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Chilblain lupus

C Fiehn
Familial chilblain lupus belongs to the group of type 1 interferonopathies and is particularly characterized by typical skin manifestations and ischemia of the acra. There are various mutations that can lead to this autosomal dominant disease. A mutation in the TREX-1 gene has been most frequently found; however, families with mutations in the SAMHD1 gene and recently in the gene which codes for the stimulator of interferon genes (STING) protein were also described. A common feature of these genetic defects is that they are all involved in the process of detection of intracellular free DNA, which as a result leads to increased production of type 1 interferons and the induced gene products...
April 7, 2017: Zeitschrift Für Rheumatologie
Peng Li, Juan Du, John L Goodier, Jingwei Hou, Jian Kang, Haig H Kazazian, Ke Zhao, Xiao-Fang Yu
Maintaining genome integrity is important for cells and damaged DNA triggers autoimmunity. Previous studies have reported that Three-prime repair exonuclease 1(TREX1), an endogenous DNA exonuclease, prevents immune activation by depleting damaged DNA, thus preventing the development of certain autoimmune diseases. Consistently, mutations in TREX1 are linked with autoimmune diseases such as systemic lupus erythematosus, Aicardi-Goutières syndrome (AGS) and familial chilblain lupus. However, TREX1 mutants competent for DNA exonuclease activity are also linked to AGS...
March 15, 2017: Nucleic Acids Research
Takaya Komori, Atsushi Otsuka, Tetsuya Honda, Yo Kaku, Kenji Kabashima
Chilblain lupus erythematosus (CHLE) is an acral erythema with cutaneous lesion of lupus erythematosus (LE) that is exacerbated during the winter (1). LE/lichen planus (LP) overlap syndrome is a rare cutaneous disorder characterized by mixed histological features of LE and LP at the same lesion (2). Although both CHLE and LE/LP overlap syndrome are immune mediated diseases (3), there is no indication that the same lymphocyte subset induces two distinct cutaneous lesions. This article is protected by copyright...
March 21, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
F Chasset, J-D Bouaziz, N Costedoat-Chalumeau, C Francès, L Arnaud
BACKGROUND: The antimalarials (AMs) hydroxychloroquine (HCQ) or chloroquine (CQ) have demonstrated variable cutaneous response rates in Cutaneous Lupus Erythematosus (CLE). OBJECTIVES: We sought to assess the global cutaneous response rate to HCQ and CQ, with respect to CLE subtypes, based on previously published studies. METHODS: We performed a systematic review and meta-analysis of studies published in MEDLINE, Embase, Cochrane library between 1965 and December 2015...
January 23, 2017: British Journal of Dermatology
Anna Sophie Klaeschen, Dominik Wolf, Peter Brossart, Thomas Bieber, Joerg Wenzel
This study was stimulated by the clinical observation of a rapid response of a chilblain lupus patient to treatment with JAK1/2-kinase inhibitor ruxolitinib. We investigated the in-vivo expression of phospho-JAK2 in CLE skin samples as well as the immunomodulatory in-vitro effect of ruxolitinib in cultured immortalized keratinocytes and in a 3D human epidermis model (epiCS). Our results demonstrate that ruxolitinib significantly decreases the production of CLE-typical cytokines (CXCL10, CXCL9, MxA) and might be a promising drug for future clinical studies in patients with CLE and related autoimmune skin diseases...
November 28, 2016: Experimental Dermatology
Nadja König, Christoph Fiehn, Christine Wolf, Max Schuster, Emanuel Cura Costa, Victoria Tüngler, Hugo Ariel Alvarez, Osvaldo Chara, Kerstin Engel, Raphaela Goldbach-Mansky, Claudia Günther, Min Ae Lee-Kirsch
OBJECTIVES: Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. METHODS: Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-β reporter and Western blotting...
August 26, 2016: Annals of the Rheumatic Diseases
A M Saracino, C H Orteu
Fumaric acid esters (FAEs) have proven efficacy in the treatment of psoriasis and have been in use for decades. More recently, as their mechanism of action and abundant immunomodulatory effects become clearer, the potential benefits of treating other inflammatory skin conditions using FAEs are increasingly being recognized. The use of FAEs as combination systemic therapy has not been well studied and data are lacking regarding the safety and efficacy of this type of therapy. In this case report, three patients with severe, extensive and recalcitrant cutaneous manifestations of systemic lupus erythematosus (SLE) (one case of disseminated discoid lesions and two with severe chilblain lesions) were treated with Fumaderm(®) (containing the FAE dimethylfumarate and monoethylhydrogen fumarate salts), after failing to respond to a multitude of other monotherapies and combination therapies...
February 2017: British Journal of Dermatology
Joerg Wenzel, Nadine van Holt, Judith Maier, Maria Vonnahme, Thomas Bieber, Dominik Wolf
No abstract text is available yet for this article.
June 2016: Journal of Investigative Dermatology
Gerardo Ferrara, Lorenzo Cerroni
Cold-associated perniosis of the thighs ("equestrian cold panniculitis") is an unusual and still enigmatic entity. The authors retrieved 6 cases for a re-evaluation of their clinicopathologic features and for an immunohistochemical assessment with antibodies anti-CD3, anti-CD20, and anti-CD123. All patients were women, aged 17-45 years. One of them had elevated antinuclear antibody titers. Available anamnestic data confirmed the triggering role of prolonged/intermittent exposure to cold (not necessarily for equestrian activities)...
October 2016: American Journal of Dermatopathology
Justin Chia, Fehime Kara Eroglu, Seza Özen, Dicle Orhan, Gina Montealegre-Sanchez, Adriana A de Jesus, Raphaela Goldbach-Mansky, Edward W Cowen
Key teaching points • SAVI is a recently described interferonopathy resulting from constitutive action of STING and up-regulation of IFN-β signaling. • SAVI is characterized by facial erythema with telangiectasia, acral/cold-sensitive tissue ulceration and amputations, and interstitial lung disease. It has overlapping features with Aicardi-Goutières syndrome and familial chilblain lupus. • Traditional immunosuppressive medications and biologic therapies appear to be of limited benefit, but JAK inhibitors may impact disease progression...
January 2016: Journal of the American Academy of Dermatology
J Munoz, M Marque, M Dandurand, L Meunier, Y-J Crow, D Bessis
Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date, interferonopathies include Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, PRoteasome-associated auto-inflammatory syndrome (PRAAS) and Singleton-Merten syndrome. These diseases present phenotypic overlap including cutaneous features like chilblain lupus, that can be inaugural or present within the first months of life. This novel set of inborn errors of immunity is evolving rapidly, with recognition of new diseases and genes...
November 2015: Annales de Dermatologie et de Vénéréologie
A-C Bursztejn, T A Briggs, Y del Toro Duany, B H Anderson, J O'Sullivan, S G Williams, C Bodemer, S Fraitag, F Gebhard, B Leheup, I Lemelle, A Oojageer, E Raffo, E Schmitt, G I Rice, S Hur, Y J Crow
Cutaneous lesions described as chilblain lupus occur in the context of familial chilblain lupus or Aicardi-Goutières syndrome. To date, seven genes related to Aicardi-Goutières syndrome have been described. The most recently described encodes the cytosolic double-stranded RNA receptor IFIH1 (also known as MDA5), a key component of the antiviral type I interferon-mediated innate immune response. Enhanced type I interferon signalling secondary to gain-of-function mutations in IFIH1 can result in a range of neuroinflammatory phenotypes including classical Aicardi-Goutières syndrome...
December 2015: British Journal of Dermatology
Elizabeth E Gray, Piper M Treuting, Joshua J Woodward, Daniel B Stetson
Detection of intracellular DNA triggers activation of the stimulator of IFN genes-dependent IFN-stimulatory DNA (ISD) pathway, which is essential for antiviral immune responses. However, chronic activation of this pathway is implicated in autoimmunity. Mutations in TREX1, a 3' repair exonuclease that degrades cytosolic DNA, cause Aicardi-Goutières syndrome and chilblain lupus. Trex1 (-/-) mice develop lethal, IFN-driven autoimmune disease that is dependent on activation of the ISD pathway, but the DNA sensors that detect the endogenous DNA that accumulates in Trex1 (-/-) mice have not been defined...
September 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Justine Munoz, Michel Rodière, Nadia Jeremiah, Frédéric Rieux-Laucat, Anthony Oojageer, Gillian I Rice, Flore Rozenberg, Yanick J Crow, Didier Bessis
IMPORTANCE: The type I interferonopathies comprise a recently recognized group of mendelian diseases characterized by an upregulation of type I interferon signaling. These monogenic phenotypes include classic Aicardi-Goutières syndrome and syndromic forms of systemic lupus erythematosus, including familial chilblain lupus and spondyloenchondrodysplasia. Dermatologic features provide a major diagnostic clue to this disease grouping, as exemplified by the recently described stimulator of interferon genes-associated vasculopathy with onset in infancy (SAVI) caused by gain-of-function mutations in TMEM173...
August 2015: JAMA Dermatology
Jessica L Grieves, Jason M Fye, Scott Harvey, Jason M Grayson, Thomas Hollis, Fred W Perrino
The TREX1 gene encodes a potent DNA exonuclease, and mutations in TREX1 cause a spectrum of lupus-like autoimmune diseases. Most lupus patients develop autoantibodies to double-stranded DNA (dsDNA), but the source of DNA antigen is unknown. The TREX1 D18N mutation causes a monogenic, cutaneous form of lupus called familial chilblain lupus, and the TREX1 D18N enzyme exhibits dysfunctional dsDNA-degrading activity, providing a link between dsDNA degradation and nucleic acid-mediated autoimmune disease. We determined the structure of the TREX1 D18N protein in complex with dsDNA, revealing how this exonuclease uses a novel DNA-unwinding mechanism to separate the polynucleotide strands for single-stranded DNA (ssDNA) loading into the active site...
April 21, 2015: Proceedings of the National Academy of Sciences of the United States of America
Gillian I Rice, Mathieu P Rodero, Yanick J Crow
Considering that it is a single exon gene encoding a 314 amino acid protein, the genotype-phenotype landscape of TREX1 is remarkably complex. Here we briefly describe the human diseases so-far associated with mutations in TREX1, which include Aicardi-Goutières syndrome, familial chilblain lupus, systemic lupus erythematosus and retinal vasculopathy with cerebral leukodystrophy.
April 2015: Journal of Clinical Immunology
Claudia Günther
Lupus erythematosus is a prototypic autoimmune disease that can be triggered in genetically predisposed individuals by environmental exposures. The disease is based on an uncontrolled activation of the immune system that recognizes self antigens and induces inflammatory disease flares. The multifactorial pathogenesis is based on a polygenic model of inheritance with multiple various susceptibility genes elevating the disease risk. Many of these polymorphisms have been recently identified by genome-wide association studies...
February 2015: Der Hautarzt; Zeitschrift Für Dermatologie, Venerologie, und Verwandte Gebiete
Yanick J Crow, Diana S Chase, Johanna Lowenstein Schmidt, Marcin Szynkiewicz, Gabriella M A Forte, Hannah L Gornall, Anthony Oojageer, Beverley Anderson, Amy Pizzino, Guy Helman, Mohamed S Abdel-Hamid, Ghada M Abdel-Salam, Sam Ackroyd, Alec Aeby, Guillermo Agosta, Catherine Albin, Stavit Allon-Shalev, Montse Arellano, Giada Ariaudo, Vijay Aswani, Riyana Babul-Hirji, Eileen M Baildam, Nadia Bahi-Buisson, Kathryn M Bailey, Christine Barnerias, Magalie Barth, Roberta Battini, Michael W Beresford, Geneviève Bernard, Marika Bianchi, Thierry Billette de Villemeur, Edward M Blair, Miriam Bloom, Alberto B Burlina, Maria Luisa Carpanelli, Daniel R Carvalho, Manuel Castro-Gago, Anna Cavallini, Cristina Cereda, Kate E Chandler, David A Chitayat, Abigail E Collins, Concepcion Sierra Corcoles, Nuno J V Cordeiro, Giovanni Crichiutti, Lyvia Dabydeen, Russell C Dale, Stefano D'Arrigo, Christian G E L De Goede, Corinne De Laet, Liesbeth M H De Waele, Ines Denzler, Isabelle Desguerre, Koenraad Devriendt, Maja Di Rocco, Michael C Fahey, Elisa Fazzi, Colin D Ferrie, António Figueiredo, Blanca Gener, Cyril Goizet, Nirmala R Gowrinathan, Kalpana Gowrishankar, Donncha Hanrahan, Bertrand Isidor, Bülent Kara, Nasaim Khan, Mary D King, Edwin P Kirk, Ram Kumar, Lieven Lagae, Pierre Landrieu, Heinz Lauffer, Vincent Laugel, Roberta La Piana, Ming J Lim, Jean-Pierre S-M Lin, Tarja Linnankivi, Mark T Mackay, Daphna R Marom, Charles Marques Lourenço, Shane A McKee, Isabella Moroni, Jenny E V Morton, Marie-Laure Moutard, Kevin Murray, Rima Nabbout, Sheela Nampoothiri, Noemi Nunez-Enamorado, Patrick J Oades, Ivana Olivieri, John R Ostergaard, Belén Pérez-Dueñas, Julie S Prendiville, Venkateswaran Ramesh, Magnhild Rasmussen, Luc Régal, Federica Ricci, Marlène Rio, Diana Rodriguez, Agathe Roubertie, Elisabetta Salvatici, Karin A Segers, Gyanranjan P Sinha, Doriette Soler, Ronen Spiegel, Tommy I Stödberg, Rachel Straussberg, Kathryn J Swoboda, Mohnish Suri, Uta Tacke, Tiong Y Tan, Johann te Water Naude, Keng Wee Teik, Maya Mary Thomas, Marianne Till, Davide Tonduti, Enza Maria Valente, Rudy Noel Van Coster, Marjo S van der Knaap, Grace Vassallo, Raymon Vijzelaar, Julie Vogt, Geoffrey B Wallace, Evangeline Wassmer, Hannah J Webb, William P Whitehouse, Robyn N Whitney, Maha S Zaki, Sameer M Zuberi, John H Livingston, Flore Rozenberg, Pierre Lebon, Adeline Vanderver, Simona Orcesi, Gillian I Rice
Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills...
February 2015: American Journal of Medical Genetics. Part A
Claudia Günther, Nicole Berndt, Christine Wolf, Min Ae Lee-Kirsch
IMPORTANCE: Familial chilblain lupus is a rare, autosomal dominant form of lupus erythematosus characterized by cold-induced inflammatory lesions at acral locations presenting in early childhood. Familial chilblain lupus is usually caused by a mutation in TREX1 (3' repair exonuclease 1). OBSERVATIONS: We report on a family with dominant chilblain lupus segregating a novel TREX1 mutation (c.585C>G; H195Q) within the highly conserved exonuclease (Exo) III domain...
April 2015: JAMA Dermatology
Shikha Bansal, Alka Goel
Chilblain Lupus Erythematosus (CHLE) is a rare form of cutaneous lupus erythematosus (LE), more frequently seen in middle aged females. It is characterized by erythematous to violaceous plaques over the acral areas induced by exposure to cold or drop in temperature unlike lesions of lupus erythematosus that worsen with sun exposure. Here, we present a case of chilblain lupus erythematosus in an adolescent girl with few unique features not previously reported.
November 2014: Indian Dermatology Online Journal
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