Search

Background: Pathogenicity of donor-specific antibodies (DSAs) can be assessed using the single-antigen flow beads (SAFB) assays through mean fluorescence intensity (MFI) with or without serum ethylenediaminetetraacetic acid (EDTA) treatment, measurement of C1q or C3d binding and/or their intragraft detection [graft-bound donor-specific antibody (gDSA)]. We aimed to investigate which of these markers best associates with antibody-mediated rejection (ABMR) and kidney allograft loss at the time of a for-cause biopsy., Methods: This retrospective, single-centre study included 77 kidney transplant recipients who underwent a for-cause biopsy between December 2004 and July 2013. All displayed serum DSAs were identified on the same day as the biopsy. Sera were tested in parallel with the classical SAFB assay with or without serum EDTA treatment, C1q- and C3d-binding assays. gDSAs were eluted from biopsy fragments and identified with SAFB., Results: The median time between transplantation and biopsy was 25 months (range 0.5-251). The median follow-up was 36 months (range 0-140). ABMR was histologically proven in 40% of recipients. The sensitivity and specificity of C1q, C3d and gDSA assays for predicting ABMR were 68% and 61%, 52% and 70% and 64.5% and 56.5%, respectively. At the time of biopsy, only the DSA MFI after EDTA treatment and C3d positivity were associated with graft loss. In multivariate analyses, glomerular filtration rate, transplant glomerulopathy and C4d positivity were the only factors associated with graft loss., Conclusions: Our findings weaken the rationale for systematically implementing C1q, C3d or gDSA assays in this situation, because they do not independently predict ABMR and graft loss.

Background: Imatinib mesylate is a potent inhibitor of platelet-derived growth factor and transforming growth factor-β signalling pathways which may play a role in systemic sclerosis (SSc)-associated skin changes., Objectives: We aimed primarily at assessing the efficacy of imatinib mesylate in scleroderma skin fibrosis., Methods: We performed a phase II double-blinded trial on patients with scleroderma with either morphoea involving > 20% of body surface area or SSc with extensive skin involvement: modified Rodnan Skin Score (mRSS) ≥ 20/51. Each patient was randomized to receive either imatinib mesylate 400 mg or placebo daily for a total of 6 months, and then was followed up 6 months after therapy discontinuation. Skin fibrosis was assessed by mRSS and measurement of the dermal thickness using skin biopsies performed at inclusion and at 6 months of treatment. In addition, quality of life (Dermatology Life Quality Index and modified Health Assessment Questionnaire for Scleroderma) was recorded at each visit, and pulmonary function before and after intervention., Results: Twenty-eight patients were included in the study with a mean age of 48·9 years (range 30-71): 25 had a diagnosis of a SSc and three of diffuse cutaneous scleroderma. Demographic data, frequency of organ involvement of SSc and mRSS were comparable between groups. At 6 months, the proportion of variation of mRSS from inclusion was not statistically significantly different between the two groups (median +0·10 in imatinib group vs. -0·16 in placebo group, P = 0·098). Similarly, changes in dermal thickness, quality of life and diffusion capacity for carbon monoxide were not significantly different between groups., Conclusions: This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Background: Psoriasiform eruptions occur in association with antitumour necrosis factor (TNF)-alpha treatments in autoinflammatory diseases. The major reported clinical presentation is palmoplantar pustulosis, sometimes accompanied with plaque-like psoriasis. In some reports, histological findings suggest psoriasis whereas others favour a lichenoid drug reaction. We present a case series with a comprehensive clinical, histopathological and immunohistochemical study., Objectives: To investigate the mechanism involved in psoriasiform eruptions in patients receiving anti-TNF-alpha inhibitors., Methods: Between July 2004 and May 2008, 13 patients with psoriasiform eruptions arising under anti-TNF-alpha treatment were enrolled in the study. Punch biopsy specimens of lesions were processed for standard and immunohistochemical analyses using antibodies against CD3, CD4, CD8, CD20, CD1a, KP1, CXCR3, CXCL9, Tia1 and MxA, which is specifically induced by type I interferons (IFNs). Additionally, we analysed biopsies from lesional skin of patients with cutaneous discoid lupus erythematosus, lichen planus and psoriasis. Control biopsies were taken from unaffected skin., Results: All patients developed psoriasiform plaques on the body accompanied with palmoplantar keratoderma or pustulosis in three patients. Histological and immunohistochemical findings showed a psoriasiform pattern with focal lichenoid and spongiotic features. We detected strong production of the MxA protein in inflammatory cells, indicating involvement of type I IFNs, and the expression was higher than in control psoriasis samples. Expression of MxA was closely associated with the recruitment of CXCR3+ lymphocytes in the skin bearing markers of cytotoxic capacity., Conclusions: Results support the hypothesis that psoriasiform eruptions are a new model of drug reaction characterized by an increased expression of type I IFNs induced by anti-TNF-alpha.

Objectives: Altered angiogenesis is a characteristic feature in SSc and remains ill-understood. VEGF is believed to play a central role. Serum VEGF is elevated in SSc patients but questions remain concerning the source of circulating VEGF. Here we investigated platelet activation and the role of platelets as a source of VEGF and other angiogenic mediators in this disease., Methods: A cohort of 40 patients with SSc was included. Age- and sex-matched healthy subjects and subjects presenting a primary RP were included as controls. Platelets were isolated, activated with thrombin and the secretion of VEGF, platelet derived growth factor, homodimeric form BB (PDGF-BB), TGF-beta1 and angiopoietins-1 and -2 measured. Plasma concentrations of these mediators and the functionality of platelet-derived VEGF were also studied. Platelet activation was assayed by measuring plasma beta-thromboglobulin and expression of P-selectin on platelets. The effect of iloprost on VEGF secretion by platelets was studied., Results: Platelets from SSc patients, in contrast to controls, secreted large amounts of VEGF when activated, but not PDGF-BB, TGF-beta1 or angiopoietins. Increased expression of membrane P-selectin confirmed platelet activation in the patients. Iloprost inhibited VEGF secretion by platelets both in vivo and in vitro, through inhibition of platelet activation., Conclusions: Platelets transport high levels of VEGF in SSc. They may contribute to circulating VEGF because of ongoing activation in the course of the disease. If activated at the contact of injured endothelium, platelets may be important in the altered angiogenesis associated with the disease through the secretion of high levels of VEGF.

Background: Idiopathic facial aseptic granuloma (IFAG) was recently described in a single-centre retrospective study as a skin condition that occurs specifically in childhood., Objectives: To improve our epidemiological, clinical and pathological knowledge on IFAG, to search for an infectious aetiology, and to assess therapeutic recommendations., Methods: Children presenting with one or several acquired nodules on the face, lasting for at least 1 month, with no evidence of any other recognizable clinical entity such as infantile acne, pilomatrixoma, furuncle, tumour or vascular malformation, were enrolled in a prospective multicentre study from June 2001 to June 2004, involving the main French paediatric dermatology outpatient units. We recorded clinical details about the nodule and its duration, ultrasound study pattern, cultures for bacteria and mycobacteria, and Bartonella henselae and Afipia felis antibody testing., Results: Thirty children (17 boys and 13 girls, mean age 3.8 years) were enrolled. Ultrasound studies revealed a solid well-demarcated hypoechoic lesion without calcium deposit. Cultures for bacteria were negative in 70% of cases. Cultures for mycobacteria and cat scratch disease serologies were negative. Antibiotic therapy was ineffective; the lesion healed spontaneously with a mean duration of 11 months. Histological examination, performed in five cases, showed a chronic dermal lymphohistiocytic granuloma with numerous foreign body-type giant cells., Conclusions: IFAG is characterized by a painless facial nodule, presenting as a single lesion localized on the cheek, with a prolonged course but spontaneous healing. Oral or local antibiotics are usually ineffective. Regarding the pathophysiology, our study rules out a primary infectious disease, and allows considering IFAG either as a granulomatous process appearing around an embryological residue or as a manifestation to include in the spectrum of granulomatous rosacea in childhood.

Background: Hereditary mucoepithelial dysplasia is a dominantly inherited disease, mainly characterized by chronic mucosal lesions associated with keratitis, non-scarring alopecia, keratosis pilaris and perineal intertrigo. Since the original report by Witkop, this condition has been considered to be a disorder of desmosome/gap junction formation, but there has been no ex vivo investigation of these components using genetic and immunolabelling techniques., Objectives: To perform light and immunoelectron microscopic studies, and partial genetic analysis on five patients in a family and three sporadic cases and to point out similarities of this rare disorder with chronic mucocutaneous candidiasis and other follicular keratosis syndromes, i.e. ichthyosis follicularis-alopecia-photophobia (IFAP), keratitis-ichthyosis-deafness (KID) and Siemens syndromes., Methods: Biopsies from the involved oral mucosa and armpit skin of patient 1 were prepared for standard histopathology, electron microscopy and immunocytochemistry. Microsatellite genotyping was performed in three affected family members. Direct sequencing after polymerase chain reaction amplification of the entire coding region was performed., Results: A 14-year-old male had recurrent keratitis, widespread keratosis pilaris, perineal intertrigo, hypotrichosis and oral mucosal involvement. A similar phenotype was noted in four members of his family and in three sporadic cases. Histological examination of oral mucosa and skin samples showed a psoriasiform pattern, dyskeratotic features and cytoplasmic vacuoles. Expression of connexins (Cx), desmosomal, adherens junction and cytoskeleton proteins (Cx 26, 32 and 43, desmogleins 1 and 2, plakoglobin, desmoplakins I-II, plakophilin 1, beta-catenin, E-cadherin, keratins, beta-tubulin, vimentin and actin) was normal. Ultrastructural studies showed a reduced number of desmosomes. Dyskeratotic cells exhibited internalized gap junctions, long filamentous inclusions reactive with antikeratin antibodies, and bundles of perinuclear fibres resembling clear tonofilaments. Genetic analysis in the studied family excluded the desmosomal cadherins in chromosome 18q12 as candidate genes., Conclusions: A diagnosis of hereditary mucoepithelial dysplasia should be strongly suggested by the triad of non-scarring alopecia, well-demarcated erythema of oral mucosa and psoriasiform perineal rash, after exclusion of the clinically related follicular keratosis syndromes. Defective expression of cytoskeleton elements and/or a modification of mechanisms regulating junction-cytoskeleton assembly may be primarily responsible for impaired epithelial cohesion.

Background: In vitiligo, melanocytes are gradually lost in depigmented macules of the skin. The disappearance of melanocytes has, however, not been clearly observed and consequently the aetiology of the disease (autoimmune, neural, cytotoxic) is still elusive. The starting point of vitiligo macules is frequently determined by local conditions such as wounds and excoriations, but may also follow minor traumas such as pressure or repeated friction. This prominent feature is often neglected., Objectives: To clarify the biological consequences of repeated friction on the attachment and survival of melanocytes in non lesional vitiligo skin., Methods: Light reproducible skin friction was performed for 4 min on the volar forearm of 18 patients with extensive vitiligo and five controls with normal healthy skin. Biopsies from the test area and control skin were taken at 1, 4, 24 and 48 h following friction. Serial sections were examined with standard light microscopy, transmission electron microscopy, histochemistry and immunohistochemistry (dihydroxyphenylalanine, HMB-45, E-cadherin and an early apoptosis marker, M30 cytoDEATH antibody)., Results: The observation of sections at 1 and 48 h after friction on vitiligo skin and at all time points in controls revealed no changes. In contrast, in vitiligo skin at 4 and 24 h after friction, several melanocytes had undergone detachment and were found in various suprabasal positions, including the stratum spinosum, granular layer, and within and outside the stratum corneum., Conclusions: Detachment and transepidermal elimination of melanocytes following minor mechanical trauma in non lesional vitiligo skin is probably the cause of depigmentation occurring in the isomorphic response (Koebner phenomenon). We propose that transepidermal elimination of melanocytes in vitiligo should be regarded as a possible mechanism of chronic loss of pigment cells, perhaps previously damaged by another process.