Meeting report Lupus Sci Med: first published as 10.1136/lupus-2018-000276 on 15 June 2018. Downloaded from Report of the inaugural Interferon Research Summit: interferon in inflammatory diseases

Mary K Crow,1 Lars Rönnblom2

To cite: Crow MK, Abstract responses to distinct classes of therapeutic Rönnblom L. Report of An international summit agents. the inaugural Interferon on interferon (IFN) in inflammatory diseases, held in The inaugural International Summit on Research Summit: interferon Gaithersburg, Maryland, USA (4–5 May 2017), united 22 in inflammatory diseases. IFN in Inflammatory Diseases united 22 inter- internationally renowned clinicians and scientists with Lupus Science & Medicine nationally renowned clinicians and scientists backgrounds in basic science, translational science and 2018;5:e000276. doi:10.1136/ with backgrounds in basic science, transla- lupus-2018-000276 clinical medicine. The objectives of the summit were to assess the current knowledge of the role of type I IFN in tional science and clinical medicine. Goals inflammatory diseases and other conditions, discuss the of the summit included assessing the current ►► Additional material is available clinical trial data of anti-IFN therapeutic agents knowledge of the role type I IFN plays in published online only. To view and identify key clinical and therapeutic knowledge gaps inflammatory diseases and other conditions, please visit the journal online (http://dx.​ ​doi.org/​ ​10.1136/​ ​10.​ and future directions to advance the treatment landscape discussing available clinical data examining 1136/lupus-​ ​2018-000276)​ of diseases involving the type I IFN pathway. A discussion- anti-IFN therapies and identifying current key based consensus process was used to assess three main

clinical and therapeutic knowledge gaps. This Protected by copyright. clinical areas: the role of type I IFN in innate immunity, report summarises the key findings of the the role of type I IFN in autoimmune diseases and rational Received 18 May 2018 meeting and includes the advisors’ recom- Revised 23 May 2018 therapeutic targets in the IFN pathway. These are described Accepted 24 May 2018 here, along with current knowledge gaps and resulting mendations for future efforts to advance the recommendations. The advisors unanimously agreed that, therapeutic landscape of diseases involving despite significant obstacles, the field should transition the type I IFN pathway. from an organ-based model to a pathophysiology-based http://lupus.bmj.com/ model. A better understanding of the molecular pathways could help inform potential therapeutic targets, thus Basic function of the type I IFN system progressing towards personalised medicine by tailoring the Role of IFN in immune responses therapy to each patient. 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), Introduction IFN-β, IFN-ω, IFN-κ, and IFN-ε) with diverse Type I interferon (IFN) is involved in the effects on immune function. The type I IFN on December 5, 2019 at Uppsala Universitet BIBSAM Consortia. pathogenesis of systemic autoimmune system serves as the major line of defence diseases and several organ-targeted inflam- against viruses and microorganisms by matory diseases. Although its primary path- promoting both innate and adaptive immune ogenic role is well established for systemic responses.6–8 The IFN concentrations lupus erythematosus (SLE), the role of type required for antiviral and immunomodula- I IFNs in other autoimmune diseases is less tory effects may be distinct, and our under- clear. Evidence from analyses of peripheral standing of how different type I IFNs and 1Department of Medicine, blood of patients with rheumatoid arthritis receptors generate diverse immune functions Mary Kirkland Center for Lupus demonstrating an IFN signature and is still evolving. Research, Hospital for Special evidence from murine models of diabetes Type I IFNs are particularly important in Surgery, Weill Cornell Medical mellitus strongly suggest a pathogenic role antivirus host defence,6 and the complexity College, New York, USA 1 2Department of Medical of type I IFN in a subset of these diseases. A of the pathway may be necessary to defend Sciences, Section of more prominent type I IFN signature can be against the variety of viruses that are encoun- Rheumatology, Science for Life seen in Sjögrens syndrome, dermatomyositis tered. The innate immune response to viral Laboratory, Uppsala University, (DM) and systemic sclerosis.2–5 Although we infection initiates intense but transient type Uppsala, Sweden have gained a better understanding of the I IFN expression (figure 1).9 10 Although Correspondence to role of type I IFN in autoimmune and inflam- we know many of the triggers that initiate Dr Mary K Crow; matory diseases in recent years, key knowl- a type I IFN response after an acute viral cro​ wm@​hss.edu​ edge gaps remain, including those related to infection,8 the mechanisms by which this

Crow MK, Rönnblom L. Lupus Science & Medicine 2018;5:e000276. doi:10.1136/lupus-2018-000276 1 Lupus Science & Medicine Lupus Sci Med: first published as 10.1136/lupus-2018-000276 on 15 June 2018. Downloaded from

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 al9; right panel adapted from Zuniga et al10 (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.). Protected by copyright. response is terminated are yet to be elucidated. The type nucleic acids in the form of immune complexes can acti- I IFN pathway is dysregulated in SLE,11 12 and the advi- vate endosomal nucleic acid–sensing TLRs and drive type sors agreed that a large research gap exists in our under- I IFN and IFN-induced gene expression, mimicking a standing of what drives overproduction of this cytokine. viral infection.21 Understanding the regulatory mechanisms that control Several nucleic acid sensors (eg, TLRs) within pDCs the innate immune response may yield information bene- trigger distinct signalling pathways, including canonical ficial to the autoimmune diseases community and may type I IFN signalling—IFN-dependent activation of Janus http://lupus.bmj.com/ uncover novel drug targets. kinase (JAK)–signal transducer and activator of tran- Although increased type I IFN expression is common scription (STAT) leading to transcription of IFN-stim- in several diseases, the link between IFN signatures and ulated genes (the type I IFN gene signature (IFNGS)). various clinical manifestations of disease remains unclear, Human pDCs express TLR7 and TLR9 nucleic acid suggesting that the role of type I IFN may differ among sensors, and TLR7/TLR9 signalling induces a morpho- diseases. The advisors discussed the potential utility of IFN logical change in pDCs, from an IFN-producing cell on December 5, 2019 at Uppsala Universitet BIBSAM Consortia. blockade in HIV infection, because studies have demon- with high IFN production and low antigen presentation strated that IFN may be detrimental in these patients, to an antigen-presenting cell with low IFN production potentially contributing to T-cell exhaustion.13 14 Many and high antigen presentation.2 pDCs do not express of the immune alterations that characterise patients with TLR8 under most circumstances,22 which distinguishes autoimmune diseases may be attributable to the immuno- them from monocytes, neutrophils and cDCs, although modulatory properties of type I IFN, epigenetic modifica- recent data from patients with systemic sclerosis suggest tions and irreversible autoimmune processes. that TLR8 can be expressed in pDCs.23 Interleukin receptor–associated kinase-4 (IRAK-4) is involved Sources of IFN: plasmacytoid dendritic cells and other cells in signalling innate immune responses from TLRs. Plasmacytoid dendritic cells (pDCs) have unique IRAK-4-deficient patients produce IFN-α in response biology, are the most active type I IFN-producing cells to viral infections but not to TLR7/TLR9 ligands; thus, and contribute to both innate and adaptive immunity these patients are susceptible to pyogenic bacterial 15 16 (figure 2). pDC type I IFN production is most evident infections (Gram+ bacteria) but appear to have normal at early time points after viral infection. Over time, other resistance to viral infections.24 These data demonstrate cells (eg, conventional dendritic cells (cDCs) and epithe- the presence of non-TLR nucleic acid sensors. lial cells) become more prominent producers of type I IFN.17–19 Exogenous (eg, viral) RNA and DNA elicit type Genetic contributors to the type I IFN system: SLE I IFN production via toll-like receptor (TLR)–dependent heterogeneity and interferonopathies and TLR-independent (cytosolic) mechanisms in pDCs Understanding the molecular basis of diseases will help us and other cells.20 In autoimmune diseases, endogenous progress towards personalised medicine by tailoring the

2 Crow MK, Rönnblom L. Lupus Science & Medicine 2018;5:e000276. doi:10.1136/lupus-2018-000276 Meeting report Lupus Sci Med: first published as 10.1136/lupus-2018-000276 on 15 June 2018. Downloaded from

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; T , T helper cell; TRAIL, tumour necrosis

H Protected by copyright. 16 factor-related apoptosis-inducing ligand; TReg, T regulatory cell. Reproduced from Swiecki and Colonna (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.). therapy to the biological characteristics of each patient. identified in patients with lupus. Although most of these Evidence suggests that genetic variations, along with mutations are related to nucleic acid metabolism, other varying exposure to environmental triggers and chance, mutations associated with nucleic acid signalling, nega- http://lupus.bmj.com/ may play a role in the heterogeneous manifestations of tive regulation of IFN production or response and prote- SLE.25 For example, SLE is more common in people with asome function have been identified. These mutations non-European-American ancestry26 and more severe in primarily affect the brain, skin or both, and non-pene- people with African-American ancestry.27 Serum IFN-α trance appears to contribute to variations in autoim- activity is greater in non-European patients with SLE mune phenotypes. Given that different mutations can than in Europeans, and the predominant genes associ- have overlapping phenotypes, ultrasensitive assays of the ated with increased IFN concentrations differ between cellular source and concentration of IFN may be useful to on December 5, 2019 at Uppsala Universitet BIBSAM Consortia. European-Americans and African-Americans.28 In addi- diagnose interferonopathies.31 tion, 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, IFN in autoimmune diseases differences between populations clearly exist, and these Disease mechanisms of lupus: interplay between IFN and variants affect immune phenotypes (eg, cytokine profile, immune cells autoantibodies). Evidence indicates that genetics is more The interaction between type I IFNs and immune cells is strongly related to immune system phenotype than clin- complex.32 IFN promotes or primes the immune system ical phenotype, and the advisors suggested that future and can be considered an immune system adjuvant. IFN-α clinical trials should be stratified by immune pheno- induces B lymphocyte stimulator production, promoting types rather than clinical phenotypes. A combination of B cell survival,33 and, conversely, B cells promote IFN-α immune and genetic profiling is the future of assessing production via pDCs.34 B cells have a dose-dependent disease heterogeneity in lupus and should be considered effect on IFN-α production—as more B cells become in clinical trial design and potentially in patient manage- activated, the production of type I IFN increases.34 In T ment. cells, type I IFNs promote cell survival,35 and similarly Type I interferonopathies result from mutations that to B cells, activated T cells enhance IFN-α production lead to an overproduction of type I IFN and may be by generating some of the factors that recruit pDCs directly relevant to the pathology of lupus.30 Mutations to produce IFN.36 Natural killer (NK) cells also stimu- similar to those found in interferonopathies have been late IFN-α production, and the pDC–NK interaction

Crow MK, Rönnblom L. Lupus Science & Medicine 2018;5:e000276. doi:10.1136/lupus-2018-000276 3 Lupus Science & Medicine Lupus Sci Med: first published as 10.1136/lupus-2018-000276 on 15 June 2018. Downloaded from enhances non-IFN cytokine production.37 38 Other cells tofacitinib decreased vascular dysfunction in a murine have been implicated in type I IFN production. One lupus model.58 study showed that when monocytes are added to NK-pDC cocultures, monocytes suppress the type I IFN response. Central nervous system For patients with SLE, this suppression may be reduced Central nervous system (CNS) symptoms are present in because of decreased production of reactive oxygen approximately 40% of all patients with SLE and often species.39 40 Thrombocytes have also been implicated in occur in the first year of the disease.59 In some cases, symp- type I IFN production. Activated platelets can promote toms may be associated with the presence of autoanti- IFN-α secretion by pDCs.41 bodies,60 but in most patients the underlying mechanisms In SLE, the control of the type I IFN system is deficient, are unknown. Current hypotheses around the pathophys- leading to an overproduction of IFN.42 Type I IFN appears iological mechanism of CNS symptoms in SLE involve to be a driver rather than a consequence of the disease, increased production of peripheral IFN-α, which then and type I IFN treatment is sufficient to elicit SLE-like enters the CNS and activates reactive microglia that engulf diseases.43 44 Two pathways predominate as potential synaptic material, leading to reduced synaptic density in triggers for type I IFN activation in lupus: cell death regions of the brain that affect behaviour.61 Repeated or damage (eg, the lupus immune complex, oxidised dosing with human IFN-α can promote a depression-like DNA) and defective nucleic acid metabolism (eg, inter- phenotype in mice similar to that observed in patients feronopathies, intracellular nucleic acid accumulation). treated with recombinant IFN-α.62 63 In humans with Although the origin of pathogenic nucleic acids in lupus lupus, a peripheral blood IFN signature is present in 90% is uncertain, potential sources include NETosis, apoptosis of children and more than 50% of adults,64 and IFN-α is (in the context of inflammation), necroptosis, pyroptosis elevated in the cerebrospinal fluid of some patients.65 and autophagy.45 46 Increased generation or impaired degradation of cytosolic endogenous nucleic acids could Muscle activate cytosolic sensors. Oxidised DNA can be detected Characterisation of the contribution of type I IFN to the in skin lesions of patients with lupus and stimulates local immunopathogenesis of DM has relied on immunohisto- type I IFN production.47 In the general population, chemical analysis of muscle tissue along with gene expres- Protected by copyright. nucleases protect from lupus development by degrading sion studies. Although a previous view of DM pathogen- nucleic acids.48 Deoxyribonuclease 1 like 3 deficiency esis focused on the deposition of autoantibodies in tissue can manifest as lupus or an SLE-like disease.49 Autoanti- and complement-mediated tissue damage, observations bodies to nucleic acids develop years before SLE (the type of expression of myxovirus resistance 1 protein, a type I I IFNGS increases very early in the disease), and earlier IFN-induced gene product, in myofibres and capillaries detection may be possible in the future with more sensi- pointed to a significant pathogenic role for type I IFN http://lupus.bmj.com/ tive screening tools. in DM.66 The muscle pathology of DM is unique, char- acterised by perifascicular atrophy. A similar topology of Influence of IFN on organ systems injury to keratinocytes and myofibres exists in the skin Cardiovascular system and muscle of patients with DM.67 DM gene expression An imbalance between vascular damage and repair causes mapping shows that induced genes are type I IFN regu- cardiovascular disease in patients with SLE. In these lated,68 69 and DM and SLE microarrays revealed type I patients, IFN-α hampers vascular repair and inhibits IFN signalling far in excess of that of other skin diseases.70 on December 5, 2019 at Uppsala Universitet BIBSAM Consortia. angiogenesis,50–52 and the disease is an independent Type I IFN-inducible proteins in muscle localise to areas of risk factor for development of atherosclerosis.53 Type I perifascicular atrophy as well as endothelial cells of capil- IFNs are independently associated with functional and laries and large vessels. A strong type I IFNGS is evident in anatomical markers of subclinical cardiovascular disease the muscle, skin and blood of patients with DM.70–72 (ie, endothelial function, carotid plaque, severity of coronary calcification) in patients with SLE without a Joints history of overt cardiovascular events, after controlling Joint involvement is common in lupus and is typically for Framingham risk factors.54 non-deforming and non-erosive. American College of The prevalence of atherosclerosis has been found to Rheumatology criteria define lupus arthritis as character- be higher in patients with lupus compared with control ised by tenderness, swelling or effusion in two or more individuals (37.1% vs 15.2%).55 Young women (35 and 44 joints, but many patients report joint pain in the absence years) with SLE have a 50-fold increased risk of vascular of apparent synovitis. However, sensitive imaging (eg, complications,56 including a greater prevalence of with ultrasound) has revealed that subclinical synovitis is perioperative cardiovascular adverse events and greater present in up to 40% of these patients.73 mortality following first myocardial infarction, compared IFNs play a complex role in lupus arthritis. Expression with patients without SLE.57 In atherosclerotic lupus- of type I IFN-induced gene transcripts have been demon- prone mice, IFN blockade improved vascular repair strated in the synovial tissue of patients with SLE, and and decreased atherothrombosis.52 Inhibition of type I inhibition of osteoclastogenesis by IFN might account for IFN receptor signalling via the JAK/STAT pathway with the relatively non-erosive character of the arthritis seen

4 Crow MK, Rönnblom L. Lupus Science & Medicine 2018;5:e000276. doi:10.1136/lupus-2018-000276 Meeting report Lupus Sci Med: first published as 10.1136/lupus-2018-000276 on 15 June 2018. Downloaded from in patients with lupus.74 Evidence of type I IFN activity and in interferonopathies, genetic mutations identify the in circulation has been detected in patients with lupus, importance of IFNs in skin disease.85 and the anti-IFN-α receptor (IFNAR) therapeutic agent anifrolumab has been shown to reduce joint disease activity scores.75 Rational therapeutic targets in the IFN pathway Advisors agreed that a better understanding of the Skin molecular pathways (eg, relative roles of TLR vs cytosolic Keratinocytes are a source of IFN-κ in healthy skin.76 nucleic acid sensors) could help uncover potential novel IFN-κ maintains the basal IFN gene response in kerati- therapeutic targets,86 and future efforts should consider nocytes, induces the IFN gene response in fibroblasts and extracellular and intracellular drug targets upstream and activates dendritic cells. IFNs promote a proinflammatory downstream of IFN.87 88 Potential upstream candidates response in keratinocytes, including CXCL9, CXCL10 include cells producing IFN (eg, pDCs), nucleic acid and interleukin-6 production.77 IFNs also have a role in receptors (eg, TLRs, cytosolic sensors), signalling compo- protecting skin. In wild-type mice, ultraviolet (UV) light nents (eg, kinases, adaptors) and transcriptional regula- induces an IFN response that is independent of pDCs, tors. Downstream candidates include IFNAR, signalling requiring CCR2+ cells and may be protective against components (eg, JAK/STAT)89 and induced gene prod- inflammation.78 Keratinocytes produce type I/II/III IFNs ucts (eg, IFN-stimulated genes, mRNAs, proteins). Ther- after viral infection and suppress viral replication.79 apeutic agents that target the type I IFN pathway (from IFNs play a role in several skin diseases. In psoriasis, pDC to JAK-STAT activation) in clinical development IFN-β is upregulated in skin lesions,80 although the exact for IFN-driven diseases are listed in table 1. Although role of IFNs remains unclear. UV light downregulates upstream drivers of type I IFN production may be more IFNAR1, which is thought to be relevant to the thera- specific for SLE, they may differ for individuals, restricting peutic efficacy of UV light for psoriasis.81 Subacute cuta- efficacy to a subset of patients. For example, DNA-con- neous lupus erythematosus is characterised by a robust taining immune complexes may drive type I IFN produc- type I IFNGS, which is correlated with disease activity.82 tion in some patients, whereas others may have immune

In these patients, IFN-κ production increases after UV complexes that predominantly contain RNA. The advi- Protected by copyright. exposure. A strong IFN signature is also present in skin sors also expressed concern that a greater risk of toxicity lesions of patients with DM83 and Sjögren’s syndrome,84 may exist when targeting signalling pathways downstream

Table 1 Therapeutic agents targeting components of the type I IFN pathway and in clinical development for IFN-driven diseases http://lupus.bmj.com/ Drug Drug MOA Development status Disease RSLV132 RNA hydrolysis Phase II Systemic lupus erythematosus Sjögren's syndrome SM101 Anti-immune complex Phase II Systemic lupus erythematosus Lupus nephritis

BIIB059 Anti-BDCA2 (pDCs) Phase II Systemic lupus erythematosus on December 5, 2019 at Uppsala Universitet BIBSAM Consortia. MEDI-7734 Anti-ILT7 (pDCs) Phase I Dermatomyositis Polymyositis Systemic sclerosis Sjögren's syndrome Systemic lupus erythematosus JNJ-55920839 Anti-IFN-α/ω Phase I Systemic lupus erythematosus AGS-009 Anti-IFN-α Phase I* Systemic lupus erythematosus IFN-α-kinoid Anti-IFN-α Phase II Dermatomyositis Phase II Systemic lupus erythematosus Anifrolumab Anti-IFNAR1 Phase II Lupus nephritis Sjögren's syndrome Phase III Systemic lupus erythematosus Baricitinib† JAK1/JAK2 inhibitor Phase II Systemic lupus erythematosus PF-04965842 JAK1 inhibitor Phase II Systemic lupus erythematosus

*Development status unknown. †European Medicines Agency approved for rheumatoid arthritis. IFN, interferon; IFNAR1, type I interferon alpha receptor subunit 1; ILT7, immunoglobulin-like transcript 7; JAK, Janus kinase; MOA, mechanism of action; pDCs, plasmacytoid dendritic cells.

Crow MK, Rönnblom L. Lupus Science & Medicine 2018;5:e000276. doi:10.1136/lupus-2018-000276 5 Lupus Science & Medicine Lupus Sci Med: first published as 10.1136/lupus-2018-000276 on 15 June 2018. Downloaded from

Table 2 Key points to be considered in future research efforts Issue considered Comments from advisors

What drives production of type I IFNs (eg, pDCs, ►► What is the contribution of different cell types to IFN keratinocytes)? production, especially in tissue? ►► Are we measuring production of IFN or downstream effects? ►► Does the source of IFN change during the course of the disease? What are the endogenous triggers of the immune system? ►► Better understanding of the pathways Can we clearly define the signal for IFN? ►► What is the sensitivity of the assays? ►► Clear signature for IFN-β versus IFN-α What is the significance of IFN-regulated genes? ►► Measure IFN in various tissues ►► What is the role of different types of IFN (I, II, III)? ►► What is the role of IFN-α on long-lived plasma cells? Do we have a biochemical understanding of differential ►► Is there a tissue-specific difference? signalling by the various isoforms of IFN-α as well as IFN-β? What is the correlation between IFN status and phenotype? ►► What are the genetic susceptibility factors? What is our understanding of the stability of IFN signature for N/A patients with different disease activity? What is the role of IFNGS in diseases other than lupus and N/A classical systemic inflammatory rheumatic diseases (eg, Sjögren’s syndrome, SSc, RA), such as opportunity in HIV, psoriasis, others? What are the effects of blocking IFN on other compensatory N/A Protected by copyright. mechanisms? What is our understanding of the genome-wide RNA N/A sequencing for patients with several IFN diseases, pre-anifrolumab and post-anifrolumab? Is there a point where a disease becomes irreversible and IFN N/A blockage will no longer work? http://lupus.bmj.com/ How is IFN linked to sex differences in SLE? N/A Do we have a good understanding of the clinical and biological N/A characteristics of IFN-low patients?

HIV, human immunodeficiency virus; IFN, interferon; IFNGS, interferon gene signature; N/A, not applicable; pDC, plasmacytoid dendritic cells; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis. of the IFNAR because they are shared by many systems pathway in IFN-driven diseases, IFN represents a tractable on December 5, 2019 at Uppsala Universitet BIBSAM Consortia. (eg, JAK/STAT signalling). drug target that is strongly linked to the IFNGS. Type I IFN Although complex cytokine/IFN signalling is an attrac- plays an important role in the pathogenesis of SLE and tive focus, it can be a risky target (eg, the JAK2 knockout likely in other disorders characterised by IFN signalling is embryonically lethal).90 Given there are four pairs of that have not been addressed previously. Anifrolumab is a JAKs, JAK1–3 and TYK2, and JAKs exist as pairs on cyto- fully human monoclonal antibody that binds to the type I kine receptors, there will likely be a need for selective IFN receptor and is in Phase III development for moderate JAK inhibitors. Currently, two JAK inhibitors (ruxoli- to severe SLE. In the MUSE Phase IIb clinical trial,75 a tinib91 and tofacitinib92) are approved and are effective high IFNGS was a biomarker of anifrolumab response in allergic diseases. Tofacitinib is efficacious in murine compared with placebo. The outcomes of patients with a lupus,58 and a Phase II clinical trial of baricitinib for low IFNGS were not significantly different between those the treatment of lupus has completed enrolment. Like receiving drug and those receiving placebo. However, all medications, JAK inhibitors can be associated with it is notable that the percentage of patients responding adverse events, including infection, cytopenias, increased to the drug was roughly similar in the high and low lipids and gastrointestinal perforation, but are well toler- IFNGS groups, and a relatively high placebo response ated by many patients.93 was demonstrated in the low IFNGS group. The trial with The advisors discussed the advantages and limitations anifrolumab supports the hypothesis that the type I IFN of focusing on the type I IFN pathway as a therapeutic pathway is an important contributor to the pathophysi- target. Given the uncertainty surrounding the roles of ology of SLE. The data also suggest a need for additional various upstream and downstream components of the IFN research to understand whether there is a role for IFN

6 Crow MK, Rönnblom L. Lupus Science & Medicine 2018;5:e000276. doi:10.1136/lupus-2018-000276 Meeting report Lupus Sci Med: first published as 10.1136/lupus-2018-000276 on 15 June 2018. Downloaded from pathway inhibition in therapy of those with a low IFNGS. Conclusion Determining type I IFN pathway status in an individual This summit was the first meeting in a series of meet- patient based on an IFNGS test may help to predict which ings that unites clinicians and scientists with the goal of patients are more likely to respond to treatment. outlining future directions to explore novel treatment of Some advisors recognised several limitations of diseases involving the IFN pathway. The advisors unani- focusing on the type I IFN pathway as a therapeutic mously agreed that, despite significant obstacles, the field target, including safety concerns (eg, impaired antivirus should transition from an organ-based model to a patho- protection, increased susceptibility to infections such as physiology-based model. A better understanding of the Herpes zoster), unclear long-term effects on the immune molecular pathways could help inform potential thera- system, insufficient data on the link between high IFN peutic targets, progressing toward personalised medicine and B-cell and plasma-cell activation and the poten- by tailoring the therapy to the characteristics of each tial alteration of the balance between IFN-α and IFN-β patient. signalling in neurons if the antibody enters the CNS. In addition, given the diverse and complex alterations in Acknowledgements The authors wish to thank the advisors for their contributions many components of the immune response for patients 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 with SLE and other autoimmune diseases, treatment with Michael A Nissen, ELS, of AstraZeneca. drugs that target the type I IFN pathway may not be suffi- Contributors A list of meeting participants/advisors is provided in the appendix. cient to gain control of disease activity and may not treat MC and LR co-chaired the summit and contributed to manuscript preparation. all manifestations of the disease in a single patient; there- Funding This summit was fully sponsored by AstraZeneca, Gaithersburg, Maryland, fore, treatment would require several drugs. USA. Competing interests The two authors of this report, as well as the meeting Transitioning from an organ-based model to a 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 pathophysiology-based model manuscript. The advisors unanimously agreed that, despite significant Patient consent Not required.

obstacles, the field should transition from an organ-based Provenance and peer review Not commissioned; externally peer reviewed. Protected by copyright. model to a pathophysiology-based model. Key obstacles to Open access This is an Open Access article distributed in accordance with the this approach include the necessity of finding biomarkers Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which that identify the most relevant molecular pathways oper- permits others to distribute, remix, adapt, build upon this work non-commercially, ative in a given patient; the challenges in establishing the 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/​ clinically defined patient cohorts needed for investiga- licenses/by-​ ​nc/4.​ ​0/ tion of the genetic variations and gene expression signa- © Article author(s) (or their employer(s) unless otherwise stated in the text of the http://lupus.bmj.com/ tures associated with defined clinical features of disease article) 2018. All rights reserved. No commercial use is permitted unless otherwise and the uncertainty of categorising these disorders as IFN expressly granted. diseases, because other pathways also will be involved. Based on these obstacles, the advisors recommended three types of pathophysiology-based studies. In the first REFERENCES type of study, a ‘basket approach’ design, two or three 1. Crow MK. Type I interferon in organ-targeted autoimmune and diseases with common phenotypes would be selected inflammatory diseases. Arthritis Res Ther 2010;12(Suppl 1):S5. 2. Rönnblom L, Eloranta ML. The interferon signature in autoimmune on December 5, 2019 at Uppsala Universitet BIBSAM Consortia. and specific outcomes would be measured. The basket diseases. Curr Opin Rheumatol 2013;25:248–53. approach would use an observational/open-label design 3. Wu M, Assassi S. The role of type 1 interferon in systemic sclerosis. Front Immunol 2013;4:266. with the composite endpoint based on the percentage of 4. Li H, Ice JA, Lessard CJ, et al. Interferons in Sjögren's syndrome: responders for each measure. In the second type of study, genes, mechanisms, and effects. Front Immunol 2013;4:290. a ‘feature approach’ design, patients with a common 5. Baechler EC, Bilgic H, Reed AM. Type I interferon pathway in adult and juvenile dermatomyositis. Arthritis Res Ther 2011;13:249. feature (eg, arthritis) would be pooled and the response 6. Stetson DB, Medzhitov R. Type I interferons in host defense. to treatment would be measured based on that common Immunity 2006;25:373–81. 7. Boxx GM, Cheng G. The roles of Type I interferon in bacterial feature. The third type of study would use a ‘steroid- infection. Cell Host Microbe 2016;19:760–9. sparing approach’. Because many diseases are managed 8. McNab F, Mayer-Barber K, Sher A, et al. Type I interferons in with steroids, a reduction in steroid use plus an additional infectious disease. Nat Rev Immunol 2015;15:87–103. 9. Crouse J, Kalinke U, Oxenius A. Regulation of antiviral T cell clinical measure could be used as endpoints. responses by type I interferons. Nat Rev Immunol 2015;15:231–42. 10. Zuniga EI, Macal M, Lewis GM, et al. Innate and adaptive immune regulation during chronic viral infections. Annu Rev Virol 2015;2:573–97. 11. Crow MK. Advances in understanding the role of type I interferons Future directions in systemic lupus erythematosus. Curr Opin Rheumatol After identifying and discussing knowledge gaps for the 2014;26:467–74. 12. Hagberg N, Rönnblom L. Systemic lupus erythematosus – a disease role of the type I IFN pathway in autoimmune diseases, with a dysregulated type i interferon system. Scand J Immunol the advisors generated a list of 13 key questions to be 2015;82:199–207. 13. Zhen A, Rezek V, Youn C, et al. Targeting type I interferon-mediated considered in future research efforts to advance the treat- activation restores immune function in chronic HIV infection. J Clin ment landscape (table 2). Invest 2017;127:260–8.

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Crow MK, Rönnblom L. Lupus Science & Medicine 2018;5:e000276. doi:10.1136/lupus-2018-000276 9 Correction Correction: Report of the inaugural Interferon Research Summit: interferon in inflammatory diseases Crow MK, Ronnblom L. Report of the inaugural Interferon Research Summit: interferon in inflammatory diseases. Lupus Science & Medicine 2018;5:e000276. doi: 10.1136/lupus-2018-000276

The authors want to alert readers to the following two errors identified in the published version. At page 4 (column 1, 2nd sentence of last paragraph), the sentence should read as: “Young women (35–44 years) with SLE have a 50-fold increased risk of vascular complications…” In Table 1, the row under the drug “Anifrolumab” states that the drug is at Phase II for Sjögren’s syndrome. This has been stated incorrectly and has been removed. The updated Table 1 is now available below:

Table 1 Therapeutic agents targeting components of the type I IFN pathway and in clinical development for IFN-driven diseases Drug Drug MOA Development status Disease RSLV132 RNA hydrolysis Phase II Systemic lupus erythematosus Sjögren's syndrome SM101 Anti–immune Phase II Systemic lupus complex erythematosus Lupus nephritis BIIB059 Anti-BDCA2 (pDCs) Phase II Systemic lupus erythematosus MEDI-7734 Anti-ILT7 (pDCs) Phase I Dermatomyositis Polymyositis Systemic sclerosis Sjögren's syndrome Systemic lupus erythematosus JNJ-55920839 Anti–IFN-α/ω Phase I Systemic lupus erythematosus AGS-009 Anti–IFN-α Phase I* Systemic lupus erythematosus IFN-α-kinoid Anti–IFN-α Phase II Dermatomyositis Phase II Systemic lupus erythematosus Anifrolumab Anti-IFNAR1 Phase II Lupus nephritis Phase III Systemic lupus erythematosus Baricitinib† JAK1/JAK2 inhibitor Phase II Systemic lupus erythematosus PF-04965842 JAK1 inhibitor Phase II Systemic lupus erythematosus

*Development status unknown. †European Medicines Agency approved for rheumatoid arthritis. IFN, interferon; IFNAR1, type I interferon alpha receptor subunit 1; ILT7, immunoglobulin-like transcript 7; JAK, Janus kinase; MOA, mechanism of action; pDCs, plasmacytoid dendritic cell.

In the legend of figure 1, the term ‘interferon-stimulating genes’ appears. The correct term is ‘interferon-stimulated genes’.

Lupus Sci Med 2018;5:e000276corr1. doi:10.1136/lupus-2018-000276corr1 1 Lupus Science & Medicine

Figure 1 The role of IFN in viral infection over time. cDC, conventional dendritic cell; IFN, interferon; IL, interleukin; ISG, interferon-stimulated genes; pDC, plasmacytoid dendritic cells; PD-L1, programmed death ligand 1; PRR, pattern recognition receptor. Left panel adapted from Crouse J et al9; right panel adapted from Zuniga EI et al10 (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).

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