Relationship between disease activity and type 1 interferon- and other cytokine-inducible gene expression in blood in dermatomyositis and polymyositis

Greenberg, Steven A.; Higgs, Brandon W.; Morehouse, Chris; Walsh, Ronan J.; Kong, Sek Won; Brohawn, Philip Z.; Zhu, Wenhua; Amato, Anthony A.; Salajegheh, Mohammad; White, Barbara; Kiener, Peter A.; Jallal, Bahija; Yao, Yihong

doi:10.1038/gene.2011.61

Cited by 124 publications

(114 citation statements)

References 32 publications

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“…Of the 51 patients enrolled, 75% (38/51) had a positive baseline IFNGS (table 1 and see supplementary figure S1, available online only). A previous study showed that approximately 60% of dermatomyositis or polymyositis patients demonstrate an elevated IFNGS in the blood 15. The baseline IFNGS in dermatomyositis or polymyositis patients calculated using microarrays were confirmed by taqMan quantitative reverse transcriptase PCR (r=0.95; p<0.001; see supplementary figure S2, available online only).…”

Section: Resultsmentioning

confidence: 66%

“…Dermatomyositis (n=26) or polymyositis (n=25) patients enrolled in this study were screened using their baseline 13 IFNGS described previously15 (detailed in supplementary material, available online only), then randomly assigned to either placebo or sifalimumab groups. Of the 51 patients enrolled, 75% (38/51) had a positive baseline IFNGS (table 1 and see supplementary figure S1, available online only).…”

Section: Resultsmentioning

confidence: 99%

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A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients

Higgs¹,

Zhu²,

Morehouse³

et al. 2013

Ann Rheum Dis

153

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ObjectiveTo assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure.MethodsA phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab.ResultsThe IFNGS was suppressed by a median of 53–66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle.ConclusionsSifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.

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Section: Resultsmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients

Higgs¹,

Zhu²,

Morehouse³

et al. 2013

Ann Rheum Dis

153

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show abstract

“…However, expression of IFN-α and IFN-β and their inducible genes is not exclusively specific to DM and also occurs in PM [1,78], and PM patients have shown responsiveness to anti-IFN-α therapy [73,79]. Furthermore pDCs, a major source of IFN-α, have been identified in the muscle tissue of patients with PM and IBM in addition to DM [77].…”

Section: Muscle Tissuementioning

confidence: 99%

“…Such gene array studies have identified a prominent type I IFN genetic signature in DM muscle in comparison with other forms of myositis [72,78]. However, expression of IFN-α and IFN-β and their inducible genes is not exclusively specific to DM and also occurs in PM [1,78], and PM patients have shown responsiveness to anti-IFN-α therapy [73,79].…”

Section: Muscle Tissuementioning

confidence: 99%

Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications

Moran

Mastaglia

2014

Clinical and Experimental Immunology

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SummaryThe idiopathic inflammatory myopathies are a heterogeneous group of disorders characterised by diffuse muscle weakness and inflammation. A common immunopathogenic mechanism is the cytokine-driven infiltration of immune cells into the muscle tissue. Recent studies have further dissected the inflammatory cell types and associated cytokines involved in the immune-mediated myopathies and other chronic inflammatory and autoimmune disorders. In this review we outline the current knowledge of cytokine expression profiles and cellular sources in the major forms of inflammatory myopathy and detail the known mechanistic functions of these cytokines in the context of inflammatory myositis. Furthermore, we discuss how the application of this knowledge may lead to new therapeutic strategies for the treatment of the inflammatory myopathies, in particular for cases resistant to conventional forms of therapy.

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“…Overwhelming evidence points to the presence of an IFN type 1-induced gene repertory in DM patients in particular, more variable and milder upregulation of these genes could be observed in muscle tissues from patients diagnosed with PM, IBM and muscular dystrophy [8]. In addition, IFN type 1-inducible transcripts in blood of DM patients was shown to correlate with disease activity [24] and with the myopathological changes present in muscle. Expansive microarray gene expression profiling showed that only DM samples with perifascicular atrophy had marked elevation of type 1 IFN-inducible transcripts [25].…”

Section: Ifn-inducible Genes In the Immentioning

confidence: 95%

Interferons as components of the complex web of reactions sustaining inflammation in idiopathic inflammatory myopathies

Paepe

2015

Cytokine

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Relationship between disease activity and type 1 interferon- and other cytokine-inducible gene expression in blood in dermatomyositis and polymyositis

Cited by 124 publications

References 32 publications

A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients

A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients

Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications

Interferons as components of the complex web of reactions sustaining inflammation in idiopathic inflammatory myopathies

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