Cutaneous Vasculitis Associated With Interferon β-1b Treatment for Multiple Sclerosis

Szilasiová, Jarmila; Gdovinová, Zuzana; Jautová, J; Baloghová, Janette; Ficová, M; Bohus, P

doi:10.1097/wnf.0b013e3181a2b5fd

Cited by 15 publications

(11 citation statements)

References 9 publications

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“…The administration of recombinant inter-feron- α and interferon- β for the treatment of chronic hepatitis and multiple sclerosis can, in rare cases, result in vasculitis, 31,32 and interferon-induced endothelial-cell dysfunction has been implicated as a cause of premature vascular damage and atherosclerosis in patients with systemic lupus erythematosus. 33 Nevertheless, the presentation of SAVI as an inflammatory vasculopathy was unexpected.…”

Section: Discussionmentioning

confidence: 99%

Activated STING in a Vascular and Pulmonary Syndrome

et al. 2014

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BACKGROUND The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-β, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mono-nuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibro-blasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients’ lymphocytes was reduced by JAK inhibitors. CONCLUSIONS STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173.

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Section: Discussionmentioning

confidence: 99%

Activated STING in a Vascular and Pulmonary Syndrome

et al. 2014

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“…63,81,82 There were four case reports of cutaneous vasculitis as adverse cutaneous events to GA, SC IFN-β-1a, and IFN-β-1b (two patients). [83][84][85][86] Erythema elevatum diutinum, a cutaneous type of vasculitis, was described in a patient treated with SC IFN-β-1a. 87 Panniculitis was described in three patients treated with IFN-β-1b and in two patients with SC IFN-β-1a.…”

Section: Immune-mediated Cutaneous Adverse Eventsmentioning

confidence: 99%

Cutaneous adverse events associated with disease-modifying treatment in multiple sclerosis: a systematic review

et al. 2012

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Glatiramer acetate and interferon-beta are approved first-line disease-modifying treatments (DMTs) for multiple sclerosis (MS). DMTs can be associated with cutaneous adverse events, which may influence treatment adherence and patient quality of life. In this systematic review, we aimed to provide an overview of the clinical spectrum and the incidence of skin reactions associated with DMTs. A systematic literature search was performed up to May 2011 in Medline, Embase, and Cochrane databases without applying restrictions in study design, language, or publishing date. Eligible for inclusion were articles describing any skin reaction related to DMTs in MS patients. Selection of articles and data extraction were performed by two authors independently. One hundred and six articles were included, of which 41 (39%) were randomized controlled trials or cohort studies reporting incidences of mainly local injection-site reactions. A large number of patients had experienced some form of localized injection-site reaction: up to 90% for those using subcutaneous formulations and up to 33% for those using an intramuscular formulation. Sixty-five case-reports involving 106 MS patients described a wide spectrum of cutaneous adverse events, the most frequently reported being lipoatrophy, cutaneous necrosis and ulcers, and various immune-mediated inflammatory skin diseases. DMTs for MS are frequently associated with local injection-site reactions and a wide spectrum of generalized cutaneous adverse events, in particular, the subcutaneous formulations. Although some of the skin reactions may be severe and persistent, most of them are mild and do not require cessation of DMT.

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“…4 The most common complications of these side effects are flu-like syndrome and injection site reactions. 1,2,4 Injection site reactions are usually mild, manageable and self-limiting. However, in rare cases, more severe reactions may develop, such as necrotic ulcerations that sometimes limit treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The most common side effects of this treatment are; injection site reaction and flu-like syndrome. 1,2 Autoimmunity can be seen as a long-term side effect of this therapy that can cause significant clinical consequences and even interferon treatment interruption. 3 Many reports of cutaneous side effects (such as erythema, swelling, ulceration, and panniculitis) have been published.…”

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confidence: 99%