Association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) shares genetic and cytokine profiles with other autoinflammatory diseases

Abstract

The association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) has recently been described and suggested to be a new entity within the spectrum of autoinflammatory syndromes, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T-cells. We conducted an observational study on 5 patients with PASH syndrome, analyzing their clinical features, genetic profile of 10 genes already known to be involved in autoinflammatory diseases (AIDs), and cytokine expression pattern both in lesional skin and serum. In tissue skin samples, the expressions of interleukin (IL)-1β and its receptors I and II were significantly higher in PASH (P = 0.028, 0.047, and 0.050, respectively) than in controls. In PASH patients, chemokines such as IL-8 (P = 0.004), C-X-C motif ligand (CXCL) 1/2/3 (P = 0.028), CXCL 16 (P = 0.008), and regulated on activation, normal T cell expressed and secreted (RANTES) (P = 0.005) were overexpressed. Fas/Fas ligand and cluster of differentiation (CD)40/CD40 ligand systems were also overexpressed (P = 0.016 for Fas, P = 0.006 for Fas ligand, P = 0.005 for CD40, and P = 0.004 for CD40 ligand), contributing to tissue damage and inflammation. In peripheral blood, serum levels of the main proinflammatory cytokines, that is, IL-1β, tumor necrosis factor-α, and IL-17, were within the normal range, suggesting that in PASH syndrome, the inflammatory process is mainly localized into the skin. Four out of our 5 PASH patients presented genetic alterations typical of well-known AIDs, including inflammatory bowel diseases, and the only patient lacking genetic changes had clinically evident Crohn disease. In conclusion, overexpression of cytokines/chemokines and molecules amplifying the inflammatory network, along with the genetic changes, supports the view that PASH syndrome is autoinflammatory in origin.

FIGURE 1

Clinical features of patients with the association of pyoderma gangrenosum, acne and suppurative hidradenitis. Papulopustular lesions, abscesses, and fistulas involving the anogenital area (panel A); multiple ulcerative lesions of the back (panel B), which were histologically diagnosed as pyoderma gangrenosum; acne conglobata on the face (panel C); and ulcerated plaques with vegetating aspects (panel D and E), which were histologically diagnosed as pyoderma gangrenosum.

FIGURE 2

Expression of IL-1-β and its soluble receptors I and II (sIL-1RI and sIL-1RII) in homogenate samples of pyoderma gangrenosum lesional skin from 5 patients with PASH syndrome. Six NS served as controls. Numerical values represent signal intensity in a cytokine array assay. IL-1 = interleukin-1, NS = normal subjects, PASH = pyoderma gangrenosum, acne, and hidradenitis suppurativa.

FIGURE 3

Expression of TNF-α and its soluble receptors I and II (sTNFRI and sTNFRII) in homogenate samples of pyoderma gangrenosum lesional skin from 5 patients with PASH syndrome. Six NS served as controls. Numerical values represent signal intensity in a cytokine array assay. NS = normal subjects, PASH = pyoderma gangrenosum, acne, and hidradenitis suppurativa, TNF = tumor necrosis factor.

FIGURE 4

Expression of IL-17, its soluble receptor (sIL17R), L-selectin, and E-selectin in homogenate samples of pyoderma gangrenosum lesional skin from 5 patients with PASH syndrome. Six NS served as controls. Numerical values represent signal intensity in a cytokine array assay. E-selectin = endothelial selectin, IL = interleukin, L-selectin = leukocyte selectin, NS = normal subjects, PASH = pyoderma gangrenosum, acne, and hidradenitis suppurativa.

FIGURE 5

Expression of IL-8, RANTES, CXCL 1,2,3 (C = cysteine, X = any amino acid) and CXCL 16 in homogenate samples of pyoderma gangrenosum lesional skin from 5 patients with PASH syndrome. Six NS served as controls. Numerical values represent signal intensity in a cytokine array assay. CXCL = chemokine [C-X-C motif] ligand, IL = interleukin, NS = normal subjects, PASH = pyoderma gangrenosum, acne, and hidradenitis suppurativa, RANTES = regulated on activation, normal T cell expressed and secreted.

FIGURE 6

Expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 in homogenate samples of pyoderma gangrenosum lesional skin from 5 patients with PASH syndrome. Six NS served as controls. Numerical values represent signal intensity in a cytokine array assay. MMP = matrix metalloproteinase, NS = normal subjects, PASH = pyoderma gangrenosum, acne, and hidradenitis suppurativa, TIMP = tissue inhibitor of metalloproteinase.

FIGURE 7

Expression of Siglec 5, Siglec 9, Fas (also known as CD95), FasL (also known as CD178), CD40, and CD40 L (CD40 ligand) in homogenate samples of pyoderma gangrenosum lesional skin from 5 patients with PASH syndrome. Six NS served as controls. Numerical values represent signal intensity in a cytokine array assay. CD40 L = CD40 ligand, Fas = Fas protein, FasL = Fas ligand, NS = normal subjects, PASH = pyoderma gangrenosum, acne, and hidradenitis suppurativa, Siglec = sialic acid-binding immunoglobulin-type lectin.

FIGURE 8

Serum levels of IL-1β, TNF-α, and IL-17 from 5 patients with PASH syndrome. Six NS served as controls. Numerical values represent signal intensity in a cytokine array assay. IL = interleukin, NS = normal subjects, PASH = pyoderma gangrenosum, acne, and hidradenitis suppurativa, TNF = tumor necrosis factor.