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JAK inhibitors: a potential treatment for JDM in the context of the role of interferon-driven pathology

Abstract

Juvenile Idiopathic Inflammatory Myopathies (IIM) are a group of rare diseases that are heterogeneous in terms of pathology that can include proximal muscle weakness, associated skin changes and systemic involvement. Despite options for treatment, many patients continue to suffer resistant disease and lasting side-effects. Advances in the understanding of the immunopathology and genetics underlying IIM may specify new therapeutic targets, particularly where conventional treatment has not achieved a clinical response. An upregulated type I interferon signature is strongly associated with disease and could be a prime target for developing more specific therapeutics. There are multiple components of the IFN pathway that could be targeted for blockade therapy.

Downstream of the cytokine receptor complexes are the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, which consists of JAK1–3, TYK2, and STAT1–6. Therapeutic inhibitors have been developed to target components of this pathway. Promising results have been observed in case studies reporting the use of the JAK inhibitors, Baricitinib, Tofacitinib and Ruxolitinib in the treatment of refractory Juvenile Dermatomyositis (JDM). There is still the question of safety and efficacy for the use of JAK inhibitors in JDM that need to be addressed by clinical trials. Here we review the future for the use of JAK inhibitors as a treatment for JDM.

Introduction

Idiopathic Inflammatory Myopathies (IIM) are a group of rare immune-mediated diseases that are heterogeneous in terms of pathology, clinical phenotypes and age of onset (Table 1). JDM is very rare with an annual incidence of three cases per million children [2, 23, 24] and median age of onset 6.3 years old (IQR; 3.8–9.6) [1]. Children typically present with symmetrical proximal and axial muscle weakness and characteristic skin changes including Gottron’s papules and heliotrope rash. Long-term complications include lung fibrosis, lipodystrophy and calcinosis [25,26,27,28,29] . In most JDM cohorts, 60–70% of children with JDM are positive for an autoantibody [30,31,32,33]. A number of myositis specific antibodies (MSA) have been described associated with a variety of phenotypes in JDM [10].

Table 1 JDM disease features

The need for new treatments

The mainstay treatments for IIM are prednisolone and methotrexate, and even those patients who respond well to these drugs can have prolonged disease [34, 35]. Other immunotherapy treatments used include mycophenolate mofetil, cyclophosphamide, intravenous immunoglobulin (IvIG), azathioprine, cyclosporine and tacrolimus [36,37,38]. Biological targets include blockade of tumour necrosis factor alpha (TNFα) and B cells (anti-CD20). As potential treatments for JDM, efficacy was reported in a case series of the use of adalimumab and infliximab (TNFα blockades), and also in an International study of B cell depletion by rituximab (anti-CD20) [39, 40]. However, there is a need for more targeted treatments and methods to identify patients who will require these.

Several more recent emerging biologic therapies for the treatment of IIM have been reported including; belimumab, abatacept, bimagrumab, spiponimod, apremilast, gevokizumab, eculizumab and basiliximab (Table 2) [41,42,43,44,45,46,47,48]. Sifalimumab, is a fully human immunoglobulin G1 κ anti-IFNα monoclonal antibody that binds to and neutralizes the majority of IFN-α subtypes, is an important candidate therapeutic due to the wealth of evidence of the strong IFN signature identified in myositis [11, 12, 50,51,52,53,54,55]. A phase 1b clinical trial of sifalimumab in adult patients with dermatomyositis (DM) and polymyositis (PM), used outcome measures of IFN gene signature suppression against disease improvement. Initial results suggested that targeting the IFN pathway with sifalimumab showed more neutralisation of IFN gene expression in patients that had greater improvement of disease, but blockade of the type I IFN receptor (IFNAR) may offer superior clinical benefit [49]. Beyond the therapeutics highlighted in Table 2 there are potential new therapies for the treatment of IIM including JAK inhibitors to target the IFN pathway.

Table 2 Emerging biologic therapies for the treatment of adult and juvenile IIM

Interferon: mechanisms in autoimmune disease

While the interferon family are a group of molecules central to the anti-viral responses, many autoimmune diseases also have an aberrant interferon response. Gene activation is the main mechanism for the interferon anti-viral response, but interferons are also integral to intra-cellular signalling in the immune system (Additional file 1: Supplementary Fig. 1 [56]). Many autoimmune diseases have been found to have an up-regulated IFN type I signature, including systemic lupus erythematous (SLE), rheumatoid arthritis (RA) and myositis [11, 50, 51, 57,58,59]. The IFN type I comprise of thirteen types including IFN-α, IFN-β, IFN-κ, IFN-ω and IFN-ν; these bind to a common receptor, IFN-α receptor (IFNAR), but the differences in induction of cellular responses is poorly defined [60]. There are three proposed mechanisms. The first is that plasmacytoid dendritic cells (pDCs) are activated by endogenous IFN inducers to produce IFN-α [61]. The second is that genes associated with autoimmune disease risk, lie within the IFN type I signalling pathway that in turn effect the production and response of IFN-α. IFN-regulatory factor (IRF) 5 was identified as a SLE risk gene as it has increased expression and is activated in SLE patients [62,63,64]. Other autoimmune diseases have specific risk genes that associate with the IFN signature [65]. The third mechanism proposes that regulation and control of plasmacytoid dendritic cells (pDC) and the expression of interferon regulatory genes (IRG) is not functioning correctly [61]. A decrease in reactive oxygen species (ROS) production from monocytes can lead to enhanced autoimmunity. In addition there is a predominant STAT1 signature in ROS deficient disease [66]. The relative contribution of these three mechanisms may differ between autoimmune disease, severity and patient.

Role of interferons in myositis

The most abundant IFN type I are IFN-α and IFN-β. The IFNs bind to the IFN-α receptor (IFNAR) and activate the Janus kinase (JAK)-signal transducer and transcription (STAT) pathway that in turn lead to the transcription of IFN-stimulated genes (ISGs) [67, 68]. The over production of IFN in the blood and muscle is an abnormality in the pathogenesis of dermatomyositis [13, 14, 69]. The release of IFN type I leads to immune cell activation and vasculopathy. A major source of IFN type I is from plasmacytoid dendritic cells (pDC) after activation by either self-DNA or viral nucleic acid [70, 71]. Plasmacytoid dendritic cells (pDC) have been identified in JDM muscle, but IFN type I is difficult to detect in serum due to limits of sensitivity of existing assays until recently [11, 72]. The Simoa assay developed by Rodero et al. can detect IFN-α at differential levels and determine cellular sources measured from lysed cell-subsets [57]. Using this assay IFN-α levels were significantly increased in sera from a JDM cohort compared to a healthy cohort [57, 73].

Due to the difficulties in measuring IFN directly, gene expression is often used as a marker of the activation of the IFN type I pathway. An IFN score was developed to encompass a selection of the IFN response genes, IFI27, IFI44L, IFIT1, ISG15, RSAD2 and SIGLEC1, these are measured by quantitative reverse transcription polymerase chain reaction (qPCR) [74]. Other studies have also measured expression of additional genes including ISG15 ubiquitin-like modifier (G1P2), and interferon regulatory factor 7 (IRF7) [51, 71]. Variations of this score have been used to correlate with disease in multiple studies [53, 75, 76]. A signature of 43 genes was elevated in myositis compared to controls [14]. A positive correlation has been shown between an IFN score (6 genes) compared to serum IFN-α levels (n = 24, Rs = 0.620, p = 0.0004) taken from JDM patients [57]. The type II IFN signature also correlates to disease activity in JDM and other chemokines [77]. This suggests that as a whole the IFN family are upregulated in the context of JDM and adult DM. The clinical trial of sifalimumab in DM/PM showed suppression of the IFN gene signature in blood and muscle tissue of the IIM patient cohort. Patients with 15% or greater improvement from baseline manual muscle testing scores (MMT8) showed greater neutralisation of the interferon gene signature than patients with less than 15% improvement [49]. This trial highlights the potential for the therapeutic targeting of interferon in DM and JDM.

Another indirect measure is the IFN-driven protein signature which may include measurement of levels of monocyte chemoattractant protein 1 (MCP-1), monocyte chemoattractant protein 2 (MCP-2), interferon gamma-induced protein 10 (IP-10), tumour necrosis factor receptor II (TNFRII), galectin 9 and chemokine (C-XC motif) ligand 9 (CXCL9). These proteins, measured in serum, significantly correlated with disease activity in JDM [22, 78,79,80]. Chemokines and cytokines have shown to correlate with the IFN signature in peripheral blood mononuclear cells. A study in JDM showed an expansion of peripheral blood naïve immature B cells, skewed to an inflammatory profile, in early disease, that correlated with an IFN type I score taken from RNA-seq analysis of B cells and downstream IFN proteins [81].

Circulating endothelial cells (CEC) have been detected in peripheral blood and associated with vascular injury [82]. An in vitro study has shown that IFN type I treatment of HUVECs impaired endothelial cell function, with significant reduction of tubule formation when HUVECs were cultured with IFN type I + VEGF and anti-IP10 [83]. A recent study in JDM, identified higher CEC in both active and definite inactive disease (JDM n = 90; median 96(IQR 40–192) cell/ml compared to controls n = 79; median 12(IQR 8–24) cells/ml, p < 0.0001). They also showed a strong correlation with other markers of vascular injury including endothelial microparticles and galectin-9 [9]. Another study showed that CEC correlated with extra muscular disease activity but not muscular damage [84]. In JDM, CEC may prove to be a useful biomarker for underlying disease pathology.

Key sites of inflammation in JDM are the muscle and skin. Both muscle and skin tissue biopsy material can provide valuable insights to our understanding of an individual JDM patients disease [85,86,87,88]. These tissue samples are the key to understanding the pathophysiology of disease at the tissue site. IFN type I and other cytokines have been detected within the inflamed muscle [89]. The IFN proteins (IFN-α,-β,-γ) themselves have been detected in muscle, but also the IFN-stimulated proteins ISG15, MxA and class I MHC [90,91,92]. Higher levels of ISG15 were quantified in JDM muscle tissue compared to non-JDM [93]. Markers of disease activity and muscle damage have been shown to correlate with the expression of MxA in the muscle tissue [94, 95]. Research has been carried out to identify the direct effects that IFN type I has on muscle tissue types. Muscle atrophy and loss of myogenin has been detected on muscle myotubes, reduced junctions and capillary growth on endothelium [96]. A recent study has shown that these effects have been blocked in vitro by the JAK inhibitor Ruxolitinib [97]. These findings build a picture of the interferonopathy at both the tissue site and the peripheral blood.

The JAK-STAT pathway – a therapeutic target

When IFN binds to its respective receptor, IFN-R, on the cell surface membrane, this in turn activates the signalling cascade inducing the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway [98, 99] (Fig. 1). The JAK-STAT pathway consists of JAK1–3, TYK2, and STAT1–6, of these JAK1 and TYK2 are directly activated by IFN type 1 proteins. This signalling cascade triggers the receptor-associated JAK to phosphorylate the receptor and other JAKs [100]. If specific tyrosine motifs are phosphorylated in the cytokine receptor, then a docking-site for STATs is opened enabling further phosphorylation of STATs. When STATs are phosphorylated they dimerize through their Src homology domain-2 (SH2) domains, this allows them to translocate to the nucleus and activate specific genes [101]. An individual receptor is made up of several subunits, each is associated with a specific JAK. Therefore, each receptor chain can have more or less specificity to an individual JAK. The JAK-STAT pathway could offer a potential target for the blockade of the transcription of IFN genes [100].

Fig. 1
figure1

JAK-STAT pathway with JAK inhibitor targets. The activation of the JAK-STAT pathway after IFN type 1 has engaged with the associated receptor, IFNR. This induces the transcription of proteins. Tofacitinib inhibits JAK1/2/3. Ruxolitinib and Baricitinib inhibit JAK 1/2, inhibtion prevents STAT phosphorylation, dimeraziation and transolcation into the nucleuse. This in turn stops the transcription of pro-inflammatory proteins

JAK inhibition

JAKs are constructed from four domains made of seven homologous regions (JH1–7) (Fig. 2). To date JAK inhibitors (JAK-inhibitors) have generally targeted the JH1 domain. JH1 is the active catalytic phosphotransferase domain and competes with adenosine triphosphate at the catalytic site [102]. JH2 is a pseudokinase domain that supresses ligand-independent kinase activity, the mode of action is direct interaction with JH1 and activation of ligand-induced JAK [103]. Deucravacitinib is an example of a JAK inhibitor that targets the JH2 psuedokinase domain [104, 105]. JH3/4 have a primary role in stabilising the structure of the enzyme. JH5–7 associate JAKs with their cognate receptors [106]. There have been multiple JAK-inhibitors that have been or are in development. These can be defined in two categories; first-generation or next-generation JAK-inhibitors [100]. The first-generation exert pan-inhibition on all four of the JAKs, these include; tofacitinib, ruxolitinib, baricitinib, and oclacitinib [107]. The next-generation of JAK-inhibitors are more specific in their target blockade, these include; fedratinib, momelotinib, and pacritinib [108]. This specificity should help with disease targeted treatment and reduce associated side-effects.

Fig. 2
figure2

JAK domains and homologous regions. JAKs are constructed from four domains made of seven homologous regions (JH1–7)

Inhibition of TYK2 is an example of a more specific next-generation Jakinib. TYK2 has been associated with several autoimmune conditions including; RA, JIA, SLE, type 1 diabetes and MS [109,110,111,112,113,114]. A GWAS analysis of IIM in Caucasian individuals identified that a non-synonymous SNP rs2304256 in TYK2 was associated with DM, IIM but not PM (Bonferroni correction p = 0.17, [115]. In a study of a Chinese Han population, analysis of TYK2 SNPS associated with DM and PM excluded TYK2 rs2304256 as it deviated from the Hardy-Weinberg equilibrium (HWE) in healthy controls [116]. This SNP is in the protein FERM (4.1 protein, erzin, radixin, moesin) domain, mediating interaction with JAK and microtubule interacting proetin1, this is thought to be increased in DM. Examples of TYK2 inhibitors trialled in psoriasis include; brepocitinib, BMS-986165 and PF-06826647 [117]. TYK2 is just one proposed target for inhibition in IIM.

JAK inhibitor use in IIM – clinical trials

For the potential treatment of autoimmune conditions, multiple JAK inhibitors have been developed, trialled or approved [104, 107]. In adults the metabolism, pharmacokinetics and efficacy of JAK-inhibitors are highlighted in Additional file 1: Supplementary Table 1. Clinical trials are ongoing to determine the safety and efficacy of the use of multiple JAK-inhibitors as a therapy for treatment-resistant adult IIM. In addition to their small open-label, proof-of concept study of tofacitinib in 10 treatment-resistant DM patients (6 were anit-TIF1-γ positive), Paik et al. are carrying out a larger randomised controlled trial, with results pending (NCT03002649). Initial results from 10 participants showed they all met the primary outcome DOI at 12 weeks, 5 of 10 (50%) had moderate improvement and 5 of 10 (50%) had minimal improvement according to the 2016 ACR/EULAR myositis response criteria. The secondary outcome showed a significant change in CDASI disease activity score (mean average 28 ± 15.4 (baseline) vs. 9.5 ± 8.5 (12 weeks), p = 0.0005). There was also a trend towards a reduction of CXCL9/10 in serum and STAT1 signalling in 3 of 9 skin biopsies [118]. Another case report of 3 patients with refractory DM and calcinosis treated with tofacitinib showed an improvement of their calcinosis after 12 weeks (3 months) on treatment [119]. There is little know about the pathology of calcinosis but if JAK-inhibitors are effective then the JAK-STAT pathway may play a role in the underlying mechanism. Chen et al. are conducting a single centre, open-label clinical study of the use of tofacitinib in amyopathic dermatomyositis-associated ILD (Chinese Clinical Trial Registry number, ChiCTR-1,800,016,629). Initial results showed that 26 week (6-month) survival after onset of ILD was significantly higher in the prospective group (18 of 18, 100%) compared to the historical controls (25 of 32, 78%, p = 0.04), more conclusive results are pending [120]. Another ongoing study of the use of Baricitinib in adult IIM, is the MYOJAK study, a phase II, multicentre, randomised treatment delayed-start trial to receive active treatment (Baricitinib) or delayed-start after 13 weeks (NCT04208464). These trials are currently only including adult IIM patients of which have different clinical features to that of juvenile disease. Children have distinct developmental and physiological differences to adults, as such it is important to test the pharmokinectics and formulation of any given drug in the appropriate age populations.

Evidence for the use of JAK inhibitors in JDM

There have been several reports and case series which support the need to pursue testing JAK-inhibitors for the future therapeutic use in juvenile DM (Table 3). The potential for Ruxolitinib was shown in a report of compassionate treatment for a case of severe vasculopathic refractory JDM. The thirteen year old patient presented with severe disease and was admitted to ICU after 3 weeks of diagnosis with multi-symptom, systemic disease. Over a period of 78 weeks (18 months) the patient was poorly controlled with combination therapy, and developed lower limb oedema and diffuse fascia calcinosis. The IFN type I signature was investigated, which showed IFN-α serum levels and IFN score were increased compared to controls, this was also the case with constitutive phosphorylation of STAT1/3 in T-cells and monocytes. From these results the patient was taken off MMF, rituximab infusions were stopped, and switched to Ruxolitinib (10 mg BD) with Prednisolone. After 2 table there was a noted improvement in disease activity scores and no reported adverse events. During the 52 weeks (12 months) of Ruxolitnib treatment the IFN measures did not normalise, but there was decreased STAT 1 phosphorylation in T cells [121].

Table 3 Case studies or case series of JAK-inhibitors in juvenile dermatomyositis

Positive results were seen in a compassionate case of the use of the Jakinib, Baricitinib for an eleven year old male with a seven year history of refractory JDM positive for anti-TIF1-γ and anti-Ro52 autoantibodies. When Baricitinib therapy was started clear improvement of disease was recorded. The IFN biomarkers, IFN type I signature and STAT1 phosphorylation in T cells and monocytes, decreased to comparative levels seen in controls. Also observed was a marked decrease of CEC. To note this was a singular, very severe case, however for the first time in seven years prednisolone could be tapered down, progression of calcinosis was halted and the disease improved as a whole [122]. Further prospective studies need to be carried out to investigate the safety and efficacy of Baricitnib for the use in the treatment of JDM.

A report of 2 patients with anti-MDA5 AB+ JDM with uncontrolled disease were treated with tofacitinib. Disease activity scores decreased within 26 weeks (6 months) following the start of tofacitinib therapy; IFN score, STAT1 phosphorylation of T-cells and monocytes decreased. This report shows evidence that tofacitinib improves JDM at an immunopathogenic level [123]. Another recent report of 3 cases of refractory JDM showed that 26 weeks (6 months) of treatment with tofacitinib was tolerated and the patients responded well to the treatment. Comparing 0–26 weeks (0–6 months) on treatment there were significant improvements in physician global VAS (p < 0.001), manual muscle testing-8 (MMT) (p = 0.002), child myositis assessment scale (CMAS) (p = 0.006), C-HAQ (p < 0.001) and DAS (p = 0.002). This set of case reports showed that tofacitinib treatment improved signs and symptoms of JDM and could be a promising treatment option [124].

A recent retrospective study included nine refractory and one new-onset JDM patients treated with ruxolitinib (n = 7) or baricitinib (n = 3). At 26 weeks (6 months) of follow up five of the ten patients (three Ruxolitnib and two Baricitinib) had reached clinically inactive disease (CID). In these patients the mean daily dose of steroids decreased from 1.1 mg/kg (range 0.35–2) to 0.1 (range, 0–0.3, p = 0.008). Serum IFN-α levels normalised 26 weeks (6 months) after the start of treatment in all patients [125].

A larger case series of refractory JDM patients, 8/25(35%) treatment was ineffective and 17/25 (68%) glucocorticoid dependant, were treated with tofacitinib 7/25(28%) or ruxolitinib 18/25 (72%). All 25 patients were followed up for a median of 30 weeks (7 months) (range = 3–21 months). 24/25 (96%) of patients had improvement of their rash of which 16/24 (66.7%) the rash completely resolved. The cutaneous assessment tool binary method score significantly decreased (7.0(3.0–10.0) to 0.0(0.0–1.0) p < 0.001). As a measure of muscle activity 7/25 (28%) of patients showed an improvement of CMAS score (from 18.6 ± 15.0 to 35.7 ± 6.3, p = 0.018). As of follow-up in August 2019 7/25 (28%) of patients had discontinued glucocorticoids. This case series has shown promise for the use of both drugs especially to improve skin disease [126].

Recently data has been published from a compassionate use study (NCT01724580) for the treatment of JDM with Baricitinib. Four JDM patients with chronically active disease were assessed at regular intervals over a 24 week period. There was significant improvement in clinical scores from 4 weeks (Physicians Global Assessment, Pt Global activity and CDASI activity score) and down-regulation of IRG score (28 genes) and serum IP-10. In CD4+ and CD8+ T Cells there were lower levels IFN-α stimulated pSTAT1 and interleukin-2 (IL-2) stimulated pSTAT5 IC50s. In CD4+ T cells and CD19+ B cells there were lower levels of IL-10- stimulated pSTAT3 IC50s [127].

Overall, these reports provide more supportive evidence for the use of JAK-inhibitors in JDM, but these are limited case studies with the use of several distinct JAK-inhibitors. Along with specific clinical trials of the use of JAK-inhibitors in the treatment of JDM, there is a need for standardised outcome measures for both clinical and pathological disease improvement.

The future of JAK inhibitors

Clinical trials currently only include adult IIM patients. Successful results from these trials and validation of the case studies in JDM should be translatable to trials and treatment in juvenile disease. There are multiple JAK-inhibitors that are being trialled as potential new therapeutics for adult IIM, but these differ in their JAK targets and pharmokinetics. JAK-inhibitors provide one step further towards more targeted treatment beyond IFN blockade. It is vital to continue to investigate the exact pathogenic mechanism of the JAK/STAT pathway in IIM. If a more specific target can be found then a refined Jakinib can be developed for clinical trial in juvenile disease.

Concluding remarks

There is a wealth of information and evidence for the potential use of JAK-inhibitors as a therapy for JDM. There is a desperate need for therapeutics that target defined pathogenic pathways in JDM. The IFN pathway is a clear point of target. JAK-inhibitors appear to be promising, but there is still the question of safety and efficacy for the use in JDM. The choice of agent will need careful consideration before choice of trials of first generation pan-JAK-inhibitors or next-generation JAK specific inhibitors. An international collaborative approach, or novel trial design for disease trials, may be required in order to achieve clear evidence of efficacy.

Availability of data and materials

Not applicable.

Abbreviations

JAK-STAT:

Janus kinase-signal transducers and activators of transcription

JDM:

Juvenile dermatomyositis

IIM:

Idiopathic Inflammatory Myopathies

JDCBS:

UK Juvenile Dermatomyositis cohort and biobank study

MSA:

Myositis specific autoantibodies

TNFα:

Tumour necrosis factor alpha

DM:

Dermatomyositis

PM:

Polymyositis

IFNAR:

Type I IFN receptor

SLE:

Systemic lupus erythematous

IFN type I:

Interferon type I

pDCs:

Plasmacytoid dendritic cells

IFR:

IFN-regulatory factor

IRG:

Interferon regulatory genes

PCR:

Polymerase chain reaction

G1P2:

ISG15 ubiquitin-like modifier

IRF7:

Interferon regulatory factor 7

MMT8:

Manual muscle testing scores

IL-6:

Interleukin 6

MCP1:

Monocyte chemoattractant protein 1

MCP2:

Monocyte chemoattractant protein 2

IP-10:

Interferon gamma-induced protein 10

TNFRII:

Tumour necrosis factor receptor II

CEC:

Circulating endothelial cells

SH2:

Src homology domain-2

HWE:

Hardy-Weinberg equilibrium

TIS:

Total improvement score

MMT:

Manual muscle testing-8

CMAS:

Child myositis assessment scale

RA:

Rheumatoid arthritis

PsA:

Psoriatic arthritis

Ps:

Psoriasis

AS:

Ankylosing spondylitis

AA:

Alopecia areata

AD:

Atopic dermatitis

CD:

Crohn’s disease

UC:

Ulcerative colitis

Vit:

Vitiligo

HPS:

Hemophagocytic syndrome

GCA:

Giant cell arteritis

NIU:

Non-infectious uveitis

CLE:

Cutaneous lupus erythematosus

LN:

Lupus nephritis

DLE:

Discoid lupus erythematosus

dSc:

Diffuse scleroderma

References

  1. 1.

    Martin N, Krol P, Smith S, Murray K, Pilkington CA, Davidson JE, et al. A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years’ experience; the juvenile dermatomyositis national (UK and Ireland) cohort biomarker study and repository for idiopathic inflammatory Myopat. Rheumatology. 2011;50(1):137–45. https://doi.org/10.1093/rheumatology/keq261.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Meyer A, Meyer N, Schaeffer M, Gottenberg JE, Geny B, Sibilia J. Incidence and prevalence of inflammatory myopathies: a systematic review. Rheumatol. 2015;54(1):50–63.

    CAS  Article  Google Scholar 

  3. 3.

    Ramanan AV, Feldman BM. Clinical features and outcomes of juvenile dermatomyositis and other childhood onset myositis syndromes. Rheum Dis Clin N Am. 2002;28(4):833–57. https://doi.org/10.1016/S0889-857X(02)00024-8.

    CAS  Article  Google Scholar 

  4. 4.

    Fisler RE, Liang MG, Fuhlbrigge RC, Yalcindag A, Sundel RP. Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. J Am Acad Dermatol. 2002;47(4):505–11. https://doi.org/10.1067/mjd.2002.122196.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Huber AM, Lang B, LeBlanc CMA, Birdi N, Bolaria RK, Malleson P, et al. Medium- and long-term functional outcomes in a multicenter cohort of children with juvenile dermatomyositis. Arthritis Rheum. 2000;43(3):541–9. https://doi.org/10.1002/1529-0131(200003)43:3<541::AID-ANR9>3.0.CO;2-T.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Huemer C, Kitson H, Malleson PN, Sanderson S, Huemer M, Cabral DA, et al. Lipodystrophy in patients with juvenile dermatomyositis - evaluation of clinical and metabolic abnormalities. J Rheumatol. 2001;28(3):610–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Morinishi Y, Oh-Ishi T, Kabuki T, Joh K. Juvenile dermatomyositis: clinical characteristics and the relatively high risk of interstitial lung disease. Mod Rheumatol. 2007;17(5):413–7. https://doi.org/10.3109/s10165-007-0610-y.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Cantez S, Gross GJ, MacLusky I, Feldman BM. Cardiac findings in children with juvenile Dermatomyositis at disease presentation. Pediatr Rheumatol Online J. 2017;15(1):54.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Papadopoulou C, Hong Y, Krol P, Al Obaidi M, Pilkington C, Wedderburn LR, et al. The vasculopathy of juvenile dermatomyositis: endothelial injury, hypercoagulability, and increased arterial stiffness. Arthritis Rheum. 2021;73(7):1253–66. https://doi.org/10.1002/art.41639.

    CAS  Article  Google Scholar 

  10. 10.

    Betteridge Z, McHugh N. Myositis-specific autoantibodies: an important tool to support diagnosis of myositis. J Intern Med. 2016;280(1):8–23. https://doi.org/10.1111/joim.12451.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Baechler EC, Bilgic H, Reed AM. Type I interferon pathway in adult and juvenile dermatomyositis. Arthritis Res Ther. 2011;13(6):249. https://doi.org/10.1186/ar3531.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Greenberg SA, Pinkus JL, Pinkus GS, Burleson T, Sanoudou D, Tawil R, et al. Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis. Ann Neurol. 2005;57(5):664–78.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Walsh RJ, Kong SW, Yao Y, Jallal B, Kiener PA, Pinkus JL, et al. Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis. Arthritis Rheum. 2007;56(11):3784–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Baechler EC, Bauer JW, Slattery CA, Ortmann WA, Espe KJ, Novitzke J, et al. An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity. Mol Med. 2007;13(1–2):59–68.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    McDouall RM, Dunn MJ, Dubowitz V. Nature of the mononuclear infiltrate and the mechanism of muscle damage in juvenile dermatomyositis and Duchenne muscular dystrophy. J Neurol Sci. 1990;99(2–3):199–217. https://doi.org/10.1016/0022-510X(90)90156-H.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Vercoulen Y, Bellutti Enders F, Meerding J, Plantinga M, Elst EF, Varsani H, et al. Increased presence of FOXP3+ regulatory T cells in inflamed muscle of patients with active juvenile dermatomyositis compared to peripheral blood. PLoS One. 2014;9(8):e105353. https://doi.org/10.1371/journal.pone.0105353.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    López De Padilla CM, Vallejo AN, McNallan KT, Vehe R, Smith SA, Dietz AB, et al. Plasmacytoid dendritic cells in inflamed muscle of patients with juvenile dermatomyositis. Arthritis Rheum. 2007;56(5):1658–68. https://doi.org/10.1002/art.22558.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Ekholm L, Michelle Kahlenberg J, Helmers SB, Tjärnlund A, Yalavarthi S, Zhao W, et al. Dysfunction of endothelial progenitor cells is associated with the type I IFN pathway in patients with polymyositis and dermatomyositis. Rheumatol (United Kingdom). 2016;55(11):1987–92.

    CAS  Google Scholar 

  19. 19.

    Xu D, Kacha-Ochana A, Morgan GA, Huang CC, Pachman LM. Endothelial progenitor cell number is not decreased in 34 children with juvenile dermatomyositis: a pilot study. Pediatr Rheumatol. 2017;15(1):3–7. https://doi.org/10.1186/s12969-017-0171-3.

    Article  Google Scholar 

  20. 20.

    Yokota M, Suzuki K, Tokoyoda K, Meguro K, Hosokawa J, Tanaka S, et al. Roles of mast cells in the pathogenesis of inflammatory myopathy. Arthritis Res Ther. 2014;16(2).

  21. 21.

    Briones MR, Morgan GA, Amoruso MC, Rahmani B, Ryan ME, Pachman LM. Decreased CD3-CD16+CD56+ natural killer cell counts in children with orbital myositis: a clue to disease activity. RMD Open. 2017;3(1):1–5. https://doi.org/10.1136/rmdopen-2016-000385.

    Article  Google Scholar 

  22. 22.

    Wienke J, Deakin CT, Wedderburn LR, van Wijk F, van Royen-Kerkhof A. Systemic and Tissue Inflammation in Juvenile Dermatomyositis: From Pathogenesis to the Quest for Monitoring Tools. Front Immunol. 2018;9:2951.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Pachman LM, Lipton R, Ramsey-Goldman R, Shamiyeh E, Abbott K, Mendez EP, et al. History of infection before the onset of juvenile dermatomyositis: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Research Registry. Arthritis Rheum. 2005;53(2):166–72.

    PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Shah M, Mamyrova G, Targoff IN, Huber AM, Malley JD, Rice MM, et al. The clinical phenotypes of the juvenile idiopathic inflammatory myopathies. Med. 2013;92(1):25–41.

    CAS  Article  Google Scholar 

  25. 25.

    McCann LJ, Juggins AD, Maillard SM, Wedderburn LR, Davidson JE, Murray KJ, et al. The Juvenile Dermatomyositis National Registry and Repository (UK and Ireland)--clinical characteristics of children recruited within the first 5 yr. Rheumatol. 2006;45(10):1255–60.

    CAS  Article  Google Scholar 

  26. 26.

    Guseinova D, Consolaro A, Trail L, Ferrari C, Pistorio A, Ruperto N, et al. Comparison of clinical features and drug therapies among European and Latin American patients with juvenile dermatomyositis. Clin Exp Rheumatol. 2011;29(1):117–24.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ravelli A, Trail L, Ferrari C, Ruperto N, Pistorio A, Pilkington C, et al. Long-term outcome and prognostic factors of juvenile dermatomyositis: a multinational, multicenter study of 490 patients. Arthritis Care Res. 2010;62(1):63–72.

    Article  Google Scholar 

  28. 28.

    Sato JO, Sallum AM, Ferriani VP, Marini R, Sacchetti SB, Okuda EM, et al. A Brazilian registry of juvenile dermatomyositis: onset features and classification of 189 cases. Clin Exp Rheumatol. 2009;27(6):1031–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Christen-Zaech S, Seshadri R, Sundberg J, Paller AS, Pachman LM. Persistent association of nailfold capillaroscopy changes and skin involvement over thirty-six months with duration of untreated disease in patients with juvenile dermatomyositis. Arthritis Rheum. 2008;58(2):571–6.

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Tansley SL, Betteridge ZE, Shaddick G, Gunawardena H, Arnold K, Wedderburn LR, et al. Calcinosis in juvenile dermatomyositis is influenced by both anti-NXP2 autoantibody status and age at disease onset. Rheumatol. 2014;53(12):2204–8.

    Article  Google Scholar 

  31. 31.

    Tansley SL, Betteridge ZE, Gunawardena H, Jacques TS, Owens CM, Pilkington C, et al. Anti-MDA5 autoantibodies in juvenile dermatomyositis identify a distinct clinical phenotype: a prospective cohort study. Arthritis Res Ther. 2014;16(4):R138. https://doi.org/10.1186/ar4600.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Gunawardena H, Wedderburn LR, North J, Betteridge Z, Dunphy J, Chinoy H, et al. Clinical associations of autoantibodies to a p155/140 kDa doublet protein in juvenile dermatomyositis. Rheumatol. 2008;47(3):324–8. https://doi.org/10.1093/rheumatology/kem359.

    CAS  Article  Google Scholar 

  33. 33.

    Rider LG, Shah M, Mamyrova G, Huber AM, Rice MM, Targoff IN, et al. The myositis autoantibody phenotypes of the juvenile idiopathic inflammatory myopathies. Med. 2013;92(4):223–43.

    CAS  Article  Google Scholar 

  34. 34.

    Vencovský J, Alexanderson H, Lundberg IE. Idiopathic inflammatory myopathies. Rheum Dis Clin N Am. 2019;45(4):569–81. https://doi.org/10.1016/j.rdc.2019.07.006.

    Article  Google Scholar 

  35. 35.

    Deakin CT, Yasin SA, Simou S, Arnold KA, Tansley SL, Betteridge ZE, et al. Muscle biopsy in combination with myositis-specific autoantibodies aids prediction of outcomes in juvenile dermatomyositis. Arthritis Rheum. 2016;11(68):2806–16. https://doi.org/10.1002/art.39753.

    CAS  Article  Google Scholar 

  36. 36.

    Deakin CT, Campanilho-Marques R, Simou S, Moraitis E, Wedderburn LR, Pullenayegum E, et al. Efficacy and Safety of Cyclophosphamide Treatment in Severe Juvenile Dermatomyositis Shown by Marginal Structural Modeling. Arthritis Rheum. 2018;70(5):785–93.

    CAS  Article  Google Scholar 

  37. 37.

    Albayda J, Christopher-Stine L. Novel approaches in the treatment of myositis and myopathies. Ther Adv Musculoskelet Dis. 2012;4(5):369–77. https://doi.org/10.1177/1759720X12447705.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Dagher R, Desjonquères M, Duquesne A, Quartier P, Bader-Meunier B, Fischbach M, et al. Mycophenolate mofetil in juvenile dermatomyositis: a case series. Rheumatol Int. 2012;32(3):711–6. https://doi.org/10.1007/s00296-010-1653-5.

    Article  PubMed  Google Scholar 

  39. 39.

    Oddis CV, Reed AM, Aggarwal R, Rider LG, Ascherman DP, Levesque MC, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013;65(2):314–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Campanilho-marques R, Deakin CT, Simou S, Papadopoulou C, Wedderburn LR, Pilkington CA, et al. Retrospective analysis of infliximab and adalimumab treatment in a large cohort of juvenile dermatomyositis patients. 2020;5(1):1–9. https://doi.org/10.1186/s13075-020-02164-5.

  41. 41.

    Amato AA, Sivakumar K, Goyal N, David WS, Salajegheh M, Praestgaard J, et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology. 2014;83(24):2239–46. https://doi.org/10.1212/WNL.0000000000001070.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Ioannis M, Foivos P, Dimitrios K. A review on the treatment of sporadic inclusion body myositis with Bimagrumab and Alemtuzumab. Int J Neurosci. 2019;129(3):297–302. https://doi.org/10.1080/00207454.2018.1527329.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Hatemi G, Melikoglu M, Tunc R, Korkmaz C, Ozturk BT, Mat C, et al. Apremilast for Behçet’s syndrome - a phase 2, placebo-controlled study. N Engl J Med. 2015;372(16):1510–8. https://doi.org/10.1056/NEJMoa1408684.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Anyanwu CO, Chansky PB, Feng R, Carr K, Okawa J, Werth VP. The systemic management of cutaneous dermatomyositis: results of a stepwise strategy. Int J Women’s Dermatology. 2017;3(4):189–94. https://doi.org/10.1016/j.ijwd.2017.05.001.

    CAS  Article  Google Scholar 

  45. 45.

    Bitar C, Maghfour J, Ho-Pham H, Stumpf B, Boh E. Apremilast as a potential treatment for moderate to severe dermatomyositis: a retrospective study of 3 patients. JAAD Case Reports. 2019;5(2):191–4. https://doi.org/10.1016/j.jdcr.2018.11.019.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Patwardhan A, Spencer CH. Biologics in refractory myositis: experience in juvenile vs. adult myositis; part II: emerging biologic and other therapies on the horizon. Pediatr Rheumatol Online J. 2019;17(1):56.

    PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Faguer S, Belliere J, Ribes D. Complement C5-blocking Agent in Refractory Dermatomyositis. J Rheumatol Canada. 2018;45(12):1710–1. https://doi.org/10.3899/jrheum.180060.

    CAS  Article  Google Scholar 

  48. 48.

    Zou J, Li T, Huang X, Chen S, Guo Q, Bao C. Basiliximab may improve the survival rate of rapidly progressive interstitial pneumonia in patients with clinically amyopathic dermatomyositis with anti-MDA5 antibody. Ann Rheum Dis. 2014;73(8):1591–3. https://doi.org/10.1136/annrheumdis-2014-205278.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Higgs BW, Zhu W, Morehouse C, White WI, Brohawn P, Guo X, et al. A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-alpha monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients. Ann Rheum Dis. 2014;73(1):256–62.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Bilgic H, Ytterberg SR, Amin S, McNallan KT, Wilson JC, Koeuth T, et al. Interleukin-6 and type I interferon-regulated genes and chemokines mark disease activity in dermatomyositis. Arthritis Rheum. 2009;60(11):3436–46.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Gallay L, Mouchiroud G, Chazaud B. Interferon-signature in idiopathic inflammatory myopathies. Curr Opin Rheumatol. 2019;31(6):634–42. https://doi.org/10.1097/BOR.0000000000000653.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Greenberg SA, Higgs BW, Morehouse C, Walsh RJ, Won Kong S, Brohawn P, et al. Relationship between disease activity and type 1 interferon- and other cytokine-inducible gene expression in blood in dermatomyositis and polymyositis. Genes Immun. 2012;13(3):207–13. https://doi.org/10.1038/gene.2011.61.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Kim H, Gunter-Rahman F, McGrath JA, Lee E, De Jesus AA, Targoff IN, et al. Expression of interferon-regulated genes in juvenile dermatomyositis versus Mendelian autoinflammatory interferonopathies. Arthritis Res Ther. 2020;22(1):1–12. https://doi.org/10.1186/s13075-020-02160-9.

    Article  Google Scholar 

  55. 55.

    De Jesus AA, Canna SW. Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases Graphical abstract Find the latest version. 2019;130(4):1669–82.

  56. 56.

    Ronnblom L, Elkon KB. Cytokines as therapeutic targets in SLE. Nat Rev Rheumatol. 2010;6(6):339–47.

  57. 57.

    Rodero MP, Decalf J, Bondet V, Hunt D, Rice GI, Werneke S, et al. Detection of interferon alpha protein reveals differential levels and cellular sources in disease. J Exp Med. 2017;214(5):1547–55. https://doi.org/10.1084/jem.20161451.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Muskardin TLW, Niewold TB. Type i interferon in rheumatic diseases. Nat Rev Rheumatol. 2018;14(4):214–28. https://doi.org/10.1038/nrrheum.2018.31.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Cooles FAH, Anderson AE, Lendrem DW, Norris J, Pratt AG, Hilkens CMU, et al. The interferon gene signature is increased in patients with early treatment-naive rheumatoid arthritis and predicts a poorer response to initial therapy. J Allergy Clin Immunol. 2018;141(1):445–448.e4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Crow MK. Autoimmunity: interferon alpha or beta: which is the culprit in autoimmune disease? Nat Rev Rheumatol. 2016;12(8):439–40. https://doi.org/10.1038/nrrheum.2016.117.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Ronnblom L, Eloranta ML. The interferon signature in autoimmune diseases. Curr Opin Rheumatol. 2013;25(2):248–53. https://doi.org/10.1097/BOR.0b013e32835c7e32.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wiman AC, Sturfelt G, et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet. 2005;76(3):528–37. https://doi.org/10.1086/428480.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Feng D, Barnes BJ. Bioinformatics analysis of the factors controlling type I IFN gene expression in autoimmune disease and virus-induced immunity. Front Immunol. 2013;4:291. https://doi.org/10.3389/fimmu.2013.00291.

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Jiang SH, Athanasopoulos V, Ellyard JI, Chuah A, Cappello J, Cook A, et al. Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. Nat Commun. 2019;10(1):1–12. https://doi.org/10.1038/s41467-019-10242-9.

    CAS  Article  Google Scholar 

  65. 65.

    Stone RC, Feng D, Deng J, Singh S, Yang L, Fitzgerald-Bocarsly P, et al. Interferon regulatory factor 5 activation in monocytes of systemic lupus erythematosus patients is triggered by circulating autoantigens independent of type I interferons. Arthritis Rheum. 2012;64(3):788–98. https://doi.org/10.1002/art.33395.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Kelkka T, Kienhöfer D, Hoffmann M, Linja M, Wing K, Sareila O, et al. Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature. Antioxid Redox Signal. 2014;21(16):2231–45. https://doi.org/10.1089/ars.2013.5828.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14(1):36–49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    George R, Stark1,* and James E. Darnell Jr.2 *. No Title. J Immuni. 2012;36(4):503–14.

    Article  CAS  Google Scholar 

  69. 69.

    Greenberg SA, Bradshaw EM, Pinkus JL, Pinkus GS, Burleson T, Due B, et al. Plasma cells in muscle in inclusion body myositis and polymyositis. Neurology. 2005;65(11):1782–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Mauri C, Menon M. The many faces of type I interferon in systemic lupus erythematosus. J Clin Invest. 2015;125(7):2562–4. https://doi.org/10.1172/JCI82574.

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Menon M, Blair PA, Isenberg DA, Mauri C. A regulatory feedback between Plasmacytoid dendritic cells and regulatory B cells is aberrant in systemic lupus erythematosus. Immunity. 2016;44(3):683–97. https://doi.org/10.1016/j.immuni.2016.02.012.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Niewold TB, Kariuki SN, Morgan GA, Shrestha S, Pachman LM. Elevated serum interferon-alpha activity in juvenile dermatomyositis: associations with disease activity at diagnosis and after thirty-six months of therapy. Arthritis Rheum. 2009;60(6):1815–24. https://doi.org/10.1002/art.24555.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Gitiaux C, Bondet V, Bekaddour N, Nusbaum P, Hubas A, Melki I, et al. Inhibition of IFNα secretion in cells from patients with juvenile dermatomyositis under TBK1 inhibitor treatment revealed by single-molecular assay technology. Rheumatol (United Kingdom). 2020;59(5):1171–4.

    Google Scholar 

  74. 74.

    Rice GI, Melki I, Frémond ML, Briggs TA, Rodero MP, Kitabayashi N, et al. Assessment of type I interferon signaling in pediatric inflammatory disease. J Clin Immunol. 2017;37(2):123–32.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Kim H, De Jesus AA, Brooks SR, Liu Y, Huang Y, Vantries R, et al. Development of a validated interferon score using NanoString technology. J Interf Cytokine Res. 2018;38(4):171–85. https://doi.org/10.1089/jir.2017.0127.

    CAS  Article  Google Scholar 

  76. 76.

    Ekholm L, Vosslamber S, Tjärnlund A, de Jong TD, Betteridge Z, McHugh N, et al. Autoantibody specificities and type I interferon pathway activation in idiopathic inflammatory myopathies. Scand J Immunol. 2016;84(2):100–9. https://doi.org/10.1111/sji.12449.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Moneta GM, Pires Marafon D, Marasco E, Rosina S, Verardo M, Fiorillo C, et al. Muscle expression of type I and type II interferons is increased in juvenile dermatomyositis and related to clinical and histologic features. Arthritis Rheum. 2019;71(6):1011–21. https://doi.org/10.1002/art.40800.

    CAS  Article  Google Scholar 

  78. 78.

    Nistala K, Varsani H, Wittkowski H, Vogl T, Krol P, Shah V, et al. Myeloid related protein induces muscle derived inflammatory mediators in juvenile dermatomyositis. Arthritis Res Ther. 2013;15(5):R131. https://doi.org/10.1186/ar4311.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Bellutti Enders F, van Wijk F, Scholman R, Hofer M, Prakken BJ, van Royen-Kerkhof A, et al. Correlation of CXCL10, tumor necrosis factor receptor type II, and galectin 9 with disease activity in juvenile dermatomyositis. Arthritis Rheum. 2014;66(8):2281–9.

    CAS  Article  Google Scholar 

  80. 80.

    Van Den Hoogen LL, Van Roon JAG, Mertens JS, Wienke J, Lopes AP, De Jager W, et al. Galectin-9 is an easy to measure biomarker for the interferon signature in systemic lupus erythematosus and antiphospholipid syndrome. Ann Rheum Dis. 2018;77(12):1810–4. https://doi.org/10.1136/annrheumdis-2018-213497.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Piper CJM, Wilkinson MGL, Deakin CT, Otto GW, Dowle S, Duurland CL, et al. CD19(+)CD24(hi)CD38(hi) B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-alpha. Front Immunol. 2018;9:1372.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. 82.

    Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest. 2000;105(1):71–7. https://doi.org/10.1172/JCI8071.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Jia H, Thelwell C, Dilger P, Bird C, Daniels S, Wadhwa M. Endothelial cell functions impaired by interferon in vitro: insights into the molecular mechanism of thrombotic microangiopathy associated with interferon therapy. Thromb Res. 2018;163(December 2017):105–16. https://doi.org/10.1016/j.thromres.2018.01.039.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Kishi T, Chipman J, Evereklian M, Nghiem K, Stetler-Stevenson M, Rick ME, et al. Endothelial activation markers as disease activity and damage measures in juvenile dermatomyositis. J Rheumatol. 2020;47(7):1011–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. 85.

    Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292(8):403–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Wedderburn LR, Varsani H, Li CK, Newton KR, Amato AA, Banwell B, et al. International consensus on a proposed score system for muscle biopsy evaluation in patients with juvenile dermatomyositis: a tool for potential use in clinical trials. Arthritis Rheum. 2007;57(7):1192–201.

    PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Wedderburn LR, Rider LG. Juvenile dermatomyositis: new developments in pathogenesis, assessment and treatment. Best Pr Res Clin Rheumatol. 2009;23(5):665–78. https://doi.org/10.1016/j.berh.2009.07.007.

    Article  Google Scholar 

  89. 89.

    Lundberg I, Ulfgren AK, Nyberg P, Andersson U, Klareskog L. Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies. Arthritis Rheum. 1997;40(5):865–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Nagaraju K, Raben N, Loeffler L, Parker T, Rochon PJ, Lee E, et al. Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies. Proc Natl Acad Sci U S A. 2000;97(16):9209–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Li CK, Varsani H, Holton JL, Gao B, Woo P, Wedderburn LR, et al. MHC Class I overexpression on muscles in early juvenile dermatomyositis. J Rheumatol. 2004;31(3):605–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Tournadre A, Lenief V, Eljaafari A, Miossec P. Immature muscle precursors are a source of interferon-β in myositis: role of toll-like receptor 3 activation and contribution to HLA class i up-regulation. Arthritis Rheum. 2012;64(2):533–41. https://doi.org/10.1002/art.33350.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Salajegheh M, Kong SW, Pinkus JL, Walsh RJ, Liao A, Nazareno R, et al. Interferon-stimulated gene 15 (ISG15) conjugates proteins in dermatomyositis muscle with perifascicular atrophy. Ann Neurol. 2010;67(1):53–63. https://doi.org/10.1002/ana.21805.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Uruha A, Nishikawa A, Tsuburaya RS, Hamanaka K, Kuwana M, Watanabe Y, et al. Sarcoplasmic MxA expression: a valuable marker of dermatomyositis. Neurology. 2017;88(5):493–500. https://doi.org/10.1212/WNL.0000000000003568.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Soponkanaporn S, Deakin CT, Schutz PW, Marshall LR, Yasin SA, Johnson CM, et al. Expression of myxovirus-resistance protein a: a possible marker of muscle disease activity and autoantibody specificities in juvenile dermatomyositis. Neuropathol Appl Neurobiol. 2019;45(4):410–20. https://doi.org/10.1111/nan.12498.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Allenbach Y, Leroux G, Suárez-Calvet X, Preusse C, Gallardo E, Hervier B, et al. Dermatomyositis with or without anti-melanoma differentiation-associated gene 5 antibodies common interferon signature but distinct NOS2 expression. Am J Pathol. 2016;186(3):691–700. https://doi.org/10.1016/j.ajpath.2015.11.010.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Ladislau L, Suárez-Calvet X, Toquet S, Landon-Cardinal O, Amelin D, Depp M, et al. JAK inhibitor improves type i interferon induced damage: proof of concept in dermatomyositis. Brain. 2018;141(6):1609–21. https://doi.org/10.1093/brain/awy105.

    Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Coskun M, Salem M, Pedersen J, Nielsen OH. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res. 2013;76:1–8. https://doi.org/10.1016/j.phrs.2013.06.007.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Gadina M, Le MT, Schwartz DM, Silvennoinen O, Nakayamada S, Yamaoka K, et al. Janus kinases to jakinibs: From basic insights to clinical practice. Rheumatol (United Kingdom). 2019;58:i4–16.

    CAS  Google Scholar 

  100. 100.

    Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK–STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs. 2017;77(5):521–46. https://doi.org/10.1007/s40265-017-0701-9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006;25(5):745–55. https://doi.org/10.1016/j.immuni.2006.09.009.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Clark JD, Flanagan ME, Telliez JB. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014;57(12):5023–38. https://doi.org/10.1021/jm401490p.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Hammarén HM, Ungureanu D, Grisouard J, Skoda RC, Hubbard SR, Silvennoinen O. ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation. Proc Natl Acad Sci U S A. 2015;112(15):4642–7. https://doi.org/10.1073/pnas.1423201112.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Spinelli FR, Meylan F, O’Shea JJ, Gadina M. JAK inhibitors: ten years after. Eur J Immunol. 2021;51(7):1615–27. https://doi.org/10.1002/eji.202048922.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Liu C, Lin J, Langevine C, Smith D, Li J, Tokarski JS, et al. Discovery of BMS-986202: a clinical Tyk2 inhibitor that binds to Tyk2 JH2. J Med Chem. 2021;64(1):677–94.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  106. 106.

    Babon JJ, Liau NPD, Kershaw NJ. JAK1 takes a FERM hold of type II cytokine receptors. Structure. 2016;24(6):840–2. https://doi.org/10.1016/j.str.2016.05.007.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Fragoulis GE, Mcinnes IB, Siebert S, JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis. Rheumatol (United Kingdom). 2019;58:i43–54.

    CAS  Google Scholar 

  108. 108.

    Patel AA, Odenike O. The next generation of JAK inhibitors: an update on Fedratinib, Momelotonib, and Pacritinib. Curr Hematol Malig Rep. 2020;15(6):409–18. https://doi.org/10.1007/s11899-020-00596-z.

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012;44(12):1336–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Hinks A, Marion MC, Cobb J, Comeau ME, Sudman M, Ainsworth HC, et al. Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis. Arthritis Rheum. 2018;70(6):957–62.

    CAS  Article  Google Scholar 

  111. 111.

    Suarez-Gestal M, Calaza M, Endreffy E, Pullmann R, Ordi-Ros J, Domenico Sebastiani G, et al. Replication of recently identified systemic lupus erythematosus genetic associations: a case-control study. Arthritis Res Ther. 2009;11(3):1–9.

    Article  CAS  Google Scholar 

  112. 112.

    Wallace C, Smyth DJ, Maisuria-armer M, Walker NM, Todd JA. UKPMC funders group alters susceptibility to type 1 diabetes. Diabetes Res. 2010;42(1):1–13.

    Google Scholar 

  113. 113.

    Mero IL, Lorentzen ÅR, Ban M, Smestad C, Celius EG, Aarseth JH, et al. A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis. Eur J Hum Genet. 2010;18(4):502–4. https://doi.org/10.1038/ejhg.2009.195.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Papp K, Gordon K, Thaçi D, Morita A, Gooderham M, Foley P, et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis. N Engl J Med. 2018;379(14):1313–21. https://doi.org/10.1056/NEJMoa1806382.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Jani M, Massey J, Wedderburn LR, Vencovský J, Danko K, Lundberg IE, et al. Genotyping of immune-related genetic variants identifies TYK2 as a novel associated locus for idiopathic inflammatory myopathies. Ann Rheum Dis. 2014;73(9):1750–2. https://doi.org/10.1136/annrheumdis-2014-205440.

    Article  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Li L, Chen S, Wang Q, Wu C, Wen X, Yang F, et al. GLIS3 and TYK2 single nucleotide polymorphisms are not associated with dermatomyositis/polymyositis in Chinese Han population. Genet Test Mol Biomarkers. 2017;21(9):565–70. https://doi.org/10.1089/gtmb.2017.0059.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Nogueira M, Puig L, Torres T. JAK inhibitors for treatment of psoriasis: focus on selective TYK2 inhibitors. Drugs. 2020;80(4):341–52. https://doi.org/10.1007/s40265-020-01261-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Paik JJ, Casciola-Rosen L, Shin JY, Albayda J, Tiniakou E, Leung DG, et al. Study of Tofacitinib in refractory dermatomyositis: an open-label pilot study of ten patients. Arthritis Rheum. 2021;73(5):858–65.

    CAS  Article  Google Scholar 

  119. 119.

    Shneyderman M, Ahlawat S, Christopher-Stine L, J. Paik J. Calcinosis in refractory dermatomyositis improves with tofacitinib monotherapy: a case series. Rheumatology. 2021;0:1–2.

  120. 120.

    Zhiwei C, Xiaodong Wang MD, M.D. Shuang Ye MD. Tofacitinib in Amyopathic dermatomyositis–associated interstitial lung disease. N Engl J Med. 2019;381(3):291–3. https://doi.org/10.1056/NEJMc1900045.

    Article  Google Scholar 

  121. 121.

    Aeschlimann FA, Frémond ML, Duffy D, Rice GI, Charuel JL, Bondet V, et al. A child with severe juvenile dermatomyositis treated with ruxolitinib. Brain. 2018;141(11):e80.

    PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Papadopoulou C, Hong Y, Omoyinmi E, Brogan PA, Eleftheriou D. Janus kinase 1/2 inhibition with baricitinib in the treatment of juvenile dermatomyositis. Brain. 2019;142(3):E8.

    PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Sabbagh S, De Jesus AA, Hwang SJ, Kuehn HS, Kim H, Jung L, et al. Treatment of anti-MDA5 autoantibody-positive juvenile dermatomyositis using tofacitinib. Brain. 2019;142(11):E59. https://doi.org/10.1093/brain/awz293.

    Article  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Yu Z, Wang L, Quan M, Zhang T, Song H. Successful management with Janus kinase inhibitor tofacitinib in refractory juvenile dermatomyositis: a pilot study and literature review. Rheumatology. 2020;60(4):1–8. https://doi.org/10.1093/rheumatology/keaa558.

    Article  Google Scholar 

  125. 125.

    Le Voyer T, Gitiaux C, Authier F-J, Bodemer C, Melki I, Quartier P, et al. JAK inhibitors are effective in a subset of patients with juvenile dermatomyositis: a monocentric retrospective study. Rheumatology. 2021:1–8.

  126. 126.

    Ding Y, Huang B, Wang Y, Hou J, Chi Y, Zhou Z, et al. Janus kinase inhibitor significantly improved rash and muscle strength in juvenile dermatomyositis. Ann Rheum Dis. 2021;80(4):543–5. https://doi.org/10.1136/annrheumdis-2020-218582.

    Article  Google Scholar 

  127. 127.

    Kim H, Dill S, O’Brien M, Vian L, Li X, Manukyan M, et al. Janus kinase (JAK) inhibition with baricitinib in refractory juvenile dermatomyositis. Ann Rheum Dis. 2021;80(3):406–8. https://doi.org/10.1136/annrheumdis-2020-218690.

    Article  Google Scholar 

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Acknowledgments

MGLlW would like to thank all co-authors for their contributions to this review.

Funding

All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. MGLlW was supported by fellowships from Cure JM (Early Career Investigator Award GOSH042019), NIHR Great Ormond Street Hospital (GOSH) Biomedical Research Centre (BRC) (NIHR GOSH BRC 18IR33). CP was funded by the Remission Charity. CTD, DE and LRW were supported by Arthritis Research UK, now Versus Arthritis (grant 20164 and 21593). DE and LRW also acknowledge support from Great Ormond Street Hospital Children’s Charity. LRW was also supported by a NIHR Senior Investigator Award. LRW and CTD supported by NIHR Great Ormond Street Hospital (GOSH) Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR.

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MGLlW (wrote and prepared manuscript), CTD (review and edit); CP (review and edit); DE (review and edit); LRW (review and edit). The author(s) read and approved the final manuscript.

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Correspondence to Meredyth G. Ll Wilkinson.

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Supplementary Information

Additional file 1: Supplementary Figure 1

The role of type I IFN and the interaction with other cytokines in the immune system.

Additional file 2: Supplementary Table 1

Metabolism, pharmacokinetics and efficacy of JAK-inhibitors.

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Ll Wilkinson, M.G., Deakin, C.T., Papadopoulou, C. et al. JAK inhibitors: a potential treatment for JDM in the context of the role of interferon-driven pathology. Pediatr Rheumatol 19, 146 (2021). https://doi.org/10.1186/s12969-021-00637-8

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Keywords

  • Juvenile dermatomyositis
  • JDM
  • IIM
  • JAK inhibitors
  • IFN
  • JAK/STAT pathway
  • Treatment