hypothesize that there is an abnormal response to nicotine in patients with PPP, resulting in inflammation.     

他卡西醇软膏治疗27例掌跖脓疱病疗效观察

目的：观察他卡西醇软膏外用治疗掌跖脓疱病的疗效及安全性。方法：采用单盲、自身对照的方法,对27例掌跖脓疱病患者两侧皮损分别外用他卡西醇软膏和15％尿素软膏,并于用药后第2、4、8周观察疗效。结果：27例患者他卡西醇治疗侧皮损有效率为59．1％,明显优于对照侧（16．2％）,其治疗起效时间早于对照侧,患者耐受性较好,无明显不良反应。结论：他卡西醇软膏治疗掌跖脓疱病有效,而且安全。     

The role of psychological factors in palmoplantar pustulosis

OBJECTIVE: The aim of the present study was to find out whether emotional stress is related to palmoplantar pustulosis (PPP). SUBJECTS AND METHODS: Our 21 patients with palmoplantar pustulosis and 21 age- and sex-matched controls were studied with the help of a psychological interview and two psychological tests: Eysenk's Personality Questionnaire for Adults (EPQ-A) and Inventory of Situations and Response of Anxiety (ISRA). RESULTS: Anxiety, ranging from moderate to severe was higher in PPP patients than in controls (P < 0.001). CONCLUSION: Our findings seem to indicate that stress may be related to exacerbation of the palmoplantar pustulosis.     

Increased in vivo secretory activity of neutrophil granulocytes in patients with psoriasis and palmoplantar pustulosis

Summary The relationship between psoriasis and palmoplantar pustulosis (PPP) is uncertain, as is the role of the neutrophil granulocyte in these conditions. In a previous comparative study of the rate of polymorphonuclear leucocyte (PMN) phagocytosis of IGG- and IgG-C3b-coated particles, an increased uptake rate was found in both diseases. Further information on the in vivo activity of PMNs in these conditions may be obtainable by determining the level of lactoferrin (LF) in serum from such patients, since LF serves as a specific marker of the turnover and activity of the circulating pool of neutrophils. In this study on 19 patients with psoriasis and 20 patients with PPP, elevated levels of LF were found in both conditions. In contrast, the levels of lysozyme and ₂-microglobulin, which are markers of monocyte-macrophage and lymphocyte activity, respectively, were normal. This suggests the selective activation of neutrophils in these disorders. LF was significantly correlated (P<0.05 and 0.001, respectively) to the rates of phagocytosis of IgG- and IgG-C3b-coated particles, but not to the chemotaxis of isolated PMNs. There was no correlation between the severity of the disease and the levels of serum LF. The data suggest the increased in vivo activity of neutrophils in psoriasis and PPP.     

Mutation analysis of IL36RN gene in Japanese patients with palmoplantar pustulosis

Loss‐of‐function mutations of the IL36RN gene, encoding interleukin‐36 receptor antagonist (IL‐36Ra), have been reported as major pathogenic causes of generalized pustular psoriasis (GPP), especially in cases lacking previous histories of psoriasis vulgaris. Palmoplantar pustulosis (PPP), which is traditionally included among GPP‐related diseases, has a controversial association with IL36RN. While a negative view about the said association has been recently published from Europe, variations of the IL36RN gene show great ethnic differences. In this study, we performed mutation analysis of the IL36RN gene in 88 Japanese patients with PPP and identified three types of single base substitutions in four patients, namely, p.Pro82Leu in two patients, p.Asn47Ser in one and p.Thr123Met in another. All variations were heterozygous and different from previous European reports. We compared the immunohistochemical findings of IL‐36Ra on patients with and without variation of the IL36RN gene; however, no significant differences were observed. Our data and the previous European study suggest that PPP is not associated with mutations of the IL36RN gene.     

Genetic polymorphisms in the fourth component of complement (C4) and in properdin factor B (BF) in Japanese patients with palmoplantar pustulosis.

Genetic polymorphisms in the fourth component of complement (C4) and in properdin factor B (BF) were investigated in 49 and 32 Japanese patients with palmoplantar pustulosis (PPP), respectively. C4B2 was significantly increased in frequency, whereas no significant deviations were detected in BF compared with the controls. These results may indicate that complement polymorphisms are involved in the pathogenesis of PPP.     

Association analysis of IL19, IL20 and IL24 genes in palmoplantar pustulosis

BACKGROUND: Interleukin (IL) 19, IL-20 and IL-24 belong to the IL-10 cytokine family and have been identified to play a role in the regulation of epidermal functions and in inflammation. The genes encoding IL-19, IL-20 and IL-24 are located within a gene cluster on chromosome 1q31-32 and carry frequent genetic variations. OBJECTIVES: This study investigated whether variations in the IL19, IL20 and IL24 genes that have previously been associated with plaque-type psoriasis may also play a role in palmoplantar pustulosis (PPP). PATIENTS: Fifteen polymorphisms were analysed in 43 patients with PPP and in 149 healthy control subjects. RESULTS: The rare allele of IL20 1380 A-->G (rs2981573) was less frequent in patients with PPP compared with healthy controls (OR 1 x 95, 95% CI 1 x 00-3 x 79). Haplotype analyses of IL19 and IL20 suggested an increased risk for PPP associated with IL20 haplotype GAA (OR 2 x 39, 95% CI 1 x 17-4 x 86) and a reduced risk for PPP associated both with IL19 haplotype GATGATA (OR 0 x 41, 95% CI 0 x 16-1 x 05) and IL20 haplotype GGG (OR 0 x 48, 95% CI 0 x 23-0 x 98). Extended haplotype analysis revealed an association of IL19/IL20 haplotype GACACCGGAA with a higher risk for PPP (OR 2 x 31, 95% CI 1 x 05-5 x 10) and of IL20/IL24 haplotype CAAAC with a reduced risk for PPP (OR 0 x 12, 95% CI 0 x 02-0 x 82). CONCLUSIONS: This exploratory study supports the hypothesis that variations of genes of the IL-19 subfamily of cytokines influence susceptibility to PPP. However, due to the limited size of the study samples, this current concept should be considered as preliminary and the results need to be confirmed in future independent studies.     

Patients with palmoplantar pustulosis have increased IL-17 and IL-22 levels both in the lesion and serum

Recent findings about the pathogenesis of pustulosis palmaris et plantaris (PPP), also known as palmoplantar pustulosis, suggest that IL-17 expression in the acrosyringium as well as infiltration of IL-17 positive cells, e.g. Langerhans cells may play important roles. However, to date, it has not been established whether circulating IL-17 related cytokines are involved in PPP. We studied the circulating IL-17 related cytokines as well as the mRNA levels in lesional skin. IL-17 related cytokine mRNAs were increased in the PPP lesions compared with the control tissues (five patients vs five controls). The serum levels of TNF-alpha, IL-17, IL-22 and IFN-gamma also were significantly increased in PPP, but not IL-23 and IL-8 (48 patients vs 20 controls). Our findings document that not only the serum IL-17 but also tissue IL-17 are elevated in PPP and may be in the pathogenesis of this disorder.     

Retrospective analysis of the clinical response of palmoplantar pustulosis after dental infection control and dental metal removal

Both metal allergy and dental focal infection have been considered as causative factors for palmoplantar pustulosis, and several case reports described that the skin lesions were ameliorated after dental metal removal or dental infection control. However, limited data are available to evaluate the association of these factors with disease severity of palmoplantar pustulosis. This study is designed to analyze the clinical outcome of 85 palmoplantar pustulosis patients after dental infection control (n = 70), tonsillectomy (n = 6) and dental metal removal (n = 9). More than half of the patients (63%, 44/70) showed positive clinical outcome after dental infection control. The skin lesions of all patients with tonsillitis were improved after tonsillectomy (100%, 6/6). On the other hand, one‐third of patients (33%, 3/9) showed positive response after dental metal removal. These results suggest that focal infection is more closely associated with palmoplantar pustulosis than dental metal allergy. According to our findings, palmoplantar pustulosis patients should be preferentially examined for focal infections.     

Skin nerve fibres and their contacts with mast cells in patients with palmoplantar pustulosis

Abstract Patients with palmoplantar pustulosis (PPP) frequently report that stress worsens their condition. A study was therefore made of the distribution and number of nerve fibres positive for protein gene product (PGP) 9.5 (a general nerve marker) and nerve fibres with substance P- and calcitonin gene-related peptide-like immunoreactivity in involved skin from patients with PPP and in skin from healthy controls. The number of mast cells in the papillary dermis was larger (P = 0.0003) in lesional palmar PPP skin than in control skin, and the number of contacts between mast cells and nerve fibres was significantly larger (P = 0.02) in PPP skin than in control skin. Image analysis of the nerve fibres around the sweat glands showed that the positively stained area as a percentage of the total area of the sweat gland (coil + surrounding nerves) was significantly lower in PPP skin (P = 0.0006). Furthermore, the nerves seemed to be fragmented. Neutrophils within and below the pustules and in the papillary dermis showed positive substance P staining. The increased number of contacts between nerves and mast cells in PPP skin and the intense substance P-like immunoreactivity of the neutrophils indicate that neuromediation may influence the inflammation in PPP, whereas the destruction of the nerve fibres around the sweat glands might be a result of the inflammation. Received: 8 October 1999 / Revised: 25 January 2000 / Accepted: 27 January 2000     

Topical PUVA, etretinate, and combined PUVA and etretinate for palmoplantar pustulosis: comparison of therapeutic efficacy and the influences of tonsillar and dental focal infections

Twenty patients with palmoplantar pustulosis (PPP) were treated with topical PUVA, oral etretinate (Re), or combined PUVA and etretinate (Re-PUVA). Re and Re-PUVA treated sites improved and/or cleared more rapidly than PUVA treated sites. Complete clearance was observed in six of ten sites treated with Re-PUVA, two of ten with Re, and one of ten sites with PUVA within 12 weeks. UVA-control sites failed to be cleared within 12 weeks. Remission periods after stopping the treatment were 1.5 +/- 0.5 weeks (n = 2) with Re, 10.5 +/- 11.4 weeks (n = 6) with Re-PUVA, and one year (n = 1) with PUVA. These results overall suggested that Re-PUVA is the most effective treatment for PPP. Tonsillar focal infection (TFI) and dental focal infection (DFI) were found in 6/20 and 17/20 patients, respectively. However, the presence of focal infection (FI), TFI and/or DFI, did not appear to interfere with the therapeutic activities of Re and/or PUVA, because the complete clearance rates and remission periods in FI(+) patients were comparable with those in FI(-) patients.     

Clinical characteristics,genetics, comorbidities and treatment of palmoplantar pustulosis: A retrospective analysis of 66 cases in a single center in Taiwan

We retrospectively analyzed 66 patients with palmoplantar pustulosis (PPP) from January 1994 to September 2019 in our department. Interleukin-36 receptor antagonist gene (IL36RN) intron 3 c.115+6T>C mutation was present in two out of 27 patients (7.4%). Both cases developed generalized pustular psoriasis and/or acrodermatitis continua of Hallopeau later. Topical medications and phototherapy were used in 93.9% and 28.8% of patients, respectively, while 60.6% received systemic agents. The majority of patients (60.6%) responded to treatment, but episodes of flare-up existed. The demographic data of our patients with PPP showed female predominance (59.1%), middle-age onset (44.2 years old) and current smokers (62.1%). Generalized pustular psoriasis initially presenting as palmoplantar lesions may be misdiagnosed as PPP, and the presence of IL36RN mutation may serve to predict or confirm the diagnosis of future generalized pustular psoriasis or acrodermatitis continua of Hallopeau. To our knowledge, this is the largest demographic study of PPP in Taiwan.     

Interleukin-8 immunoreactivity in the skin of healthy subjects and patients with palmoplantar pustulosis and psoriasis.

Previous studies have shown that neutrophil-activating peptide 1/interleukin-8 (IL-8) is present in psoriatic scales and to a lesser extent in normal human epidermis. A panel of monoclonal antibodies and polyclonal antisera raised against IL-8 was used to localize IL-8 with immunoperoxidase techniques in non-lesional and lesional skin of patients with psoriasis and palmo-plantar pustulosis (PPP), and in corresponding sites from healthy subjects. Intracellular IL-8 immunoreactivity was found in all epidermal cell layers in biopsies of healthy subjects and in non-lesional and lesional skin in both PPP and psoriasis. The most intense immunolabeling was regularly found in the basal cell layer. Intercellular epidermal IL-8 immunolabeling was regularly detected in lesional biopsies in PPP and psoriasis, but not in healthy subjects or non-lesional skin in PPP and psoriasis. No intercellular immunolabeling was detected after successful treatment of lesional skin. The majority of cells along the eccrine sweat glands, dermal mononuclear cell infiltrates, and endothelial cells were IL-8 immunoreactive in all biopsies studied. The present study suggests that IL-8, its precursor form, or, alternatively, a degradation product is present in normal human epidermis.     

Treatment outcome and prognostic factors of tonsillectomy for palmoplantar pustulosis and pustulotic arthro‐osteitis: A retrospective subjective and objective quantitative analysis of 138 patients

Pustulosis palmaris et plantaris (PPP) and pustulotic arthro‐osteitis (PAO) are tonsil‐related diseases. Treatment outcome of tonsillectomy and prognostic factors influencing the outcome have not been analyzed quantitatively. We evaluated those using the Palmoplantar Pustulosis Area and Severity Index (PPPASI). At 1, 3, 6, 12, 24 and more than 24 months post‐tonsillectomy, 20 (31%), 34 (48%), 70 (60%), 57 (80%), 36 (95%) and 23 (96%) patients realized 80% or more improvement of PPP skin lesions, respectively, and eight (17%), 23 (36%), 30 (50%), 38 (79%), 12 (100%) and four (100%) patients showed 80% or more improvement of PPPASI (i.e. PPPASI% ≥ 80%), respectively. At 1, 3, 6, 12 and more than 12 months post‐tonsillectomy, 19 (73%), 21 (66%), 27 (73%), 19 (79%) and 15 (83%) patients realized a disappearance of PAO‐induced arthralgia, respectively. Kaplan–Meier analysis of 80 patients with PPP revealed that, at 12 and 24 months post‐tonsillectomy, lesions disappeared (i.e. PPPASI = 0) in 38% and 66% of patients, respectively, and lesions improved by 80% or more (i.e. PPPASI% ≥ 80%) in 71% and 95% of patients, respectively. The log–rank test and univariate and multivariate analyses showed that smoking cessation post‐tonsillectomy and PAO were significant predictive factors for the early disappearance of skin lesions. This report is the first demonstrating objective evidence of the great efficacy of tonsillectomy to improve PPP skin lesions. Even post‐tonsillectomy, smoking inhibited the early disappearance of the lesions.     

Rare association of pyoderma gangrenosum and palmoplantar pustulosis: A case report and review of the previous works

Pyoderma gangrenosum is a rare inflammatory, ulcerative skin disease that mainly involves the lower extremities. It frequently occurs in association with systemic diseases such as inflammatory bowel disease, myeloproliferative disorders and rheumatoid arthritis. Palmoplantar pustulosis is also an inflammatory dermatosis characterized by recurrent sterile pustules localized on the palms and soles. These two dermatoses are histologically characterized by neutrophilic infiltration into the lesional skin. Co‐occurrence of pyoderma gangrenosum and palmoplantar pustulosis in a single patient is extremely rare. We report a case of pyoderma gangrenosum occurred in a patient with palmoplantar pustulosis, with a review of the previously reported cases. A 68‐year‐old Japanese woman with a 10‐year history of palmoplantar pustulosis developed a skin ulcer on the left lower leg. The ulcer was diagnosed as pyoderma gangrenosum based on the clinical and histological findings, and rapidly improved in response to oral prednisolone. In addition to our case, five cases with palmoplantar pustulosis who developed pyoderma gangrenosum have been reported. These cases were thought to have some characteristics in common, such as marked female predominance, no association with inflammatory bowel disease and myeloproliferative disorders, and good response to less aggressive therapy. The co‐occurrence of pyoderma gangrenosum and palmoplantar pustulosis in our case may have an etiological link, rather than being a coincidental complication.     

Evaluation of the efficacy of granulocyte and monocyte adsorption apheresis on skin manifestation and joint symptoms of patients with pustulotic arthro‐osteitis

Pustulotic arthro‐osteitis, occasionally complicated with palmoplantar pustulosis, affects patients’ activities of daily living. Granulocyte and monocyte adsorption apheresis selectively removes activated granulocytes and monocytes by means of extracorporeal circulation. Although the efficacy of granulocyte and monocyte adsorption apheresis in the treatment of generalized pustular psoriasis has been proved, very few reports have assessed its efficacy in the treatment of palmoplantar pustulosis and pustulotic arthro‐osteitis. Ten pustulotic arthro‐osteitis patients with five palmoplantar skin manifestations were treated with weekly granulocyte and monocyte adsorption apheresis over 5 weeks. Skin manifestations were assessed using palmoplantar pustulosis area and severity index, and joint symptoms were assessed using a visual analog scale of joint pain, tender joint count, swollen joint count and C‐reactive protein immediately before, after and at the 3‐month follow up of the five granulocyte and monocyte adsorption apheresis sessions. Two out of five patients with skin manifestations achieved more than 50% improvement in their score (remarkably improved). However, in two patients, deterioration was noted, in one of whom the skin manifestations remained unchanged at the 3‐month follow up. In five out of the 10 patients, the joint symptoms were assessed as better than improved at the 3‐month follow up. No deterioration was noted at the 3‐month follow up. In three patients, reduction or cessation of medication for arthralgia was possible. We concluded that granulocyte and monocyte adsorption apheresis is a therapeutic option to consider when pustulotic arthro‐osteitis is recalcitrant to conventional therapy.     

Immunohistochemical Localization of Nitric Oxide Synthase in Normal Human Skin: Expression of Endothelial-type and Inducible-type Nitric Oxide Synthase in Keratinocytes

Nitric oxide (NO) is a critical mediator of various biological functions. NO is generated from L-arginine by nitric oxide synthase (NOS), which has three isoforms; endothelial-type NOS (eNOS) and brain-type NOS (bNOS) are constitutive enzymes, and inducible-type NOS (iNOS) is expressed after stimulation. We investigated the expression of NOS in normal human skin by an immunohistochemical technique and western blotting analysis. In human skin, epidermal keratinocytes and the outer root sheath were labeled with not only eNOS antibody but also with iNOS antibody. Both eNOS and iNOS protein in epidermal keratinocytes were confirmed by western blotting. eNOS immunoreactivity was observed in endothelial cells, fibroblasts, the arrector pili muscle, apocrine secretory gland, eccrine coiled duct, and eccrine secretory gland. bNOS immunoreactivity was observed in mast cells. No staining with anti-bNOS antibody was observed in any other cell type. Our present findings suggest that epidermal keratinocytes in normal human skin contain both eNOS and iNOS.     

Effectiveness of iontophoresis with alternating current (AC) in the treatment of patients with palmoplantar hyperhidrosis

Conventionally, iontophoresis employing direct current (DC) has been used in the treatment of palmoplantar hyperhidrosis, but this is accompanied by side effects such as pain and burns. In the present study, a prototype apparatus using alternating current (AC) was constructed, and iontophoresis with AC was performed in palmoplantar hyperhidrosis patients to determine its effectiveness. The average amount of perspiration of the palmoplantar hyperhidrosis patients was significantly reduced after the third session when iontophoresis treatments were performed once per week. By the eighth treatment, perspiration was reduced to nearly the normal level, and there were no particular side-effects during the treatment period. This treatment therefore appears to be both safe and effective. The treatment effect tended to appear sooner when alternating current iontophoresis was combined with the administration of anticholinergic drugs than when alternating current iontophoresis was used alone. Alternating current iontophoresis is an effective treatment for palmoplantar hyperhidrosis. Guidelines for this treatment for patients with palmoplantar hyperhidrosis will need to be established in the future.     

长岛型掌跖角化病二例SERPINB7基因突变研究

目的 报告2例长岛型掌跖角化病,确定其致病基因突变。 方法 收集患者及其父母外周血和临床资料,提取基因组DNA,PCR扩增SERPINB7基因8个外显子及其侧翼序列,对扩增产物进行DNA测序以查找基因突变位点,并以200例无关健康人DNA作为对照进行扩增测序。 结果 2例患者均存在SERPINB7基因c.796C > T纯合突变,导致编码蛋白质第266位氨基酸出现终止改变（p.R266*）,其父母均为c.796C > T杂合突变,而无关健康对照未发现上述突变。 结论 SERPINB7基因的c.796C > T突变可能是引起2例患者长岛型掌跖角化病的原因。