You are here

Article Text

Article menu

This article has a correction. Please see:

Download PDFPDF

Meeting report
Report of the inaugural Interferon Research Summit: interferon in inflammatory diseases
  1. Mary K Crow1 and
  2. Lars Rönnblom2
  1. 1 Department of Medicine, Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, Weill Cornell Medical College, New York, USA
  2. 2 Department of Medical Sciences, Section of Rheumatology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  1. Correspondence to Dr Mary KCrow; crowm{at}hss.edu

Abstract

An international summit on interferon (IFN) in inflammatory diseases, held in Gaithersburg, Maryland, USA (4–5 May 2017), united 22 internationally renowned clinicians and scientists with backgrounds in basic science, translational science and clinical medicine. The objectives of the summit were to assess the current knowledge of the role of type I IFN in inflammatory diseases and other conditions, discuss the available clinical trial data of anti-IFN therapeutic agents and identify key clinical and therapeutic knowledge gaps and future directions to advance the treatment landscape of diseases involving the type I IFN pathway. A discussion-based consensus process was used to assess three main clinical areas: the role of type I IFN in innate immunity, the role of type I IFN in autoimmune diseases and rational therapeutic targets in the IFN pathway. These are described here, along with current knowledge gaps and resulting recommendations. The advisors unanimously agreed that, despite significant obstacles, the field should transition from an organ-based model to a pathophysiology-based model. A better understanding of the molecular pathways could help inform potential therapeutic targets, thus progressing towards personalised medicine by tailoring the therapy to each patient.

  • Interferon
  • inflammatory diseases
  • systemic lupus erythematous

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/lupus-2018-000276

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Type I interferon (IFN) is involved in the pathogenesis of systemic autoimmune diseases and several organ-targeted inflammatory diseases. Although its primary pathogenic role is well established for systemic lupus erythematosus (SLE), the role of type I IFNs in other autoimmune diseases is less clear. Evidence from analyses of peripheral blood of patients with rheumatoid arthritis demonstrating an IFN signature and evidence from murine models of diabetes mellitus strongly suggest a pathogenic role of type I IFN in a subset of these diseases.1 A more prominent type I IFN signature can be seen in Sjögrens syndrome, dermatomyositis (DM) and systemic sclerosis.2–5 Although we have gained a better understanding of the role of type I IFN in autoimmune and inflammatory diseases in recent years, key knowledge gaps remain, including those related to responses to distinct classes of therapeutic agents.

    The inaugural International Summit on IFN in Inflammatory Diseases united 22 internationally renowned clinicians and scientists with backgrounds in basic science, translational science and clinical medicine. Goals of the summit included assessing the current knowledge of the role type I IFN plays in inflammatory diseases and other conditions, discussing available clinical data examining anti-IFN therapies and identifying current key clinical and therapeutic knowledge gaps. This report summarises the key findings of the meeting and includes the advisors’ recommendations for future efforts to advance the therapeutic landscape of diseases involving the type I IFN pathway.

    Basic function of the type I IFN system

    Role of IFN in immune responses

    IFNs (types I–III) are a highly complex family of cytokines (type I IFN subtypes (IFN-α; 13 IFN-α genes, 12 IFN-α proteins in humans), IFN-β, IFN-ω, IFN-κ, and IFN-ε) with diverse effects on immune function. The type I IFN system serves as the major line of defence against viruses and microorganisms by promoting both innate and adaptive immune responses.6–8 The IFN concentrations required for antiviral and immunomodulatory effects may be distinct, and our understanding of how different type I IFNs and receptors generate diverse immune functions is still evolving.

    Type I IFNs are particularly important in antivirus host defence,6 and the complexity of the pathway may be necessary to defend against the variety of viruses that are encountered. The innate immune response to viral infection initiates intense but transient type I IFN expression (figure 1).9 10 Although we know many of the triggers that initiate a type I IFN response after an acute viral infection,8 the mechanisms by which this response is terminated are yet to be elucidated. The type I IFN pathway is dysregulated in SLE,11 12 and the advisors agreed that a large research gap exists in our understanding of what drives overproduction of this cytokine. Understanding the regulatory mechanisms that control the innate immune response may yield information beneficial to the autoimmune diseases community and may uncover novel drug targets.

    Figure 1
    Figure 1

    The role of IFN in viral infection over time. cDC, conventional dendritic cell; IFN, interferon; IL, interleukin; ISG, interferon-stimulating genes; pDC, plasmacytoid dendritic cells; PD-L1, programmed death ligand 1; PRR, pattern recognition receptor. Left panel adapted from Crouse et al 9; right panel adapted from Zuniga et al 10 (Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature, Nature Reviews Immunology; Regulation of antiviral T cell responses by type I interferons. Crouse J, Kalinke U, Oxenius A, © 2015. Republished with permission of Annual Reviews, from Innate and Adaptive Immune Regulation During Chronic Viral Infections, Zuniga EI, Macal M, Lewis GM, et al, Vol. 2, © 2015; permission conveyed through Copyright Clearance Center.).

    Although increased type I IFN expression is common in several diseases, the link between IFN signatures and various clinical manifestations of disease remains unclear, suggesting that the role of type I IFN may differ among diseases. The advisors discussed the potential utility of IFN blockade in HIV infection, because studies have demonstrated that IFN may be detrimental in these patients, potentially contributing to T-cell exhaustion.13 14 Many of the immune alterations that characterise patients with autoimmune diseases may be attributable to the immunomodulatory properties of type I IFN, epigenetic modifications and irreversible autoimmune processes.

    Sources of IFN: plasmacytoid dendritic cells and other cells

    Plasmacytoid dendritic cells (pDCs) have unique biology, are the most active type I IFN-producing cells and contribute to both innate and adaptive immunity (figure 2).15 16 pDC type I IFN production is most evident at early time points after viral infection. Over time, other cells (eg, conventional dendritic cells (cDCs) and epithelial cells) become more prominent producers of type I IFN.17–19 Exogenous (eg, viral) RNA and DNA elicit type I IFN production via toll-like receptor (TLR)–dependent and TLR-independent (cytosolic) mechanisms in pDCs and other cells.20 In autoimmune diseases, endogenous nucleic acids in the form of immune complexes can activate endosomal nucleic acid–sensing TLRs and drive type I IFN and IFN-induced gene expression, mimicking a viral infection.21

    Figure 2
    Figure 2

    PDCs control many immune functions. APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor; CCL, chemokine (C–C motif) ligand; ICOSL, inducible costimulator ligand; IDO, indoleamine dioxygenase; IFN, interferon; IL, interleukin; iNKT, invariant natural killer T cell; MHC, major histocompatibility complex; NK, natural killer; pDC, plasmacytoid dendritic cells; PD-L1, programmed death ligand 1; TGF, transforming growth factor; TH, T helper cell; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand; TReg, T regulatory cell. Reproduced from Swiecki and Colonna16 (Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature, Nature Reviews Immunology; The multifaceted biology of plasmacytoid dendritic cells. Swiecki M, Colonna M, © 2015.).

    Several nucleic acid sensors (eg, TLRs) within pDCs trigger distinct signalling pathways, including canonical type I IFN signalling—IFN-dependent activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) leading to transcription of IFN-stimulated genes (the type I IFN gene signature (IFNGS)). Human pDCs express TLR7 and TLR9 nucleic acid sensors, and TLR7/TLR9 signalling induces a morphological change in pDCs, from an IFN-producing cell with high IFN production and low antigen presentation to an antigen-presenting cell with low IFN production and high antigen presentation.2 pDCs do not express TLR8 under most circumstances,22 which distinguishes them from monocytes, neutrophils and cDCs, although recent data from patients with systemic sclerosis suggest that TLR8 can be expressed in pDCs.23 Interleukin receptor–associated kinase-4 (IRAK-4) is involved in signalling innate immune responses from TLRs. IRAK-4-deficient patients produce IFN-α in response to viral infections but not to TLR7/TLR9 ligands; thus, these patients are susceptible to pyogenic bacterial infections (Gram+ bacteria) but appear to have normal resistance to viral infections.24 These data demonstrate the presence of non-TLR nucleic acid sensors.

    Genetic contributors to the type I IFN system: SLE heterogeneity and interferonopathies

    Understanding the molecular basis of diseases will help us progress towards personalised medicine by tailoring the therapy to the biological characteristics of each patient. Evidence suggests that genetic variations, along with varying exposure to environmental triggers and chance, may play a role in the heterogeneous manifestations of SLE.25 For example, SLE is more common in people with non-European-American ancestry26 and more severe in people with African-American ancestry.27 Serum IFN-α activity is greater in non-European patients with SLE than in Europeans, and the predominant genes associated with increased IFN concentrations differ between European-Americans and African-Americans.28 In addition, many genetic variants related to the IFN-α pathway are associated with SLE.29 Although we are still mapping the genetic associations with lupus in many populations, differences between populations clearly exist, and these variants affect immune phenotypes (eg, cytokine profile, autoantibodies). Evidence indicates that genetics is more strongly related to immune system phenotype than clinical phenotype, and the advisors suggested that future clinical trials should be stratified by immune phenotypes rather than clinical phenotypes. A combination of immune and genetic profiling is the future of assessing disease heterogeneity in lupus and should be considered in clinical trial design and potentially in patient management.

    Type I interferonopathies result from mutations that lead to an overproduction of type I IFN and may be directly relevant to the pathology of lupus.30 Mutations similar to those found in interferonopathies have been identified in patients with lupus. Although most of these mutations are related to nucleic acid metabolism, other mutations associated with nucleic acid signalling, negative regulation of IFN production or response and proteasome function have been identified. These mutations primarily affect the brain, skin or both, and non-penetrance appears to contribute to variations in autoimmune phenotypes. Given that different mutations can have overlapping phenotypes, ultrasensitive assays of the cellular source and concentration of IFN may be useful to diagnose interferonopathies.31

    IFN in autoimmune diseases

    Disease mechanisms of lupus: interplay between IFN and immune cells

    The interaction between type I IFNs and immune cells is complex.32 IFN promotes or primes the immune system and can be considered an immune system adjuvant. IFN-α induces B lymphocyte stimulator production, promoting B cell survival,33 and, conversely, B cells promote IFN-α production via pDCs.34 B cells have a dose-dependent effect on IFN-α production—as more B cells become activated, the production of type I IFN increases.34 In T cells, type I IFNs promote cell survival,35 and similarly to B cells, activated T cells enhance IFN-α production by generating some of the factors that recruit pDCs to produce IFN.36 Natural killer (NK) cells also stimulate IFN-α production, and the pDC–NK interaction enhances non-IFN cytokine production.37 38 Other cells have been implicated in type I IFN production. One study showed that when monocytes are added to NK-pDC cocultures, monocytes suppress the type I IFN response. For patients with SLE, this suppression may be reduced because of decreased production of reactive oxygen species.39 40 Thrombocytes have also been implicated in type I IFN production. Activated platelets can promote IFN-α secretion by pDCs.41

    In SLE, the control of the type I IFN system is deficient, leading to an overproduction of IFN.42 Type I IFN appears to be a driver rather than a consequence of the disease, and type I IFN treatment is sufficient to elicit SLE-like diseases.43 44 Two pathways predominate as potential triggers for type I IFN activation in lupus: cell death or damage (eg, the lupus immune complex, oxidised DNA) and defective nucleic acid metabolism (eg, interferonopathies, intracellular nucleic acid accumulation). Although the origin of pathogenic nucleic acids in lupus is uncertain, potential sources include NETosis, apoptosis (in the context of inflammation), necroptosis, pyroptosis and autophagy.45 46 Increased generation or impaired degradation of cytosolic endogenous nucleic acids could activate cytosolic sensors. Oxidised DNA can be detected in skin lesions of patients with lupus and stimulates local type I IFN production.47 In the general population, nucleases protect from lupus development by degrading nucleic acids.48 Deoxyribonuclease 1 like 3 deficiency can manifest as lupus or an SLE-like disease.49 Autoantibodies to nucleic acids develop years before SLE (the type I IFNGS increases very early in the disease), and earlier detection may be possible in the future with more sensitive screening tools.

    Influence of IFN on organ systems

    Cardiovascular system

    An imbalance between vascular damage and repair causes cardiovascular disease in patients with SLE. In these patients, IFN-α hampers vascular repair and inhibits angiogenesis,50–52 and the disease is an independent risk factor for development of atherosclerosis.53 Type I IFNs are independently associated with functional and anatomical markers of subclinical cardiovascular disease (ie, endothelial function, carotid plaque, severity of coronary calcification) in patients with SLE without a history of overt cardiovascular events, after controlling for Framingham risk factors.54

    The prevalence of atherosclerosis has been found to be higher in patients with lupus compared with control individuals (37.1% vs 15.2%).55 Young women (35 and 44 years) with SLE have a 50-fold increased risk of vascular complications,56 including a greater prevalence of perioperative cardiovascular adverse events and greater mortality following first myocardial infarction, compared with patients without SLE.57 In atherosclerotic lupus-prone mice, IFN blockade improved vascular repair and decreased atherothrombosis.52 Inhibition of type I IFN receptor signalling via the JAK/STAT pathway with tofacitinib decreased vascular dysfunction in a murine lupus model.58

    Central nervous system

    Central nervous system (CNS) symptoms are present in approximately 40% of all patients with SLE and often occur in the first year of the disease.59 In some cases, symptoms may be associated with the presence of autoantibodies,60 but in most patients the underlying mechanisms are unknown. Current hypotheses around the pathophysiological mechanism of CNS symptoms in SLE involve increased production of peripheral IFN-α, which then enters the CNS and activates reactive microglia that engulf synaptic material, leading to reduced synaptic density in regions of the brain that affect behaviour.61 Repeated dosing with human IFN-α can promote a depression-like phenotype in mice similar to that observed in patients treated with recombinant IFN-α.62 63 In humans with lupus, a peripheral blood IFN signature is present in 90% of children and more than 50% of adults,64 and IFN-α is elevated in the cerebrospinal fluid of some patients.65

    Muscle

    Characterisation of the contribution of type I IFN to the immunopathogenesis of DM has relied on immunohistochemical analysis of muscle tissue along with gene expression studies. Although a previous view of DM pathogenesis focused on the deposition of autoantibodies in tissue and complement-mediated tissue damage, observations of expression of myxovirus resistance 1 protein, a type I IFN-induced gene product, in myofibres and capillaries pointed to a significant pathogenic role for type I IFN in DM.66 The muscle pathology of DM is unique, characterised by perifascicular atrophy. A similar topology of injury to keratinocytes and myofibres exists in the skin and muscle of patients with DM.67 DM gene expression mapping shows that induced genes are type I IFN regulated,68 69 and DM and SLE microarrays revealed type I IFN signalling far in excess of that of other skin diseases.70 Type I IFN-inducible proteins in muscle localise to areas of perifascicular atrophy as well as endothelial cells of capillaries and large vessels. A strong type I IFNGS is evident in the muscle, skin and blood of patients with DM.70–72

    Joints

    Joint involvement is common in lupus and is typically non-deforming and non-erosive. American College of Rheumatology criteria define lupus arthritis as characterised by tenderness, swelling or effusion in two or more joints, but many patients report joint pain in the absence of apparent synovitis. However, sensitive imaging (eg, with ultrasound) has revealed that subclinical synovitis is present in up to 40% of these patients.73

    IFNs play a complex role in lupus arthritis. Expression of type I IFN-induced gene transcripts have been demonstrated in the synovial tissue of patients with SLE, and inhibition of osteoclastogenesis by IFN might account for the relatively non-erosive character of the arthritis seen in patients with lupus.74 Evidence of type I IFN activity in circulation has been detected in patients with lupus, and the anti-IFN-α receptor (IFNAR) therapeutic agent anifrolumab has been shown to reduce joint disease activity scores.75

    Skin

    Keratinocytes are a source of IFN-κ in healthy skin.76 IFN-κ maintains the basal IFN gene response in keratinocytes, induces the IFN gene response in fibroblasts and activates dendritic cells. IFNs promote a proinflammatory response in keratinocytes, including CXCL9, CXCL10 and interleukin-6 production.77 IFNs also have a role in protecting skin. In wild-type mice, ultraviolet (UV) light induces an IFN response that is independent of pDCs, requiring CCR2+ cells and may be protective against inflammation.78 Keratinocytes produce type I/II/III IFNs after viral infection and suppress viral replication.79

    IFNs play a role in several skin diseases. In psoriasis, IFN-β is upregulated in skin lesions,80 although the exact role of IFNs remains unclear. UV light downregulates IFNAR1, which is thought to be relevant to the therapeutic efficacy of UV light for psoriasis.81 Subacute cutaneous lupus erythematosus is characterised by a robust type I IFNGS, which is correlated with disease activity.82 In these patients, IFN-κ production increases after UV exposure. A strong IFN signature is also present in skin lesions of patients with DM83 and Sjögren’s syndrome,84 and in interferonopathies, genetic mutations identify the importance of IFNs in skin disease.85

    Rational therapeutic targets in the IFN pathway

    Advisors agreed that a better understanding of the molecular pathways (eg, relative roles of TLR vs cytosolic nucleic acid sensors) could help uncover potential novel therapeutic targets,86 and future efforts should consider extracellular and intracellular drug targets upstream and downstream of IFN.87 88 Potential upstream candidates include cells producing IFN (eg, pDCs), nucleic acid receptors (eg, TLRs, cytosolic sensors), signalling components (eg, kinases, adaptors) and transcriptional regulators. Downstream candidates include IFNAR, signalling components (eg, JAK/STAT)89 and induced gene products (eg, IFN-stimulated genes, mRNAs, proteins). Therapeutic agents that target the type I IFN pathway (from pDC to JAK-STAT activation) in clinical development for IFN-driven diseases are listed in table 1. Although upstream drivers of type I IFN production may be more specific for SLE, they may differ for individuals, restricting efficacy to a subset of patients. For example, DNA-containing immune complexes may drive type I IFN production in some patients, whereas others may have immune complexes that predominantly contain RNA. The advisors also expressed concern that a greater risk of toxicity may exist when targeting signalling pathways downstream of the IFNAR because they are shared by many systems (eg, JAK/STAT signalling).

    View this table:
    Table 1

    Therapeutic agents targeting components of the type I IFN pathway and in clinical development for IFN-driven diseases

    Although complex cytokine/IFN signalling is an attractive focus, it can be a risky target (eg, the JAK2 knockout is embryonically lethal).90 Given there are four pairs of JAKs, JAK1–3 and TYK2, and JAKs exist as pairs on cytokine receptors, there will likely be a need for selective JAK inhibitors. Currently, two JAK inhibitors (ruxolitinib91 and tofacitinib92) are approved and are effective in allergic diseases. Tofacitinib is efficacious in murine lupus,58 and a Phase II clinical trial of baricitinib for the treatment of lupus has completed enrolment. Like all medications, JAK inhibitors can be associated with adverse events, including infection, cytopenias, increased lipids and gastrointestinal perforation, but are well tolerated by many patients.93

    The advisors discussed the advantages and limitations of focusing on the type I IFN pathway as a therapeutic target. Given the uncertainty surrounding the roles of various upstream and downstream components of the IFN pathway in IFN-driven diseases, IFN represents a tractable drug target that is strongly linked to the IFNGS. Type I IFN plays an important role in the pathogenesis of SLE and likely in other disorders characterised by IFN signalling that have not been addressed previously. Anifrolumab is a fully human monoclonal antibody that binds to the type I IFN receptor and is in Phase III development for moderate to severe SLE. In the MUSE Phase IIb clinical trial,75 a high IFNGS was a biomarker of anifrolumab response compared with placebo. The outcomes of patients with a low IFNGS were not significantly different between those receiving drug and those receiving placebo. However, it is notable that the percentage of patients responding to the drug was roughly similar in the high and low IFNGS groups, and a relatively high placebo response was demonstrated in the low IFNGS group. The trial with anifrolumab supports the hypothesis that the type I IFN pathway is an important contributor to the pathophysiology of SLE. The data also suggest a need for additional research to understand whether there is a role for IFN pathway inhibition in therapy of those with a low IFNGS. Determining type I IFN pathway status in an individual patient based on an IFNGS test may help to predict which patients are more likely to respond to treatment.

    Some advisors recognised several limitations of focusing on the type I IFN pathway as a therapeutic target, including safety concerns (eg, impaired antivirus protection, increased susceptibility to infections such as Herpes zoster), unclear long-term effects on the immune system, insufficient data on the link between high IFN and B-cell and plasma-cell activation and the potential alteration of the balance between IFN-α and IFN-β signalling in neurons if the antibody enters the CNS. In addition, given the diverse and complex alterations in many components of the immune response for patients with SLE and other autoimmune diseases, treatment with drugs that target the type I IFN pathway may not be sufficient to gain control of disease activity and may not treat all manifestations of the disease in a single patient; therefore, treatment would require several drugs.

    Transitioning from an organ-based model to a pathophysiology-based model

    The advisors unanimously agreed that, despite significant obstacles, the field should transition from an organ-based model to a pathophysiology-based model. Key obstacles to this approach include the necessity of finding biomarkers that identify the most relevant molecular pathways operative in a given patient; the challenges in establishing the clinically defined patient cohorts needed for investigation of the genetic variations and gene expression signatures associated with defined clinical features of disease and the uncertainty of categorising these disorders as IFN diseases, because other pathways also will be involved.

    Based on these obstacles, the advisors recommended three types of pathophysiology-based studies. In the first type of study, a ‘basket approach’ design, two or three diseases with common phenotypes would be selected and specific outcomes would be measured. The basket approach would use an observational/open-label design with the composite endpoint based on the percentage of responders for each measure. In the second type of study, a ‘feature approach’ design, patients with a common feature (eg, arthritis) would be pooled and the response to treatment would be measured based on that common feature. The third type of study would use a ‘steroid-sparing approach’. Because many diseases are managed with steroids, a reduction in steroid use plus an additional clinical measure could be used as endpoints.

    Future directions

    After identifying and discussing knowledge gaps for the role of the type I IFN pathway in autoimmune diseases, the advisors generated a list of 13 key questions to be considered in future research efforts to advance the treatment landscape (table 2).

    View this table:
    Table 2

    Key points to be considered in future research efforts

    Conclusion

    This summit was the first meeting in a series of meetings that unites clinicians and scientists with the goal of outlining future directions to explore novel treatment of diseases involving the IFN pathway. The advisors unanimously agreed that, despite significant obstacles, the field should transition from an organ-based model to a pathophysiology-based model. A better understanding of the molecular pathways could help inform potential therapeutic targets, progressing toward personalised medicine by tailoring the therapy to the characteristics of each patient.

    Uncited online supplementary appendix 1.

    Acknowledgments

    The authors wish to thank the advisors for their contributions during the IFN Research Summit. Editorial support was provided by Lourdes W H Yun, MD, MSPH, and Francis Golder, BVSc, PhD, of JK Associates, as well as Michael A Nissen, ELS, of AstraZeneca.

    References

    1. 1.↵
      1. Crow MK
      . Type I interferon in organ-targeted autoimmune and inflammatory diseases. Arthritis Res Ther 2010;12(Suppl 1):S5. doi:10.1186/ar2886
      OpenUrlCrossRefPubMed
    2. 2.↵
      1. Rönnblom L,
      2. Eloranta ML
      . The interferon signature in autoimmune diseases. Curr Opin Rheumatol 2013;25:248–53. doi:10.1097/BOR.0b013e32835c7e32
      OpenUrlCrossRefPubMed
    3. 3.↵
      1. Wu M,
      2. Assassi S
      . The role of type 1 interferon in systemic sclerosis. Front Immunol 2013;4:266. doi:10.3389/fimmu.2013.00266
    4. 4.↵
      1. Li H,
      2. Ice JA,
      3. Lessard CJ, et al
      . Interferons in Sjögren's syndrome: genes, mechanisms, and effects. Front Immunol 2013;4:290. doi:10.3389/fimmu.2013.00290
    5. 5.↵
      1. Baechler EC,
      2. Bilgic H,
      3. Reed AM
      . Type I interferon pathway in adult and juvenile dermatomyositis. Arthritis Res Ther 2011;13:249. doi:10.1186/ar3531
      OpenUrlCrossRefPubMed
    6. 6.↵
      1. Stetson DB,
      2. Medzhitov R
      . Type I interferons in host defense. Immunity 2006;25:373–81. doi:10.1016/j.immuni.2006.08.007
      OpenUrlCrossRefPubMedWeb of Science
    7. 7.↵
      1. Boxx GM,
      2. Cheng G
      . The roles of Type I interferon in bacterial infection. Cell Host Microbe 2016;19:760–9. doi:10.1016/j.chom.2016.05.016
      OpenUrl
    8. 8.↵
      1. McNab F,
      2. Mayer-Barber K,
      3. Sher A, et al
      . Type I interferons in infectious disease. Nat Rev Immunol 2015;15:87–103. doi:10.1038/nri3787
      OpenUrlCrossRefPubMed
    9. 9.↵
      1. Crouse J,
      2. Kalinke U,
      3. Oxenius A
      . Regulation of antiviral T cell responses by type I interferons. Nat Rev Immunol 2015;15:231–42. doi:10.1038/nri3806
      OpenUrlCrossRefPubMed
    10. 10.↵
      1. Zuniga EI,
      2. Macal M,
      3. Lewis GM, et al
      . Innate and adaptive immune regulation during chronic viral infections. Annu Rev Virol 2015;2:573–97. doi:10.1146/annurev-virology-100114-055226
      OpenUrlCrossRef
    11. 11.↵
      1. Crow MK
      . Advances in understanding the role of type I interferons in systemic lupus erythematosus. Curr Opin Rheumatol 2014;26:467–74. doi:10.1097/BOR.0000000000000087
      OpenUrlCrossRefPubMed
    12. 12.↵
      1. Hagberg N,
      2. Rönnblom L
      . Systemic lupus erythematosus – a disease with a dysregulated type i interferon system. Scand J Immunol 2015;82:199–207. doi:10.1111/sji.12330
      OpenUrlCrossRefPubMed
    13. 13.↵
      1. Zhen A,
      2. Rezek V,
      3. Youn C, et al
      . Targeting type I interferon-mediated activation restores immune function in chronic HIV infection. J Clin Invest 2017;127:260–8. doi:10.1172/JCI89488
      OpenUrl
    14. 14.↵
      1. Cheng L,
      2. Ma J,
      3. Li J, et al
      . Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs. J Clin Invest 2017;127:269–79. doi:10.1172/JCI90745
      OpenUrl
    15. 15.↵
      1. Eloranta ML,
      2. Alm GV,
      3. Rönnblom L
      . Disease mechanisms in rheumatology--tools and pathways: plasmacytoid dendritic cells and their role in autoimmune rheumatic diseases. Arthritis Rheum 2013;65:853–63. doi:10.1002/art.37821
      OpenUrlCrossRefPubMedWeb of Science
    16. 16.↵
      1. Swiecki M,
      2. Colonna M
      . The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol 2015;15:471–85. doi:10.1038/nri3865
      OpenUrlCrossRefPubMed
    17. 17.↵
      1. Asselin-Paturel C,
      2. Brizard G,
      3. Chemin K, et al
      . Type I interferon dependence of plasmacytoid dendritic cell activation and migration. J Exp Med 2005;201:1157–67. doi:10.1084/jem.20041930
      OpenUrlAbstract/FREE Full Text
    18. 18.↵
      1. Fitzgerald-Bocarsly P,
      2. Feng D
      . The role of type I interferon production by dendritic cells in host defense. Biochimie 2007;89(6-7):843–55. doi:10.1016/j.biochi.2007.04.018
      OpenUrlCrossRefPubMed
    19. 19.↵
      1. Ioannidis I,
      2. Ye F,
      3. McNally B, et al
      . Toll-like receptor expression and induction of type I and type III interferons in primary airway epithelial cells. J Virol 2013;87:3261–70. doi:10.1128/JVI.01956-12
      OpenUrlAbstract/FREE Full Text
    20. 20.↵
      1. Junt T,
      2. Barchet W
      . Translating nucleic acid-sensing pathways into therapies. Nat Rev Immunol 2015;15:529–44. doi:10.1038/nri3875
      OpenUrlCrossRefPubMed
    21. 21.↵
      1. Gürtler C,
      2. Bowie AG
      . Innate immune detection of microbial nucleic acids. Trends Microbiol 2013;21:413–20. doi:10.1016/j.tim.2013.04.004
      OpenUrlCrossRefPubMedWeb of Science
    22. 22.↵
      1. Kadowaki N,
      2. Ho S,
      3. Antonenko S, et al
      . Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 2001;194:863–70. doi:10.1084/jem.194.6.863
      OpenUrlAbstract/FREE Full Text
    23. 23.↵
      1. Ah Kioon MD,
      2. Tripodo C,
      3. Fernandez D, et al
      . Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8. Sci Transl Med 2018;10:eaam8458. doi:10.1126/scitranslmed.aam8458
    24. 24.↵
      1. Picard C,
      2. von Bernuth H,
      3. Ghandil P, et al
      . Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 2010;89:403–25. doi:10.1097/MD.0b013e3181fd8ec3
      OpenUrlCrossRefPubMed
    25. 25.↵
      1. Deng Y,
      2. Tsao BP
      . Updates in lupus genetics. Curr Rheumatol Rep 2017;19:68. doi:10.1007/s11926-017-0695-z
    26. 26.↵
      1. Molokhia M,
      2. McKeigue P
      . Risk for rheumatic disease in relation to ethnicity and admixture. Arthritis Res 2000;2:115–25. doi:10.1186/ar76
      OpenUrlCrossRefPubMedWeb of Science
    27. 27.↵
      1. Contreras G,
      2. Lenz O,
      3. Pardo V, et al
      . Outcomes in African Americans and Hispanics with lupus nephritis. Kidney Int 2006;69:1846–51. doi:10.1038/sj.ki.5000243
      OpenUrlCrossRefPubMedWeb of Science
    28. 28.↵
      1. Niewold TB,
      2. Kelly JA,
      3. Kariuki SN, et al
      . IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis 2012;71:463–9. doi:10.1136/annrheumdis-2011-200463
      OpenUrlAbstract/FREE Full Text
    29. 29.↵
      1. Ghodke-Puranik Y,
      2. Niewold TB
      . Genetics of the type I interferon pathway in systemic lupus erythematosus. Int J Clin Rheumtol 2013;8:657–669. doi:10.2217/ijr.13.58
    30. 30.↵
      1. Lee-Kirsch MA
      . The type I interferonopathies. Annu Rev Med 2017;68:297–315. doi:10.1146/annurev-med-050715-104506
      OpenUrl
    31. 31.↵
      1. Rodero MP,
      2. Decalf J,
      3. Bondet V, et al
      . Detection of interferon alpha protein reveals differential levels and cellular sources in disease. J Exp Med 2017;214:1547–55. doi:10.1084/jem.20161451
      OpenUrlAbstract/FREE Full Text
    32. 32.↵
      1. Bloom BR, et al
      . Interactions between interferon and cells of the immune system. Interferons 1982:269–78.
    33. 33.↵
      1. Rustgi V,
      2. Nelson DR,
      3. Balan V, et al
      . Changes in B-lymphocyte stimulator protein levels during treatment with albinterferon alfa-2b in patients with chronic hepatitis C who have failed previous interferon therapy. Hepatol Res 2009;39:455–62. doi:10.1111/j.1872-034X.2008.00475.x
      OpenUrlPubMed
    34. 34.↵
      1. Berggren O,
      2. Hagberg N,
      3. Weber G, et al
      . B lymphocytes enhance interferon-α production by plasmacytoid dendritic cells. Arthritis Rheum 2012;64:3409–19. doi:10.1002/art.34599
      OpenUrlCrossRefPubMedWeb of Science
    35. 35.↵
      1. Marrack P,
      2. Kappler J,
      3. Mitchell T
      . Type I interferons keep activated T cells alive. J Exp Med 1999;189:521–30. doi:10.1084/jem.189.3.521
      OpenUrlAbstract/FREE Full Text
    36. 36.↵
      1. Leonard D,
      2. Eloranta ML,
      3. Hagberg N, et al
      . Activated T cells enhance interferon-α production by plasmacytoid dendritic cells stimulated with RNA-containing immune complexes. Ann Rheum Dis 2016;75:1728–34. doi:10.1136/annrheumdis-2015-208055
      OpenUrlAbstract/FREE Full Text
    37. 37.↵
      1. Hagberg N,
      2. Berggren O,
      3. Leonard D, et al
      . IFN-α production by plasmacytoid dendritic cells stimulated with RNA-containing immune complexes is promoted by NK cells via MIP-1β and LFA-1. J Immunol 2011;186:5085–94. doi:10.4049/jimmunol.1003349
      OpenUrlAbstract/FREE Full Text
    38. 38.↵
      1. Saïdi H,
      2. Bras M,
      3. Formaglio P, et al
      . HMGB1 is involved in IFN-alpha production and TRAIL expression by HIV-1-exposed plasmacytoid dendritic cells: impact of the crosstalk with NK cells. PLoS Pathog 2016;12:e1005407. doi:10.1371/journal.ppat.1005407
    39. 39.↵
      1. Eloranta ML,
      2. Lövgren T,
      3. Finke D, et al
      . Regulation of the interferon-alpha production induced by RNA-containing immune complexes in plasmacytoid dendritic cells. Arthritis Rheum 2009;60:2418–27. doi:10.1002/art.24686
      OpenUrlCrossRefPubMedWeb of Science
    40. 40.↵
      1. Olsson LM,
      2. Johansson ÅC,
      3. Gullstrand B, et al
      . A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus. Ann Rheum Dis 2017;76:1607–13. doi:10.1136/annrheumdis-2017-211287
      OpenUrlAbstract/FREE Full Text
    41. 41.↵
      1. Duffau P,
      2. Seneschal J,
      3. Nicco C, et al
      . Platelet CD154 potentiates interferon-alpha secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci Transl Med 2010;2:ra63. doi:10.1126/scitranslmed.3001001
    42. 42.↵
      1. Crow MK
      . Type I interferon in the pathogenesis of lupus. J Immunol 2014;192:5459–68. doi:10.4049/jimmunol.1002795
      OpenUrlAbstract/FREE Full Text
    43. 43.↵
      1. Niewold TB
      . Interferon alpha-induced lupus: proof of principle. J Clin Rheumatol 2008;14:131–2. doi:10.1097/RHU.0b013e318177627d
      OpenUrlCrossRefPubMed
    44. 44.↵
      1. Rönnblom LE,
      2. Alm GV,
      3. Oberg KE
      . Possible induction of systemic lupus erythematosus by interferon-alpha treatment in a patient with a malignant carcinoid tumour. J Intern Med 1990;227:207–10. doi:10.1111/j.1365-2796.1990.tb00144.x
      OpenUrlCrossRefPubMedWeb of Science
    45. 45.↵
      1. Barrat FJ,
      2. Elkon KB,
      3. Fitzgerald KA
      . Importance of nucleic acid recognition in inflammation and autoimmunity. Annu Rev Med 2016;67:323–36. doi:10.1146/annurev-med-052814-023338
      OpenUrlCrossRefPubMed
    46. 46.↵
      1. Mahajan A,
      2. Herrmann M,
      3. Muñoz LE
      . Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE. Front Immunol 2016;7:35. doi:10.3389/fimmu.2016.00035
    47. 47.↵
      1. Gehrke N,
      2. Mertens C,
      3. Zillinger T, et al
      . Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 2013;39:482–95. doi:10.1016/j.immuni.2013.08.004
      OpenUrlCrossRefPubMed
    48. 48.↵
      1. Rigby RE,
      2. Rehwinkel J
      . RNA degradation in antiviral immunity and autoimmunity. Trends Immunol 2015;36:179–88. doi:10.1016/j.it.2015.02.001
      OpenUrlCrossRefPubMed
    49. 49.↵
      1. Wilber A,
      2. O'Connor TP,
      3. Lu ML, et al
      . Dnase1l3 deficiency in lupus-prone MRL and NZB/W F1 mice. Clin Exp Immunol 2003;134:46–52. doi:10.1046/j.1365-2249.2003.02267.x
      OpenUrlCrossRefPubMedWeb of Science
    50. 50.↵
      1. Denny MF,
      2. Thacker S,
      3. Mehta H, et al
      . Interferon-alpha promotes abnormal vasculogenesis in lupus: a potential pathway for premature atherosclerosis. Blood 2007;110:2907–15. doi:10.1182/blood-2007-05-089086
      OpenUrlAbstract/FREE Full Text
    51. 51.↵
      1. Thacker SG,
      2. Berthier CC,
      3. Mattinzoli D, et al
      . The detrimental effects of IFN-α on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. J Immunol 2010;185:4457–69. doi:10.4049/jimmunol.1001782
      OpenUrlAbstract/FREE Full Text
    52. 52.↵
      1. Thacker SG,
      2. Zhao W,
      3. Smith CK, et al
      . Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis. Arthritis Rheum 2012;64:2975–85. doi:10.1002/art.34504
      OpenUrlCrossRefPubMedWeb of Science
    53. 53.↵
      1. El-Magadmi M,
      2. Bodill H,
      3. Ahmad Y, et al
      . Systemic lupus erythematosus: an independent risk factor for endothelial dysfunction in women. Circulation 2004;110:399–404. doi:10.1161/01.CIR.0000136807.78534.50
      OpenUrlAbstract/FREE Full Text
    54. 54.↵
      1. Somers EC,
      2. Zhao W,
      3. Lewis EE, et al
      . Type I interferons are associated with subclinical markers of cardiovascular disease in a cohort of systemic lupus erythematosus patients. PLoS One 2012;7:e37000. doi:10.1371/journal.pone.0037000
    55. 55.↵
      1. Roman MJ,
      2. Shanker BA,
      3. Davis A, et al
      . Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349:2399–406. doi:10.1056/NEJMoa035471
      OpenUrlCrossRefPubMedWeb of Science
    56. 56.↵
      1. Manzi S,
      2. Meilahn EN,
      3. Rairie JE, et al
      . Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997;145:408–15. doi:10.1093/oxfordjournals.aje.a009122
      OpenUrlCrossRefPubMedWeb of Science
    57. 57.↵
      1. Yazdanyar A,
      2. Wasko MC,
      3. Scalzi LV, et al
      . Short-term perioperative all-cause mortality and cardiovascular events in women with systemic lupus erythematosus. Arthritis Care Res 2013;65:986–91. doi:10.1002/acr.21915
      OpenUrl
    58. 58.↵
      1. Furumoto Y,
      2. Smith CK,
      3. Blanco L, et al
      . Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheumatol 2017;69:148–60. doi:10.1002/art.39818
      OpenUrl
    59. 59.↵
      1. van Dam AP
      . Diagnosis and pathogenesis of CNS lupus. Rheumatol Int 1991;11:1–11. doi:10.1007/BF00290244
      OpenUrlCrossRefPubMedWeb of Science
    60. 60.↵
      1. DeGiorgio LA,
      2. Konstantinov KN,
      3. Lee SC, et al
      . A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 2001;7:1189–93. doi:10.1038/nm1101-1189
      OpenUrlCrossRefPubMedWeb of Science
    61. 61.↵
      1. Bialas AR,
      2. Presumey J,
      3. Das A, et al
      . Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature 2017;546:539–43. doi:10.1038/nature22821
      OpenUrlCrossRefPubMed
    62. 62.↵
      1. Pinto EF,
      2. Andrade C
      . Interferon-related depression: a primer on mechanisms, treatment, and prevention of a common clinical problem. Curr Neuropharmacol 2016;14:743–8. doi:10.2174/1570159X14666160106155129
      OpenUrl
    63. 63.↵
      1. Siddegowda NK,
      2. Kumar Rao NS,
      3. Andrade C
      . Development of a murine animal model of depression for repeated dosing with human interferon alpha. Indian J Psychiatry 2011;53:239–43. doi:10.4103/0019-5545.86815
      OpenUrlPubMed
    64. 64.↵
      1. Di Domizio J,
      2. Cao W
      . Fueling autoimmunity: type I interferon in autoimmune diseases. Expert Rev Clin Immunol 2013;9:201–10. doi:10.1586/eci.12.106
      OpenUrl
    65. 65.↵
      1. Shiozawa S,
      2. Kuroki Y,
      3. Kim M, et al
      . Interferon-alpha in lupus psychosis. Arthritis Rheum 1992;35:417–22. doi:10.1002/art.1780350410
      OpenUrlCrossRefPubMedWeb of Science
    66. 66.↵
      1. Banker BQ,
      2. childhood Dof
      . Dermatomyostis of childhood, ultrastructural alteratious of muscle and intramuscular blood vessels. J Neuropathol Exp Neurol 1975;34:46–75.
      OpenUrl
    67. 67.↵
      1. Greenberg SA,
      2. Fiorentino D
      . Similar topology of injury to keratinocytes and myofibres in dermatomyositis skin and muscle. Br J Dermatol 2009;160:464–5. doi:10.1111/j.1365-2133.2008.08967.x
      OpenUrlPubMed
    68. 68.↵
      1. Greenberg SA,
      2. Pinkus JL,
      3. Pinkus GS, et al
      . Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis. Ann Neurol 2005;57:664–78. doi:10.1002/ana.20464
      OpenUrlCrossRefPubMedWeb of Science
    69. 69.↵
      1. Greenberg SA,
      2. Sanoudou D,
      3. Haslett JN, et al
      . Molecular profiles of inflammatory myopathies. Neurology 2002;59:1170–82. doi:10.1212/WNL.59.8.1170
      OpenUrlCrossRefPubMed
    70. 70.↵
      1. Wong D,
      2. Kea B,
      3. Pesich R, et al
      . Interferon and biologic signatures in dermatomyositis skin: specificity and heterogeneity across diseases. PLoS One 2012;7:e29161. doi:10.1371/journal.pone.0029161
    71. 71.↵
      1. Liao AP,
      2. Salajegheh M,
      3. Nazareno R, et al
      . Interferon β is associated with type 1 interferon-inducible gene expression in dermatomyositis. Ann Rheum Dis 2011;70:831–6. doi:10.1136/ard.2010.139949
      OpenUrlAbstract/FREE Full Text
    72. 72.↵
      1. Walsh RJ,
      2. Kong SW,
      3. Yao Y, et al
      . Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis. Arthritis Rheum 2007;56:3784–92. doi:10.1002/art.22928
      OpenUrlCrossRefPubMedWeb of Science
    73. 73.↵
      1. Ossandon A,
      2. Iagnocco A,
      3. Alessandri C, et al
      . Ultrasonographic depiction of knee joint alterations in systemic lupus erythematosus. Clin Exp Rheumatol 2009;27:329–32.
      OpenUrlPubMed
    74. 74.↵
      1. Nzeusseu Toukap A,
      2. Galant C,
      3. Theate I, et al
      . Identification of distinct gene expression profiles in the synovium of patients with systemic lupus erythematosus. Arthritis Rheum 2007;56:1579–88. doi:10.1002/art.22578
      OpenUrlCrossRefPubMedWeb of Science
    75. 75.↵
      1. Furie R,
      2. Khamashta M,
      3. Merrill JT, et al
      . CD1013 Study Investigators. Anifrolumab, an anti-interferon-alpha receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol 2017;69:376–86. doi:10.1002/art.39962
      OpenUrl
    76. 76.↵
      1. LaFleur DW,
      2. Nardelli B,
      3. Tsareva T, et al
      . Interferon-kappa, a novel type I interferon expressed in human keratinocytes. J Biol Chem 2001;276:39765–71. doi:10.1074/jbc.M102502200
      OpenUrlAbstract/FREE Full Text
    77. 77.↵
      1. Jacquemin C,
      2. Rambert J,
      3. Guillet S, et al
      . Heat shock protein 70 potentiates interferon alpha production by plasmacytoid dendritic cells: relevance for cutaneous lupus and vitiligo pathogenesis. Br J Dermatol 2017;177:1367–75. doi:10.1111/bjd.15550
      OpenUrl
    78. 78.↵
      1. Sontheimer C,
      2. Liggitt D,
      3. Elkon KB
      . Ultraviolet B irradiation causes stimulator of interferon genes-dependent production of protective type i interferon in mouse skin by recruited inflammatory monocytes. Arthritis Rheumatol 2017;69:826–36. doi:10.1002/art.39987
      OpenUrl
    79. 79.↵
      1. Bernard E,
      2. Hamel R,
      3. Neyret A, et al
      . Human keratinocytes restrict chikungunya virus replication at a post-fusion step. Virology 2015;476:1–10. doi:10.1016/j.virol.2014.11.013
      OpenUrl
    80. 80.↵
      1. van der Fits L,
      2. van der Wel LI,
      3. Laman JD, et al
      . In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered. J Invest Dermatol 2004;122:51–60. doi:10.1046/j.0022-202X.2003.22113.x
      OpenUrlCrossRefPubMedWeb of Science
    81. 81.↵
      1. Nakamura M,
      2. Farahnik B,
      3. Bhutani T
      . Recent advances in phototherapy for psoriasis. F1000Res 2016;5:1684. doi:10.12688/f1000research.8846.1
      OpenUrl
    82. 82.↵
      1. Braunstein I,
      2. Klein R,
      3. Okawa J, et al
      . The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score. Br J Dermatol 2012;166:971–5. doi:10.1111/j.1365-2133.2012.10825.x
      OpenUrlCrossRefPubMed
    83. 83.↵
      1. Huard C,
      2. Gullà SV,
      3. Bennett DV, et al
      . Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon β in dermatomyositis. Br J Dermatol 2017;176:1224–30. doi:10.1111/bjd.15006
      OpenUrl
    84. 84.↵
      1. Yao Y,
      2. Liu Z,
      3. Jallal B, et al
      . Type I interferons in Sjögren's syndrome. Autoimmun Rev 2013;12:558–66. doi:10.1016/j.autrev.2012.10.006
      OpenUrlCrossRefPubMed
    85. 85.↵
      1. Rodero MP,
      2. Crow YJ
      . Type I interferon-mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J Exp Med 2016;213:2527–38. doi:10.1084/jem.20161596
      OpenUrlAbstract/FREE Full Text
    86. 86.↵
      1. Bengtsson AA,
      2. Rönnblom L
      . Role of interferons in SLE. Best Pract Res Clin Rheumatol 2017;31:415–28. doi:10.1016/j.berh.2017.10.003
      OpenUrl
    87. 87.↵
      1. Oon S,
      2. Wilson NJ,
      3. Wicks I
      . Targeted therapeutics in SLE: emerging strategies to modulate the interferon pathway. Clin Transl Immunology 2016;5:e79. doi:10.1038/cti.2016.26
      OpenUrlCrossRef
    88. 88.↵
      1. Schmidt KN,
      2. Ouyang W
      . Targeting interferon-alpha: a promising approach for systemic lupus erythematosus therapy. Lupus 2004;13:348–52. doi:10.1191/0961203304lu1025oa
      OpenUrlCrossRefPubMedWeb of Science
    89. 89.↵
      1. O'Shea JJ,
      2. Schwartz DM,
      3. Villarino AV, et al
      . The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 2015;66:311–28. doi:10.1146/annurev-med-051113-024537
      OpenUrlCrossRefPubMed
    90. 90.↵
      1. Grisouard J,
      2. Hao-Shen H,
      3. Dirnhofer S, et al
      . Selective deletion of Jak2 in adult mouse hematopoietic cells leads to lethal anemia and thrombocytopenia. Haematologica 2014;99:e52–e54. doi:10.3324/haematol.2013.100016
      OpenUrlFREE Full Text
    91. 91.↵
      Jakari™ (ruxolitinib) prescribing information. 2011. Available athttps://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202192lbl.pdf (accessed 01 Feb 2018).
    92. 92.↵
      XELJANZ®(tofacitinib) prescribing information. 2012. Available athttps://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203214s000lbl.pdf (accessed 01 Feb 2018).
    93. 93.↵
      1. Winthrop KL
      . The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol 2017;13:320. doi:10.1038/nrrheum.2017.51

    Footnotes

    • Contributors A list of meeting participants/advisors is provided in the appendix. MC and LR co-chaired the summit and contributed to manuscript preparation.

    • Funding This summit was fully sponsored by AstraZeneca, Gaithersburg, Maryland, USA.

    • Competing interests The two authors of this report, as well as the meeting participants, received fees for their time in preparing for and presenting at/attending this meeting. They received no fees for their work as authors of the manuscript.

    • Patient consent Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.