Immune-mediated skin lesions in patients treated with anti-tumour necrosis factor alpha inhibitors

Exarchou, Sofia; Voulgari, Paraskevi V.; Markatseli, Theodora E.; Zioga, Aikaterini; Drosos, Alexandros A.

doi:10.1080/03009740902922612

Cited by 91 publications

(75 citation statements)

References 13 publications

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“…We additionally observed a relative decrease in production of TNF-α in subjects carrying the high-risk MHC class II haplotype. The role of TNF-α in the pathogenesis of vitiligo is less clear (30)(31)(32)(33); in the skin of vitiligo patients, TNF-α is produced by perilesional T cells and is involved in the development of cytotoxic T lymphocytes (34). However, treatment with TNF-α blocking agents, such as adalimumab and infliximab, can be paradoxically associated with de novo vitiligo development in patients with other autoimmune conditions (30)(31)(32)(33)35).…”

Section: Discussionmentioning

confidence: 99%

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

Cavalli

Hayashi

Jin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genomewide association study of 2,853 Caucasian vitiligo patients. The superenhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5-and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an "adjuvant" during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.A utoimmune diseases are a group of over 80 disorders that together affect 3-5% of the United States population (1, 2). Many autoimmune diseases are associated with genetic variation in the HLA class I and class II gene regions of the major histocompatibility complex (MHC) on chromosome 6p21.3. HLA class I molecules present peptide antigens on the surface of almost all cells, whereas HLA class II molecules present antigens on the surface of antigen-presenting cells, such as dendritic cells, mononuclear phagocytes, and B cells. Contributions of HLA molecules to autoimmunity have almost exclusively focused on antigenic diversity and specificity. Although polymorphisms in intergenic regions of the MHC might additionally affect the complex transcriptional regulation of HLA genes, the potential role of these noncoding regions in the pathogenesis of autoimmune diseases has received much less attention.Vitiligo is an autoimmune disease in which white spots of skin and overlying hair result from progressive destruction of melanocytes by autoreactive T cells (3). In previous genome-wide association studies of autoimmune vitiligo in European-derived Caucasian (EUR) populations, we have identified association with 27 different loci (4-6), most strongly with MHC class II r...

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Section: Discussionmentioning

confidence: 99%

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

Cavalli

Hayashi

Jin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…tempered skin inflammation with lymphocytes leaving the skin (15-17); impaired adhesion molecule expression [e.g. CLA-counterligand E-selectin) on skin microvasculature (18,19); relapsing patients: IFN-alphamediated disease relapse with skin-infiltrating lymphocytes (20)(21)(22)(23), provoking role of underlying infections (24)(25)(26)(27)(28)]. We recommend further investigations to find clear elucidation for our observations and confirm our primary results establishing a potential role of CLA in predicting long-term effectiveness of TNFalpha inhibitor therapy in psoriasis.…”

Section: Discussionmentioning

confidence: 99%

Cutaneous lymphocyte‐associated antigen as a novel predictive marker of TNF‐alpha inhibitor biological therapy in psoriasis

Jókai

Szakonyi

Kontár

et al. 2013

Experimental Dermatology

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system and IL-13, IL-17E/IL-25 as well as COX-2 might be key factors to aggravate Ag-induced AD-like symptoms. AcknowledgementsThis study was supported by a grant from the Korean Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A091121). Author contributionsJi-Yun Kim performed the research, designed the research study, analysed the data and wrote the paper; Mi Sook Jeong performed the research and analysed the data; Kui Young Park designed the research study and analysed the data; Seong Jun Seo designed the research study, analysed the data and wrote the paper. Ethics approval for animal careAll experiments with mice were performed in accordance with the regulations and the approval of the Institutional Animal Care and Use Committee of Chung-Ang University (Approval No. 10-1011) and Korea Conformity Laboratories (KCL). Conflict of interestsThe authors have declared no conflicting interests. Supporting InformationAdditional Supporting Information may be found in the online version of this article: Data S1. Supplementary Materials and Methods. Figure S1. Effects of FA inhalation on the clinical skin severity score and the infiltration of inflammatory cells in ear skin of NC/Nga mice. Table S1. Effect of FA inhalation on the production of total levels of immunoglobulin (Ig) isotypes in plasma. Table S2. Effect of FA inhalation on the protein expressions of cytokines in splenocytes. Abstract: A considerable number of patients with psoriasis show secondary resistance during long-term TNF-alpha inhibitor therapy, necessitating the identification of reliable predictive markers. Predictive role of cutaneous lymphocyte-associated antigen (CLA) was investigated. Thirty-eight severe patients with psoriasis were treated for a 24-week-long study period. Clinical responsiveness (PASI) and changes in flow cytometry-measured peripheral lymphocyte CLA expression (week 0-2-6) were statistically analysed. Regarding 24-week-long treatment outcome patients were divided into two groups: During the first 6 weeks, mean CLA expression showed significant (P = 0.034604) increase among responders (32/38), while after a preliminary increase, it was significantly (P = 0.012539) decreasing in the relapsing group (6/38). Pearson's correlation analysis showed significant negative correlation between PASI and CLA changes. Responders showed (not significantly) lower initial CLA expression than relapsing patients. Our observations suggest change in CLA expression during the first 6 weeks of induction period to serve as a potential predictive marker of TNF-alpha inhibitor therapy in psoriasis.

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“…Not only have studies shown this not to be the case [15], alopecia areata has actually been found to occur during treatment with TNF-α inhibitors. The first case was reported in 2004 with the use of infliximab [16] and since then we have identified 34 cases in the literature, including the TNF-α inhibitors adalimumab [4,[17][18][19][20][21][22][23][24][25][26][27], infliximab [16,23,[28][29][30][31][32], and etanercept (Table 1) [4,22,33,34]. In these cases, alopecia areata was diagnosed by both clinical presentation and histopathology, which was available in the majority of cases.…”

Section: Clinical Subtypes Of Alopecia Seen During Treatment With Tnfmentioning

confidence: 99%

Hair Loss Induced by Tumor Necrosis Factor Alpha Inhibitors

Tosti¹

2014

J Clin Investig Dermatol

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Background: Alopecia is a possible adverse reaction to Tumor Necrosis Factor alpha (TNF-α) inhibitors. This side effect has become more recognized in recent years through FDA postmarketing surveillance and it description in case reports/case series. Objective:We review the literature and summarize the pathogenesis, clinical presentation, prognosis, and management strategies for TNF-α inhibitor induced alopecia. Methods:We performed a Medline search from January 1998 until August 2013 to identify all cases of alopecia during anti-TNF-α therapy described in the literature. We also reviewed FDA postmarketing data and clinical trials.Results: There were 62 cases of hair loss occurring during therapy with TNF-α inhibitors that we identified during our literature search. The causes of hair loss included alopecia areata, psoriatic alopecia, lichen planopilaris, drug-induced lupus erythematosus, androgenetic alopecia, and telogen effluvium. Alopecia was also a mentioned side effect in three clinical trials and in FDA postmarketing surveillance.Limitations: There are few controlled trials directly studying TNF-α inhibitor induced alopecia and most of our understanding of this clinical condition comes from anecdotal experience.Conclusions: TNF-α inhibitors can cause different types of hair loss including severe alopecia areata and scarring alopecia.

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Immune-mediated skin lesions in patients treated with anti-tumour necrosis factor alpha inhibitors

Abstract: Our results on patients treated with TNF antagonists strongly support a link between TNF inhibition and IMSL development. Although these clinical complications are rare, clinicians should be aware of their occurrence and should recognize them.

Cited by 91 publications

References 13 publications

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

Cutaneous lymphocyte‐associated antigen as a novel predictive marker of TNF‐alpha inhibitor biological therapy in psoriasis

Hair Loss Induced by Tumor Necrosis Factor Alpha Inhibitors

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