Autoinflammation in pyoderma gangrenosum and its syndromic form (pyoderma gangrenosum, acne and suppurative hidradenitis)

Marzano, Angelo Valerio; Damiani, Giovanni; Ceccherini, Isabella; Berti, Emilio; Gattorno, Marco; Cugno, Massimo

doi:10.1111/bjd.15226

Cited by 166 publications

(177 citation statements)

References 35 publications

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“…The dominant hypothesis is that altered innate immunity leads to systemic autoinflammation (5). This view is supported by the finding that PG and its syndromic form PASH (PG, acne, supparative hidradenitis) are linked to alterations in autoinflammatory genes (6–8). An alternative view is that T cells are involved in PG pathophysiology (9, 10), yet there are no current theories on autoimmune targets.…”

Section: Introductionmentioning

confidence: 89%

Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies

et al. 2018

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Background: Pyoderma gangrenosum (PG) is a debilitating ulcerative skin disease that is one of the most common associated diseases seen in patients with inflammatory bowel disease and rheumatoid arthritis. Although PG is classified as a neutrophilic dermatosis, its pathophysiology is poorly understood.objective: Use data obtained from patient-reported histories, immunohistochemistry, and gene expression analysis to formulate a hypothesis on PG pathophysiology.Methods: Ten PG patients participated and answered questions about new ulcer formation. Skin biopsies of healed prior ulcers and adjacent normal skin were obtained from four patients for immunohistochemistry. Scars from healthy patients and patients with discoid lupus were used as additional controls. New onset PG papules were analyzed using immunohistochemistry and gene expression analysis via quantitative real-time PCR.results: All PG patients reported that healed sites of previous ulceration are refractory to re-ulceration. Simultaneous biopsies of healed and uninvolved skin triggered ulceration only in the latter. On immunohistochemistry, healed PG scars showed complete loss of pilosebaceous units, which were present in normal skin, and to a lesser extent in control scars, and discoid scars. Early PG papules showed perivascular and peripilosebaceous T cell infiltrates, rather than neutrophils. These early inflammatory events were dominated by increased gene expression of CXCL9, CXCL10, CXCL11, IFNG, and transcription factors consistent with Th1 phenotype.Limitations: Small sample size was the main limitation. Conclusion:We put forth the hypothesis that PG is a T cell response resulting in the destruction of pilosebaceous units.

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Section: Introductionmentioning

confidence: 89%

Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies

et al. 2018

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“…Moreover, Marzano et al . recently reported mutations in some autoinflammatory genes [Mediterranean fever (MEFV), NLR family pyrin domain containing 3 (NLRP3), NLRP12, nucleotide binding oligomerization domain containing 2 (NOD2), lipin 2 (LPIN2), proline‐serine‐threonine phosphatase interacting protein 1 (PSTPIP1)] in patients with PG and its syndromic form PASH (PG, acne, suppurative hydradenitis) .…”

Section: Introductionmentioning

confidence: 99%

T helper type 1-related molecules as well as interleukin-15 are hyperexpressed in the skin lesions of patients with pyoderma gangrenosum

Antiga

Maglie

Volpi

et al. 2017

Clinical and Experimental Immunology

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Pyoderma gangrenosum (PG) is a rare, immune-mediated skin disease classified into the group of neutrophilic dermatoses. Although a number of studies confirmed the central role of innate immunity, only few studies have investigated the possible contributing role of acquired immunity. In particular, no reports concerning T helper type 1 (Th1) and Th2 cells are available as yet. Therefore, 15 patients with PG, five with Sweet's syndrome (SS) and nine skin specimens from healthy controls (HC) were investigated, evaluating the expression of Th1-related markers interleukin (IL)-12, interferon (IFN)-γ, C-X-C motif chemokine receptor 3 (CXCR3) and C-C motif chemokine receptor 5 (CCR5), of the Th2-related molecules IL-4, IL-5, IL-13 and CCR3, of the co-stimulatory axis CD40/CD40 ligand, of IL-15 and the natural killer (NK) cell marker CD56 in skin lesions by immunohistochemistry. Patients with PG and SS showed a higher expression of Th1 markers than HC. Conversely, IL-5- and CCR3-expressing cells were less numerous in PG skin lesions compared to SS (P = 0·0157 and < 0·0001, respectively). Both CD40 and CD40L were expressed more in PG than in SS and HC (P < 0·0001 for both). Finally, the number of IL-15 and CD56 cells was higher in the skin of patients with PG than in those of SS and HC (P < 0·0001 for both). Our results suggest that Th2 cells are down-regulated in PG. At the same time, over-expression of the co-stimulatory axis CD40/CD40L amplifies the impairment of the Th1/Th2 balance. Both these findings might explain the most aggressive behaviour of PG in comparison to SS. Moreover, over-expression of IL-15 and CD56 cells may suggest a possible role of NK cells in the pathogenesis of the disease.

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“…The recent identification of autoinflammatory syndromes (AIS) manifesting with HS, such as PASH (PG, acne, and HS) and PAPASH (pyogenic arthritis, PG, acne and HS), has served to foster interest in the investigation of possible connections between autoinflammation, genetic background, and the development of HS. Multiple mutations in autoinflammatory genes have been seen in patients with HS‐related syndromes; these include PSTPIP1 , NLRP3 , IL1RN , MEFV , NOD2 , PSMB8 and the γ‐secretase complex, suggesting polygenic inheritance . Genetic mutations of the Notch pathway, such as Notch–MKP‐1 signalling variations, and loss‐of‐function mutations in the γ‐secretase genes, have been identified .…”

mentioning

confidence: 99%

Association of pyrin mutations and autoinflammation with complex phenotype hidradenitis suppurativa: a case–control study

Vural¹,

Gündoğdu²,

İli³

et al. 2019

Br J Dermatol

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Summary Background Hidradenitis suppurativa (HS) is a rare, debilitating neutrophilic dermatosis characterized by chronic inflammation of hair follicles. Many inflammatory conditions may accompany HS. Objectives To investigate the association of variants of the MEFV gene with a complex HS phenotype. Methods Firstly, we identified the clinical characteristics of 119 patients with HS with a complex phenotype (Hurley stage III disease and/or additional inflammatory symptoms). Then, we searched for MEFV variants among these patients. The odds ratios (ORs) for pathogenic MEFV mutations were calculated using data from these patients with HS and 191 healthy controls. Results The male/female ratio was higher, and the mean age of onset was earlier, in our complex HS group compared with patients with HS in general. Five of the patients with HS (4·2%) had a diagnosis of familial Mediterranean fever (FMF) with a standardized morbidity ratio of 45 [95% confidence interval (CI) 16·50–99·84, P < 0·001] when compared with the frequency of FMF in the general Turkish population. Of the patients with complex HS, 38% were positive for pathogenic variants of MEFV. The OR for carrying a pathogenic MEFV allele was 2·80 (95% CI 1·31–5·97, P < 0·001). Conclusions The frequency of MEFV mutations in the group of patients with complex HS was higher than that in healthy controls, suggesting that MEFV mutations may contribute to the pathogenesis of HS. Understanding the role of autoinflammation in HS is of fundamental importance for the development of novel therapies.

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Autoinflammation in pyoderma gangrenosum and its syndromic form (pyoderma gangrenosum, acne and suppurative hidradenitis)

Abstract: Overexpression of cytokines/chemokines, along with genetic changes, supports the hypothesis that PG and its syndromic form, PASH, are a spectrum of polygenic autoinflammatory conditions.

Cited by 166 publications

References 35 publications

Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies

Classic Ulcerative Pyoderma Gangrenosum Is a T Cell-Mediated Disease Targeting Follicular Adnexal Structures: A Hypothesis Based on Molecular and Clinicopathologic Studies

T helper type 1-related molecules as well as interleukin-15 are hyperexpressed in the skin lesions of patients with pyoderma gangrenosum

Association of pyrin mutations and autoinflammation with complex phenotype hidradenitis suppurativa: a case–control study

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