Paradoxical Autoinflammatory Skin Reaction to Tumor Necrosis Factor Alpha Blockers Manifesting as Amicrobial Pustulosis of the Folds in Patients With Inflammatory Bowel Diseases

Abstract

The therapy of inflammatory bowel disease, particularly with tumor necrosis factor (TNF) blockers, may be associated with a number of cutaneous adverse effects, including psoriasis-like, eczema-like, and lichenoid eruptions. Other rare skin complications are neutrophilic dermatoses such as amicrobial pustulosis of the folds (APF), which is a chronic relapsing pustular disorder classified in this spectrum.The authors analyzed clinical, histopathologic, and cytokine expression profiles of 3 inflammatory bowel disease patients with APF triggered by adalimumab (patient 1) and infliximab (patients 2 and 3).All 3 patients presented with sterile pustules involving the cutaneous folds, genital regions, and scalp 6 months after starting adalimumab (patient 1) and 9 months after starting infliximab (patients 2 and 3). Histology was characterized by epidermal spongiform pustules with a dermal neutrophilic and lymphocytic infiltrate. Tumor necrosis factor blocker withdrawal associated with topical and systemic corticosteroids induced complete remission of APF in all 3 patients. The expressions of interleukin (IL)-1 beta and its receptors as well as TNF alpha and its receptors were significantly higher in APF than in controls. Also IL-17, leukocyte selectin, and chemokines, such as IL-8, [C-X-C motif] chemokine ligand 1/2/3 (C = cysteine, X = any amino acid), [C-X-C motif] chemokine ligand 16 (C = cysteine, X = any amino acid), and RANTES (regulated on activation, normal T cell expressed and secreted) were significantly overexpressed. Finally, the authors found significant overexpression of both metalloproteinases 2/9 and their inhibitors 1/2.The observation of 3 patients with APF following anti-TNF therapy expands not only the clinical context of APF but also the spectrum of anti-TNF side effects. Overexpression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that APF is autoinflammatory in origin.

FIGURE 1

Clinical features of amicrobial pustulosis of the folds triggered by tumor necrosis factor alpha blockers. A, Erythematous pustules involving the axilla in patient 3. B, Erosive area because of coalescence of pustules on the axilla in patient 3. C, Erosions with vegetating aspects on the inguinal fold in patient 2. D, Erythematous erosive lesions on the anogenital region in patient 1.

FIGURE 2

Clinical features of amicrobial pustulosis of the folds triggered by tumor necrosis factor alpha blockers. Macerated erosive lesions with crusts on the retroauricular region in patient 2 (A) and in patient 3 (B). C, Erythematous plaque surrounded by an exudating erosive area on the intergluteal region in patient 1.

FIGURE 3

Histopathologic features of amicrobial pustulosis of the folds triggered by tumor necrosis factor alpha blockers. The histology shows pustules (highlighted with arrows) and a mainly neutrophilic infiltrate in the epidermis as well as a predominantly lymphocytic infiltrate in the upper dermis (hematoxylin and eosin stain; original magnification, ×200).

FIGURE 4

Expression of IL-1 beta and its soluble receptors I and II in homogenate samples of lesional skin from 3 patients with amicrobial pustulosis of the folds triggered by tumor necrosis factor alpha blockers. Six normal subjects served as controls. Numerical values represent signal intensity in a cytokine array assay.

FIGURE 5

Expression of tumor necrosis factor alpha and its soluble receptors I and II in homogenate samples of lesional skin from 3 patients with amicrobial pustulosis of the folds triggered by tumor necrosis factor alpha blockers. Six normal subjects served as controls. Numerical values represent signal intensity in a cytokine array assay.

FIGURE 6

Expression of interleukin-17, its soluble receptor, and leukocyte selectin in homogenate samples of lesional skin from 3 patients with amicrobial pustulosis of the folds triggered by tumor necrosis factor alpha blockers. Six normal subjects served as controls. Numerical values represent signal intensity in a cytokine array assay.

FIGURE 7

Expression of interleukin-8, regulated on activation, normal T cell expressed and secreted, [C-X-C motif] chemokine ligand 1,2,3 (C = cysteine, X = any amino acid), and [C-X-C motif] chemokine ligand 16 (C = cysteine, X = any amino acid) in homogenate samples of lesional skin from 3 patients with amicrobial pustulosis of the folds triggered by tumor necrosis factor alpha blockers. Six normal subjects served as controls. Numerical values represent signal intensity in a cytokine array assay.

FIGURE 8

Expression of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase 1, and tissue inhibitor of metalloproteinase 2 in homogenate samples of lesional skin from 3 patients with amicrobial pustulosis of the folds triggered by tumor necrosis factor alpha blockers. Six normal subjects served as controls. Numerical values represent signal intensity in a cytokine array assay.