Background. The acrosyringium is the target for inflammation in the chronic and intensely inflammatory skin disease palmoplantar pustulosis (PPP). The sweat-gland apparatus seems to be an immunocompetent structure that probably contributes to skin defence. Furthermore, the sweat gland and duct may be a hitherto unrecognized neuroendocrine organ.Aim. To obtain further information about the neuroendocrine properties of the sweat-gland apparatus by examining expression of the somatostatin receptors (SSTRs) 1-5 in healthy palmar skin and in PPP skin.Methods. Biopsy specimens were taken from 25 patients with PPP and 25 healthy controls. Immunohistochemical analysis was used to investigate expression of SSTRs 1-5.Results. SSTRs 1-5 were expressed in both epidermal and endothelial structures. The staining intensity of the sweat-gland apparatus was more pronounced than that of the epidermis. Expression differed significantly between lesional PPP and normal plantar skin, with increased expression of SSTRs 3 and 4 in ducts in epidermis, and decreased expression of SSTR 1 in ducts in both papillary and reticular dermis. In specimens with pronounced inflammation, numerous dendritic cells with strong expression of SSTRs 1.. 2 and 4 were seen, especially in the papillary dermis.Conclusions. The presence of SSTRs in palmoplantar skin, and specifically at high density in the sweat glands and ducts, might be of particular importance in skin neuroimmunoendocrinology. Although the relevance of the changes in SSTR expression in PPP skin compared with normal skin is unclear, our hypothesis is that these differences might influence the function of both the neuroendocrine and neuroimmunological properties of palmoplantar skin, especially in the sweat-gland apparatus.

BACKGROUND:Palmoplantar pustulosis (PPP) is a common disease strongly associated with smoking, autoimmune comorbidities and a deranged calcium homeostasis. It is unclear whether these changes in calcium homeostasis are a consequence of vitamin D status, abnormal dermal vitamin D synthesis or whether they are substantiated in effects on bone mineral density (BMD).OBJECTIVES:To study the vitamin D status and BMD in patients with PPP.METHODS:In comparisons with two sets of controls (n=101 for serum analyses and n=5123 for BMD analyses), we therefore aimed to investigate whether PPP (59 cases) was associated with serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, whether patients with PPP had decreased BMD and finally if the dermal expression of 25-hydroxyvitamin D(3) -1α-hydroxylase (CYP27B1) and the vitamin D receptor (VDR) were affected in PPP skin lesions.RESULTS:We found no differences in mean serum 25-hydroxyvitamin D levels between cases and controls, whereas PPP cases displayed 17·8 pmol L(-1) lower (P=0·04) values in 1,25-dihydroxyvitamin D. BMD at the hip, lumbar spine or of total body did not differ substantially between cases and controls. Finally, patients with PPP had lower dermal expression of CYP27B1 and VDR in affected skin lesions.CONCLUSIONS:The increase in serum calcium levels and suppressed parathyroid hormone in patients with PPP were not attributable to derangements in vitamin D status and these patients did not have lower BMD.

Backgound  Palmoplantar pustulosis (PPP) is a chronic and intensely inflammatory skin disease with pustules, erythema and scaling localized to the palms and soles. To date, no specific treatment is known. Earlier findings indicate the acrosyringium as the target for the inflammation.

BACKGROUND:Palmoplantar pustulosis (PPP) is a chronic inflammatory disease affecting mainly smoking women. Some patients also have psoriasis. A subgroup of patients with psoriasis has been shown to have silent gluten sensitivity with relevance for their psoriasis. Nothing is known about gluten sensitivity in PPP.OBJECTIVES:To find out whether any patients with PPP are gluten-sensitive and whether this might be relevant for the PPP activity.PATIENTS AND METHODS:One hundred and twenty-three patients (113 women) with PPP participated. Screening for IgA antibodies against gliadin and tissue transglutaminase (tTG) was performed, the duodenal mucosa in patients with and without these antibodies was studied and the effect of a gluten-free diet (GFD) was followed up.RESULTS:Twenty-two patients (18%) had IgA antibodies against gliadin and nine of 94 (10%) against tTG. Twelve patients with antibodies and 11 without underwent gastro-duodenoscopy. Four displayed villous atrophy, whereas all other specimens were judged as essentially normal at routine staining. However, with immunohistochemistry, the numbers of CD3+ and CD8+ lymphocytes in the epithelium were found to be increased in patients with any type of antibody, although they were most numerous in those with both types of antibodies. Seven of 123 patients (6%) had coeliac disease (three previously diagnosed). Patients with antibodies who adhered to the GFD displayed total or nearly total clearance of the skin lesions and normalization of the antibody levels.CONCLUSIONS:Patients with PPP should be screened for antibodies against gliadin and tTG. Those with antibodies can be much improved on a GFD regardless of the degree of mucosal abnormalities.

Objective. To determine if there is evidence of inflammation in the duodenal mucosa in patients with psoriatic arthritis (PsA) and to compare the results with those in patients with psoriasis vulgaris (PsV). Methods. Nineteen consecutive patients with PsA underwent gastroduodenoscopy, and biopsy specimens were taken from the duodenal and gastric mucosa. In addition to routine processing, the duodenal mucosal specimens were stained for CD3+, CD8+ and CD4+ T lymphocytes, tryptase-positive mast cells, and EG2-positive eosinophil granulocytes. The results were compared with those in duodenal mucosal specimens from patients with PsV and patients with irritable bowel syndrome. Results. Compared with PsV patients (without antibodies against gliadin), patients with PsA had a highly significant increase in intraepithelial CD3+ and CD8+ lymphocytes and also in CD4+ lymphocytes in the lamina propria in the villi. The lymphocyte increase was not related to presence of IgA antibodies against gliadin, endomysium, or transglutaminase, or to concomitant gastritis. Patients with PsA and PsV showed a pronounced increase in mast cells and eosinophil granulocytes. Conclusion. The increased lymphocyte infiltration in the duodenal mucosa in PsA, but not in PsV, might indicate different pathogenetic mechanisms in these psoriasis variants.

To the Editor: The psoriasis variant palmoplantar pustulosis (PPP) is closely associated with smoking; 95% of patients are smokers at the onset of the disease.1Eriksson M.O. Hagforsen E. Lundin I.P. Michaëlsson G. Palmoplantar pustulosis: a clinical and immunohistological study.Br J Dermatol. 1998; 138: 390-398Crossref PubMed Scopus (152) Google Scholar In addition, 90% are women and the risk that a woman who is a smoker will develop PPP is 74 times higher than the risk for a nonsmoking healthy woman of the same age.2Hagforsen E. Michaëlsson K. Lundgren E. Olofsson H. Petersson A. Lagumdzija A. et al.Women with palmoplantar pustulosis have disturbed calcium homeostasis and a high prevalence of diabetes mellitus and psychiatric disorders: a case control study.Acta Derm Venereol. 2005; 85: 225-232PubMed Google Scholar Nicotine is excreted in the eccrine palmar duct,3Kintz P. Henrich A. Cirimele V. Ludes B. Nicotine monitoring in sweat with a sweat patch.J Chromatogr B Biomed Sci Appl. 1998; 705: 357-361Crossref PubMed Scopus (47) Google Scholar which is the target for the inflammation in PPP.1Eriksson M.O. Hagforsen E. Lundin I.P. Michaëlsson G. Palmoplantar pustulosis: a clinical and immunohistological study.Br J Dermatol. 1998; 138: 390-398Crossref PubMed Scopus (152) Google Scholar Despite the possible role of smoking as a precipitating or aggravating factor for PPP, there are no reports on the clinical course of PPP in relation to cessation of smoking. We have tried to perform a prospective study with the aim of gaining more information about the clinical course of PPP in patients who were able to stop smoking in comparison with those who were not. In all, 63 consecutive patients with PPP (59 women and 4 men, mean age 54 ± 10 years, range 25-73 years), all smokers, answered a questionnaire concerning their medical history and smoking habits. All had been smokers (in the majority about 20 years) at onset of PPP. The mean duration of their PPP was 9 ± 8 years (range 1-30 years). All were examined by the same dermatologist (G. M.). The number of fresh pustules, the degree of erythema and scaling (0-3), and the percentage area affected on each palm and sole were recorded and a severity score calculated. All patients were informed about a possible role of smoking in PPP and detailed written and oral information about PPP was given.1Eriksson M.O. Hagforsen E. Lundin I.P. Michaëlsson G. Palmoplantar pustulosis: a clinical and immunohistological study.Br J Dermatol. 1998; 138: 390-398Crossref PubMed Scopus (152) Google Scholar, 2Hagforsen E. Michaëlsson K. Lundgren E. Olofsson H. Petersson A. Lagumdzija A. et al.Women with palmoplantar pustulosis have disturbed calcium homeostasis and a high prevalence of diabetes mellitus and psychiatric disorders: a case control study.Acta Derm Venereol. 2005; 85: 225-232PubMed Google Scholar, 4Hagforsen E. Einarsson A. Aronsson F. Nordlind K. Michaëlsson G. The distribution of choline acetyltransferase- and acetylcholinesterase-like immunoreactivity in the palmar skin of patients with palmoplantar pustulosis.Br J Dermatol. 2000; 142: 234-242Crossref PubMed Scopus (34) Google Scholar, 5Hagforsen E. Edvinsson M. Nordlind K. Michaëlsson G. Expression of nicotinic receptors in the skin of patients with palmoplantar pustulosis.Br J Dermatol. 2002; 146: 383-391Crossref PubMed Scopus (82) Google Scholar After being given this information, the patients were asked whether they were willing to try to stop smoking and, if so, when (within 1-2 months or later). Irrespective of their intention to stop smoking, the patients were also asked whether they were willing to fill in a protocol once weekly for at least 3 months concerning the activity of their PPP. The patients were instructed how to count fresh (yellow) pustules and were also asked to mark on a 10-cm visual analog scale how severe they considered their PPP on the day they counted the pustules. Most of the patients filling in protocols were followed up clinically after 3 to 6 months. Some patients did not want to fill in protocols but were followed up clinically. The degree of significance was tested with the nonparametric Wilcoxon signed rank test for paired 2-group comparison. The medical ethics committee of Uppsala University, Sweden, approved the study and the patients gave their informed consent. Only 34 patients (54%) were willing to try to stop smoking within a month. In 6 patients with serology indicating gluten intolerance, further medical investigations had to be done and the smoking cessation trial was, therefore, stopped. As shown in Table I, there was a highly significant improvement in those who stopped smoking but not in those who continued. However, the number of patients is low as some were not motivated, dropped out, or sent in diaries that could not be evaluated.Table IPatient evaluationnBeforeAfterPPatient evaluation Total no. pustules Stopped smoking923 ± 3210 ± 22.0117 Did not stop smoking820 ± 2252 ± 44.2367 Total VAS Stopped smoking911.3 ± 5.75.1 ± 6.8.0173 Did not stop smoking89.8 ± 4.610.1 ± 4.8.3980Dematologist evaluation Total no. fresh pustules Stopped smoking1521 ± 92 ± 2.0185 Did not stop smoking1322 ± 2737 ± 42.1361 Total score Stopped smoking159.6 ± 8.32.3 ± 2.0.007 Did not stop smoking137.0 ± 4.17.8 ± 5.8.7837Patient evaluation of number of pustules and severity of palmoplantar pustulosis based on diaries before and after 3-month attempts to stop smoking and dermatologist evaluation of number of pustules and total score (based on erythema, scaling, and area involved) at baseline and at follow-up after 3 to 6 months in patients who stopped and did not stop smoking.VAS, Visual analog scale. Open table in a new tab Patient evaluation of number of pustules and severity of palmoplantar pustulosis based on diaries before and after 3-month attempts to stop smoking and dermatologist evaluation of number of pustules and total score (based on erythema, scaling, and area involved) at baseline and at follow-up after 3 to 6 months in patients who stopped and did not stop smoking. VAS, Visual analog scale. The number of patients who stopped smoking was also low. Those who were not able to stop failed as a result of abstinence symptoms, low motivation, or both. Despite the limitations of the study the conclusion is that cessation of smoking can result in a substantial improvement of PPP.

Journal Article Infliximab can precipitate as well as worsen palmoplantar pustulosis: possible linkage to the expression of tumour necrosis factor‐α in the normal palmar eccrine sweat duct? Get access G. Michaëlsson, G. Michaëlsson Department of Medical Sciences/Dermatology and Venereology, University Hospital, S‐751 85 Uppsala, Sweden, Department of Internal Medicine, Västerviks Hospital, Västervik, Sweden E‐mail: gerd.michaelsson@medsci.uu.se Search for other works by this author on: Oxford Academic Google Scholar U. Kajermo, U. Kajermo Department of Medical Sciences/Dermatology and Venereology, University Hospital, S‐751 85 Uppsala, Sweden, Department of Internal Medicine, Västerviks Hospital, Västervik, Sweden E‐mail: gerd.michaelsson@medsci.uu.se Search for other works by this author on: Oxford Academic Google Scholar A. Michaëlsson, A. Michaëlsson Department of Medical Sciences/Dermatology and Venereology, University Hospital, S‐751 85 Uppsala, Sweden, Department of Internal Medicine, Västerviks Hospital, Västervik, Sweden E‐mail: gerd.michaelsson@medsci.uu.se Search for other works by this author on: Oxford Academic Google Scholar E. Hagforsen E. Hagforsen Department of Medical Sciences/Dermatology and Venereology, University Hospital, S‐751 85 Uppsala, Sweden, Department of Internal Medicine, Västerviks Hospital, Västervik, Sweden E‐mail: gerd.michaelsson@medsci.uu.se Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 153, Issue 6, 1 December 2005, Pages 1243–1244, https://doi.org/10.1111/j.1365-2133.2005.06977.x Published: 01 December 2005

Palmoplantar pustulosis is characterized by pustule formation in the acrosyringium. Nearly 50% of palmoplantar pustulosis sera produce immunofluorescence of the palmar papillary endothelium from healthy subjects, but also of the endothelium of normal parathyroid gland. With a case-control design the levels of calcium and parathyroid hormone in serum were measured in 60 women with palmoplantar pustulosis and 154 randomly selected population-based control women. One-third of the controls had been smokers, whereas 95% of the cases were or had been smokers. Mean age-adjusted serum calcium was increased in the patients compared with the controls (2.43 vs 2.36 mmol/l; p<0.0001), whereas the parathyroid hormone concentration was suppressed (23.2 vs 31.1 ng/l; p<0.0001). The plasma levels of parathyroid hormone-related protein were normal in patients but there was a strong expression of this protein in the acrosyringium both in palmoplantar pustulosis and control skin. As even a marginal elevation of serum calcium is associated with an increased risk for diabetes, cardiovascular disease and psychiatric disease, we analysed the risk for these disorders in palmoplantar pustulosis patients compared with that in the control group. Both diabetes mellitus and psychiatric disorders were associated with palmoplantar pustulosis with an odds ratio of 8.7 (95% CI 3.3-22.8) and 5.6 (95% CI 2.2-14.4), respectively. Palmoplantar pustulosis is a complex disease with an increased risk for several non-dermatological disorders. The role of the mildly increased serum calcium for the high risk for diabetes and depression deserves to be studied.

Ninety-five percent of patients with palmoplantar pustulosis are smokers at onset of the disease. The aim of this study was to determine whether these patients have serum antibodies to nicotinic acetylcholine receptors (nAChR ab) and if their sera induce a specific immunofluorescence in normal palmar skin. Sera from 45 patients with palmoplantar pustulosis and 23 patients with chronic hand eczema were analysed for muscle nAChR ab, and immunofluorescence was performed on healthy palmar skin. Forty-two percent of the patients with palmoplantar pustulosis but none of the eczema patients had raised levels of nAChR ab. Immunofluorescence showed staining on endothelial cells in the papillary dermis in 47% of all sera from patients with palmoplantar pustulosis and in those with nAChR ab in 68%. On palmar skin from smokers there was also a staining of the sweat duct. Sera from patients with chronic hand eczema were negative. Our findings indicate that palmoplantar pustulosis is an autoimmune disease, possibly induced by smoking.

OBJECTIVES:To find out whether patients with psoriatic arthritis (PsoA) have an increased prevalence of antibodies to gliadin (AGA) and of coeliac disease.METHODS:One hundred and fourteen PsoA patients with skin disease of 20+/-13 yr and joint disease of 11+/-10 yr duration answered a questionnaire concerning their medical history and underwent clinical examination, including radiology. Serum IgA AGA and IgG AGA, IgA antibodies to endomysium and immunoglobulins, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration were determined.RESULTS:Five of the 114 patients (4.4%) had coeliac disease. After exclusion of these five patients, the mean IgA AGA concentration was significantly higher (P=0.0005) than that in a reference group. None of the patients had IgA antibodies to endomysium. The mean serum IgA concentration was significantly increased and IgM decreased. Patients with a high concentration of IgA AGA had significantly higher ESR and CRP and a longer duration of morning stiffness than those with a low AGA concentration.CONCLUSIONS:Patients with PsoA have an increased prevalence of raised serum IgA AGA and of coeliac disease. Patients with raised IgA AGA seem to have more pronounced inflammation than those with a low IgA AGA concentration.

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.

In a previous screening study, 16% of patients with psoriasis had IgA and/or IgG antibodies to gliadin (AGA). The aim of the present study was to evaluate the effect of a gluten-free diet (GFD) in 33 AGA-positive and six AGA-negative psoriasis patients. Of the 33 AGA-positive patients, two had IgA antibodies to endomysium (EmA) and 15 an increased number of lymphocytes in the duodenal epithelium, but in some this increase was slight. Two patients had villous atrophy. A 3-month period on a GFD was followed by 3 months on the patient's ordinary diet. The severity of psoriasis was evaluated with the psoriasis area and severity index (PASI). The examining dermatologists were unaware of the EmA and duodenal biopsy results throughout the study. Thirty of the 33 patients with AGA completed the GFD period, after which they showed a highly significant decrease in mean PASI. This included a significant decrease in the 16 AGA-positive patients with normal routine histology in duodenal biopsy specimens. The AGA-negative patients were not improved. After GFD, the AGA values were lower in 82% of those who improved. There was a highly significant decrease in serum eosinophil cationic protein in patients with elevated AGA. When the ordinary diet was resumed, the psoriasis deteriorated in 18 of the 30 patients with AGA who had completed the GFD period. In conclusion, psoriasis patients with raised AGA might improve on a GFD even if they have no EmA or if the increase in duodenal intraepithelial lymphocytes is slight or seemingly absent.

Retinoic acid, vitamin D3 and triiodothyronine regulate keratinocyte proliferation and differentiation--processes that are disturbed in psoriatic skin--via binding to nuclear receptors for retinoic acid (RAR-alpha,-gamma), vitamin D3 (VDR), thyroid hormone (TR-alpha,-beta) plus the common heterodimer partners, the 9-cis-retinoic acid receptors (RXR-alpha,-beta). By using a new quantitative real-time polymerase chain reaction assay, the expression of these receptors and three housekeeping genes (cyclophilin, GAPDH and beta-actin) was studied in psoriatic skin. The expression of housekeeping genes was consistently 2.7-4.3 times higher in lesional than in non-lesional skin. When the beta-actin expression was used to normalize the receptor mRNA values, the RARalpha, RXRalpha and TRalpha transcripts were found to be 58-75% lower in lesional vs. non-lesional skin and the RXRalpha:RARgamma ratio was reduced from 3.2 to 1.5. Topical treatment for 4 days with 0.025% all-trans-retinoic acid or calcipotriol under occlusion did not normalize the altered mRNA expression of RARs, RXR and VDR in lesional skin. The results suggest that retinoid and thyroid hormone signalling is abnormal in lesional psoriatic skin, but how this relates to the pathogenesis of the disease is still unclear.

This study was aimed to investigate the prevalence of celiac disease and antibodies to gliadin (AGA) in psoriatic arthritis (PsA) and to study the association to clinical features. Five patients of 114 (4.2%) had celiac disease. The mean IgA AGA (patients with celiac disease excluded) was found significantly higher (p=0.0005) compared to the reference group. None of the patients had IgA antibodies to endomysium, The mean serum IgA was increased and the mean IgM decreased in PsA. Patients with asymmetric small-joint involvement had the highest mean IgA AGA and those with distal joint involvement the lowest. Patients with high IgA AGA had significantly higher ESR, CRP and morning stiffness. We found an increased prevalence of celiac disease and raised IgA AGA. associated to more pronounced inflammatory disease in PsA. Serum IgA was particularly elevated in those with raised IgA ACA. Further studies will show if gluten avoidance may decrease the severity of arthritis in PsA.