Inhibiting interferon pathways in dermatomyositis: rationale and preliminary evidence

Abstract

Purpose of review:

Dermatomyositis (DM) is a systemic autoimmune disease affecting multiple organs, including skeletal muscle, skin, and lungs. Although DM disease mechanisms are incompletely understood, accumulating evidence suggests that interferons may play a significant role. Consequently, it is of considerable interest that drugs blocking the activity of interferons by inhibiting the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway have been approved for use in other autoimmune diseases. This manuscript will examine the IFN pathways and their importance in DM, review the existing literature on the use of JAK-STATs inhibitors in patients with adult or juvenile DM, and discuss the potential utility of JAK-STAT inhibitors to treat this disease.

Recent findings:

Recent reports suggest that muscle and skin involvement in patients with either adult or juvenile DM respond favorably to JAK-STAT inhibitors. Moreover, preliminary data indicates that JAK-STAT inhibitors may be useful to treat clinical manifestations of this disease that are complicated to manage otherwise, such as calcinosis or rapidly progressive interstitial lung disease in DM patients with anti-MDA5 autoantibodies.

Summary:

An increasing number of reports suggest that JAK-STAT inhibitors may be useful to treat the varied manifestations of adult and juvenile DM. However, as most studies were either small or lacked appropriate comparators, further research will be necessary to define the role of these drugs in DM treatment.

Introduction:

Inflammatory myopathies

The inflammatory myopathies are a heterogeneous group of diseases affecting multiple organs and systems, including the skeletal muscle the skin, the lungs, and/or the joints. Myositis can be subclassified in dermatomyositis (DM), the antisynthetase syndrome (AS), immune-mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). [1] Around 70% of the patients with myositis have myositis-specific autoantibodies (MSAs) targeting nuclear or cytoplasmic proteins. These MSAs include anti-Mi2, anti-NXP2, anti-TIF1gamma, anti-MDA5, anti-tRNA synthetases, anti-HMGCR, and anti-SRP.[2]

DM can affect both adults and children (juvenile DM [JDM]). Patients with DM have characteristic skin rashes [3] including purple discoloration on the eyelids (heliotrope rash) and purple discoloration (Gottron’s rash) or purple plaques (Gottron’s sign) on the extensor surfaces of the joints. The presence of perifascicular atrophy is a highly specific finding in the muscle biopsies patients with dermatomyositis and is usually accompanied by other features, such as the presence of endomysial or perivascular inflammation, MHC-I overexpression, or complement deposition in the capillaries and muscle fibers.[4] A subset of patients with DM and autoantibodies recognizing MDA5 frequently suffers from a highly lethal form of rapidly progressive interstitial lung disease.[5]

Most clinical manifestations of DM have been associated with overactivation of the interferon pathway. In the following sections, we will review the interferons and what is known about the interferon pathway in DM.

The interferons

In the 1930s, research conducted by Hoskins demonstrated that rabbits previously infected by the herpes simplex virus were protected against subsequent infections by the same type of virus.[6] Soon later, it was discovered that virus-infected animals were also protected against other types of viruses. But it was not until 1957 when it was observed that cells previously infected by a virus could produce a substance, the “interferon”, that made other cells immune to different viruses. It was later discovered that viral interference was caused by a family of proteins, the interferons, and not by a single molecule.[7, 8]

The interferons represent a widely expressed group of cytokines, including three main classes. Type I is encoded in chromosome 9[9] and includes alpha and beta IFN among others. Type II, or interferon gamma, is also encoded in chromosome 9[7]. Finally, type III IFN or IFNλ,[10, 11] is encoded in chromosome 12.[7]

The various IFNs are encoded by different genes, produced by distinct cells, and their release is triggered by different molecules. Interferon alpha is produced by macrophages, lymphocytes, tumor cells, cells infected by a virus, or affected by mitogens. Interferon beta is produced in the epithelial cells and fibroblasts and its production is triggered by viruses. Finally, interferon gamma is produced in T cells and natural killer cells after stimulation by external mitogens. Interferons have a wide variety of roles including antiviral, antiproliferative, and immunomodulatory functions.[12] These functions are mediated by the binding of these cytokines to receptors in the surface of the cell which activate the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway, leading to the expression of the so-called interferon-inducible genes.

The JAK-STAT pathway

The role of cytokines in the regulation of the immune system by binding to surface receptors and their different modes of signaling through the JAK-STAT pathway has been long understood. Examples of cytokines using the JAK-STAT pathway include erythropoietin, growth hormone, interleukin (IL) 2, IL 6, IL 7, and interferon (IFN), among others.[13, 14]

The JAK family is composed of four proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYR).[15] The STAT protein family in mammalians is composed of STAT 1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.[14] Most of the previously described cytokines bind to multiple receptors, whereas JAK3 binds only to one receptor subunit, the common gamma chain or IL2-Rγ chain (γc).[13]

The interferon signaling pathway and its importance in myositis

The best known IFN signaling pathway is the canonical type I IFN signaling pathway. The binding of the IFN I (alpha or beta) or IFN III to its receptors (IFNAR and IFNLR1 or IL10-R2 respectively) on the cell surface activates Janus Kinase 1 (JAK1) and Tyrosine Kinase 2 (TYK2). This leads to the phosphorylation of cytoplasmic transcription factors STAT1 and STAT2 [11, 16] and the creation of a heterodimer that translocates to the nucleus. Once inside the nucleus, the dimer assembles with IFN-regulatory factor 9 (IRF9) creating the IFN-stimulated gene factor 3 (ISGF3). ISGF3 binds to its cognate DNA sequences known as IFN-stimulated response elements (ISREs), leading to the activation of the ISGs.[17] Unlike IFN I and IFN III, when IFN II binds its receptor IFNGR (IFNGR1 and IFNGR2) JAK1 and JAK2 (instead JAK1 and TYK2) are activated, leading to the creation of the homodimer STAT1. This homodimer binds to its cognate IFN gamma activated sequence (GAS) inside the nucleus (instead of the ISREs), leading to the activation of the interferon-stimulated genes (ISGs).[18] (Figure 1)

Figure 1.

Mechanism of action of JAK-STAT inhibitors used in myositis

The pathogenesis of DM is not completely understood. However, the upregulation of interferon-alpha/beta inducible genes and proteins has been widely reported both in DM[19–23] and JDM.[24–26] This overexpression occurs in the muscle,[19, 23, 25] skin,[27] and blood of these patients[21, 28] More recently, our group and others have shown that also IFN 2 inducible genes are also overexpressed in DM.[23, 29] Moreover, the expression of IFN inducible genes correlates with disease activity in DM,[22, 23, 28] and JDM.[25]

JAK-STAT inhibitors: history, types, and uses

Autoimmune diseases have been classically treated with non-specific immunosuppressive therapies like corticosteroids and corticosteroid-sparing agents. More recently, these diseases have been treated with pathway-specific immunosuppressant treatments like monoclonal antibodies and JAK-STAT inhibitors.[30] (Table 1). The development of JAK inhibitors has its origin in the 1993 work of Riedy et al. which reported the sequence and chromosomal localization of JAK3.[31]

Table 1.

JAK-STAT inhibitors used in myositis.

REFERENCES	DRUG	DOSE	TYPE OF DERMATOMYOSITIS	PATIENTS	CONCOMITANT TREATMENT
Adult dermatomyositis
Hornung, 2014[48]	Ruxolitinib	5mg/d up to 15 mg/bid	Treatment of myelofibrosis in a patient with refractory DM	1	Prednisone, mycophenolate, IVIg
Kurtzman DJ, 2016[49]	Tofacitinib	10 mg/bid (1 patient), 5 mg/bid (2 patients)	3 patient with refractory DM	3	HCQ (1 patient)
Paik JJ, 2016[51]	Tofacitinib	5 mg/bid	Refractory DM	1	Prednisolone
Paik JJ, 2018[53]	Tofacitinib	11 mg/d	Refractory DM (6 patients anti-TIF1g)	10	Washed out of any steroid sparing agent and not allowed more than 20 mg of prednisone/d prior to study entry
Ladislau L, 2018[54]	Ruxolitinib	Up to 40 mg/d	3 refractory anti-TIF1g DM and 1 refractory anti-SAE DM	4	Prednisone +/− IVIG
Kurasawa K, 2018[59]	Tofacitinib	10 mg/d	Refractory anti-MDA5 JDM with ILD	5	Glucocorticoid pulse therapy, prednisolone, CYC, CP
Kato M, 2019[60]	Tofacitinib	5 mg/bid	Refractory MDA5 refractory JDM with ILD	1	Methilprednisolone, CP
Chen Z, 2019[61]	Tofacitinib	5 mg/bid	18 early-stage anti-MDA5 DM with ILD and 32 historical comparators with anti-MDA5 DM with ILD	18	Prednisone
Wendel S, 2019[62]	Tofacitinib	5 mg/bid	1 anti-Mi2 DM with calcinosis and 1 anti MDA5 DM with ILD	2	MTX and prednisone(1 patient)/ Monotherapy with Tofacitinib (1 patient)
Ishikawa Y, 2020[63]	Tofacitinib	10 mg/d	Refractory anti-MDA5 DM with ILD	1	Prednisolone
Juvenile dermatomyositis
Aeschlimann FA, 2018[64]	Ruxolitinib	10 mg/bid	Refractory anti-NXP2 JDM	1	Rituximab, MYC
Papadopoulou C, 2019[65]	Baricitinib	6 mg/bid	Refractory anti-TIF1g JDM with calcinosis	1	Prednisolone
Sabbagh S, 2019[66]	Tofacitinib	5 mg/bid up to 10 mg/bid (1 patient)/ 5 mg/bid (1 patient)	Refractory anti-MDA5 JDM with and calcinosis	2	Pulse methylprednisolone, prednisone, MMF (1)/ CYC, rituximab, sildenafil (1)
Kim H, 2020[67]	Baricitinib	4–8 mg/d divided in 2 times per day	2 Anti-TIF1g and 2 anti-NXP2 refractory JDM	4	Biologics other than IVIg were washed out and other medications continued: MYC (4), MTX (1), CYC (1), TAC (1)
Yu Z, 2020[68]	Tofacitinib	5 mg/bid	Refractory JDM	3	Prednisone + HCQ (2 patients) / Prednisone (1 patient)

DM: dermatomyositis, JDM: juvenile DM, ILD: interstitial lung disease

IVIG: intravenous immunoglobulin, MYC: mycophenolate, HCQ: hydroxychloroquine, MMF: mycophenolate, CP: cyclophosphamide, CYC: ciclosporin, MTX: methotrexate; d: day, bid: two times a day

Currently, there are five JAK-STAT inhibitors approved by the FDA: tofacitinib, ruxolitinib, baricitinib, upadacitinib, and fedratinib. These have been approved to treat myeloproliferative neoplasms and autoimmune diseases such as ulcerative colitis, rheumatoid arthritis(RA), and psoriatic arthritis.[30]

Tofacitinib was the first JAK-STAT inhibitor to be developed. This drug interferes with the IFN pathway by inhibiting JAK 1 and JAK3 signaling pathways and was shown to impair Th1 and Th2 differentiation as well as the production of Th17 cells.[32] Tofacitinib was approved by the FDA in 2012 for the treatment of RA patients with poor response to methotrexate[33] and ulcerative colitis.[34, 35] Ruxolitinib, which blocks the IFN pathway inhibiting the JAK1 and JAK2 signaling, was the first JAK inhibitor treatment approved by the FDA for myeloproliferative diseases.[36–38] This drug has also been approved to treat acute graft-versus-host disease[39] and is also effective to treat RA.[40, 41] Baricitinib inhibits the JAK1/JAK2 and, which has demonstrated efficacy in RA [42], has been approved by the FDA for the treatment of this disease since 2018.[30] Upadacitinib inhibits the JAK1 and was recently approved to be used for the treatment of RA.[30] Finally, fedratinib, a JAK2 inhibitor, has been approved to treat myelofibrosis.[30]

Several other JAK-STAT inhibitors are being tested for the treatment of autoimmune diseases, myeloproliferative diseases, or other neoplasms.[36] For example, Filgotinib, a JAK1 inhibitor[43, 44] has been studied as a treatment for RA in combination with methotrexate in patients who don’t respond to monotherapy. This revealed that filgotinib has a rapid onset of action and improves the symptoms of active RA within 24 weeks.[45–47]

Application of JAK-STAT inhibitors in dermatomyositis

As discussed in the previous section, the JAK-STAT inhibitors are only FDA-approved for a limited number of autoimmune diseases. Nevertheless, these drugs have been used in patients with DM that were not responsive to the usual therapy. In the following sections, we will discuss the use of JAK-STAT inhibitors in DM and JDM.

Adult dermatomyositis:

The first case of a DM patient treated with a drug that inhibits the JAK-STAT cascade was published in 2014. A patient with long-standing and poorly controlled DM developed myelofibrosis and, for this latter reason, was treated with Ruxolitinib. Surprisingly, not only the myelofibrosis, but also the signs and symptoms of DM, improved after treatment with this drug.[48] As previously mentioned, IFN activates JAK-STATs leading to the expression of genes that may have a role in the pathogenesis of DM. Thus, with the premise that JAK inhibitors, by blocking the activation of JAK-STAT may cause a downregulation in the inflammatory cascade, other researchers reported treating patients with DM with this type of medications. First, in 2016, Kurtzman et al reported a series of 3 with refractory cutaneous DM that were treated with the tofacitinib for an average of 9.3 months.[49] An improvement in skin disease was documented using the validated Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score.[50] The authors also reported the adverse effects, the need for other therapies, and the tolerability of the drug. The patients had been previously refractory to prednisone, methotrexate, hydroxychloroquine, mycophenolate, or intravenous immunoglobulins (IVIGs), among others. An average improvement of 12 points in the CDASI was noted and muscle weakness was subjectively improved in two of the three patients. No adverse event was reported, and two of the three patients continued using tofacitinib as monotherapy. Also, in 2016, Paik et al. reported a refractory DM patient with persistent involvement of the muscle, skin, and joint even after treatment with methotrexate, mycophenolate, azathioprine, and intravenous immunoglobulin (each administered for at least for 6 months (as well as two cycles of rituximab). After receiving tofacitinib, the patient had marked improvements in muscle strength, an improved rash, and less severe arthritis.[51]

Following their case report, Paik and colleagues initiated an open-label clinical trial that included 10 DM patients, including 6 with anti-TIF1 gamma autoantibodies (ClinicalTrials.gov NCT03002649). The preliminary results of this study have been reported as a communication to the American College of Rheumatology meeting in 2018. Their first objective was to assess the proportion of patients achieving the definition of improvement defined by the International Myositis Assessment and Clinical Studies (IMACS)[52] at 12 weeks of treatment. Other objectives of this clinical trial were to assess the mean change in the CDASI, the safety and tolerability of tofacitinib, and the steroid-sparing effect of the drug. Patients were washed out of any other steroid-sparing agent and treated for 12 weeks with 11mg/day of tofacitinib. They were allowed to maintain up to 20 mg of prednisone a day when entering the study. All of the participants showed an improvement of the disease (half with “minimal” and half with “moderate” improvement), decreased CDASI scores, and a trend towards a decrease in levels of the IFN-induced chemokines CXCL-9/10.[53]

An interesting study including not only the treatment of refractory DM patients with JAK inhibitors but also assessing the in vitro effects of manipulating the IFN 1 pathway in muscle cells and endothelial cells was performed by Ladislau et al. They aimed to determine the pathogenicity of type 1 IFN and to assess the role of type 1 IFN pathway blockade as a treatment for DM.[54] For this purpose, they used human primary skeletal muscle cells and human clonal microvascular endothelial cells (HMEC-I cells) treated with IFN stimulators and IFN suppressors. In the muscle cells, it was shown that the activation of the IFN 1 pathway impaired the formation of myotubes, diminished the expression of myogenin, and reduced the area of the myotubes. Moreover, it upregulated some genes previously linked to atrophy. On the contrary, when the myoblast and myotubes were preincubated with IFN 1 pathway suppressors before being incubated with the IFN 1 activators, the abovementioned pathogenic effects were not observed. Type I IFN was also shown to impair the formation of capillaries, having a deleterious effect on the segment length, the number of meshes and the number of endothelial cell junctions compared with those that were not treated with IFN 1 activators. Moreover, pretreatment of both the muscle and the endothelial cells with ruxolitinib prevented damage to the muscle and endothelial cells induced by the activation of the IFN 1 pathway. Next, these investigators aimed to confirm their findings in vivo by analyzing six frozen muscle biopsies of patients with DM. For the immunohistochemical analysis, they used anti-FBXO32, anti-MXA, anti-VEGF, and anti-ISG15. They showed that the atrophic muscle fibers located in the perifascicular area that were positive for MxA expressed also FBXO32/atrogin and that there was a co-localization of VEGF and MX1/MxA in the capillaries.

Based on the abovementioned results, the authors initiated a three-month treatment trial of ruxolitinib in four refractory DM patients while maintaining concommitant treatment with low-dose prednisone with or without IVIG. The refractoriness of the disease was based on continued disease activity after treatment with two different immunosuppressive drugs in combination with IVIG or corticosteroids. Apart from the typical DM skin rash, two patients had skeletal muscle weakness, and one of them had high creatine kinase (CK) levels. The authors reported an improvement in the skin features as well as in the strength and CK levels after the treatment. Moreover, the IFN levels in the serum and the ISG score in the PBMCs decreased. Despite the limited sample size, both the in vitro and in-vivo findings of this study are very promising.

As mentioned earlier, DM patients often have MSAs that define the phenotype of the disease. Among these autoantibodies, those directed against the melanoma differentiation-associated protein 5 (MDA5) are associated with severe DM-skin involvement, minimal or no clinical muscle involvement[5, 55], and a rapidly progressive interstitial lung disease.[56–58] Given the high mortality of anti-MDA5 patients with rapidly progressive interstitial lung disease (RP-ILD), finding effective treatments to prevent or revert the lung involvement is an important area of research.

There are published several cases and case series as well as an open-label clinical trial of anti-MDA5-positive DM patients with refractory ILD treated with JAK-STAT inhibitors. Kurasawa et al. published a series of 5 such patients who received tofacitinib in combination with other immunosuppressant drugs. They showed that tofacitinib combined with the other therapies controlled refractory ILD in anti-MDA5-positive DM patients. However, these patients did experience an increased risk of infection.[59] Similarly, Kato et al. reported a patient with anti-MDA5-positive DM and refractory ILD that improved after being treated with tofacitinib along with other immunosuppressant drugs.[60] Importantly, in 2019, 18 patients with anti-MDA5-positive amyopathic DM were treated with tofacitinib and glucocorticoids and compared with a historical cohort of 32 patients. Six months after ILD onset all the patients treated with tofacitinib were alive compared with 78% in the historical control comparator group. Moreover, the ferritin levels, FVC, DLCO, and high-resolution CT findings in the patients treated with tofacitinib improved over time. These patients experienced minimal side effects.[61] Finally, Wendel[62] and Ishikawa[63] also reported a good response to tofacitinib in a small number of anti-MDA5-positive DM patients with ILD.

Juvenile dermatomyositis

There is also accumulating evidence that JAK-STAT inhibitors may be useful in JDM. In 2018, Aeschlimann et al. described a 13 years-old female with severe refractory anti-NXP2-positive JDM complicated by vasculopathy.[64] She did not improve with high-dose corticosteroids and methotrexate and had to be admitted to the ICU with dysphagia, tetraparesis, dysphonia, abdominal pain, bloody diarrhea, and worsening of her cutaneous features. She seemed to improve under an intensive treatment regimen consisting of prednisone (1.6 mg/kg/day), IVIG ((2 g/kg for three consecutive days), plasma exchange, and rituximab (three weekly doses at 375 mg/m²). These treatments were tapered but soon after she started getting weak and developing skin lesions. Despite starting mycophenolate mofetil, increasing the dose of prednisone, and administering additional cycles of IVIG, plasma exchange, and rituximab, she continued having flares of the disease. The authors found high levels of IFN protein in serum and that serum ISGs were overexpressed. They also reported that the phosphorylation of STAT1 and STAT3 in T lymphocytes and monocytes was higher than in the controls. Thus, ruxolitinib was started, and soon after the clinical manifestations of the patient improved. Moreover, compared with the controls, STAT1 phosphorylation decreased in CD3 + lymphocytes as well as in monocytes; 2 months after the ruxolitinib was started the STAT 1 phosphorylation was only present in monocytes.

Similar cases of refractory JDM patients treated with JAK-STAT inhibitors have been reported in the literature. Papadopoulou et al. described the case of an 11-year-old Caucasian male with anti-TIF 1 gamma-positive JDM and anti-Ro52 autoantibodies since 2.5 years-old.[65] Later in life, his disease worsened and he began to experience dysphagia, elevated CK and LDH levels, as well as subcutaneous calcinosis. Over subsequent years, he was treated with corticosteroids, methotrexate, cyclophosphamide, and IVIg. At 11.5 years-old, after the patient was started on baricitinib due to the progression of his skin lesions, the skin involvement, muscle weakness, and CK levels improved. The patient experienced a relapse after stopping the JAK-STAT inhibitor voluntarily. Strikingly, only15 days after baricitinib was reintroduced, the patient experienced improvement. Furthermore, he was able to taper the corticosteroids after 18 months of treatment. As in the case described by Aeschilmann’s, following treatment with baricitinib, STAT1 phosphorylation in lymphocytes decreased to levels similar to that seen in controls.

In 2019, Sabbagh et al. described cases of a 12-year-old male and a 15-year-old female with refractory JDM and anti-MDA5 autoantibodies with calcinosis who were treated with tofacitinib. Both patients achieved clinical improvement in their muscle weakness, skin involvement, and ILD.[66] One of the patients also experienced an improvement in calcinosis. Moreover, a 28-gene IFN score improved in these patients following with the JAK-STAT inhibitor.

Recently, four patients with refractory JDM were treated with baricinib in a compassionate use study at the NIH (ClinicalTrials.gov NCT03002649). Other immunosuppressant medications were continued during the treatment with the JAK-STAT inhibitor. Biologics were washed out before starting the baricitinib and patients received 4–8mg of the drug divided two times per day. The activity of the disease as well as the CDASI showed an improvement. Moreover, two of the patients with baseline weakness experienced an improvement in their strength.[67]

Most recently, Zhongxun Yu et al. reported that treating three cases of JDM with tofacitinib resulted in improvement of the muscle strength, resolution of cutaneous lesions, increased daily quality of life, and successful tapering of the corticosteroids.[68]

Future of JAK-STAT inhibitors in myositis

As described here, preliminary experiences with JAK-STAT inhibitors in DM have been encouraging. However, these studies were either too small to draw definite conclusions or lacked the appropriate controls to verify the efficacy of the drug. Thus, well-designed, placebo-controlled, randomized clinical trials will be key to demonstrate the efficacy of JAK-STAT inhibitors to treat key features of the disease.

One of the most relevant clinical problems in patients with DM is the presence of muscle weakness. Considerable evidence now suggests that over-activation of the interferon pathway plays an important role in the development of muscle dysfunction. Thus, it was suspected that inhibiting this pathway would have a therapeutic effect. However, given the high efficacy of conventional immunosuppressant treatments in most patients with DM, the challenge will be to demonstrate the efficacy of JAK-STAT inhibitors compared to standard therapies.

Most of these preliminary studies have focused on demonstrating the improvement of skin involvement with JAK-STAT inhibitors. Given that skin involvement is often more refractory to treatment than muscle weakness, JAK-STAT inhibitors may have a therapeutic role here. The main difficulty in demonstrating the efficacy of these drugs in a randomized clinical trial will be to use tools to evaluate the skin involvement that is quantitative and sensitive enough. Current evaluation systems, like the CDASI, may be insensitive to small differences between study arms using relatively small sample sizes.

Finally, some manifestations of DM and JDM, such as calcinosis and/or ILD are often difficult to treat with current immunosuppressant treatments. For these manifestations of DM, the JAK-STAT inhibitors may be useful therapeutic modalities in selected patients. Although the pathogenesis of calcinosis is still not well understood, IL 6 has been found in the calcium-laden fluid collections of patients with JDM[69] and it is known that this cytokine signals through the JAK-STAT pathway. Thus, it would be reasonable to hypothesize, that, as the abovementioned preliminary evidence suggests,[65, 66] JAK-STAT inhibitors could be effective, if not to improve, at least to stabilize the spread of calcinosis. Also, in certain clinical groups with a high risk of developing recalcitrant calcinosis, such as those patients with anti-NXP2-positive DM,[70] it would be interesting to know if early treatment with JAK-STAT inhibitors could prevent the initiation of calcinosis.

Alternatively, in patients with ILD, particularly those with anti-MDA5 autoantibodies, the JAK-STAT inhibitors may be helpful not only to treat but to prevent the development of this highly lethal manifestation of the disease. Given the recently published preliminary evidence of their efficacy,[61] it may be ethically questionable to randomize patients to receive placebo in anti-MDA5-positive DM patients with rapidly progressive ILD. Alternatively, larger series of patients treated with JAK-STAT inhibitors may be helpful to verify the efficacy of these drugs in preventing the progression of the ILD anti-MDA5 DM.

In conclusion, over the past two decades, the pathogenic relevance of the interferon pathway has been established in DM. Now, preliminary evidence discussed in this review suggests that JAK-STAT inhibitors may be helpful to treat patients with DM. Notwithstanding these encouraging findings, more studies with a higher level of evidence will be necessary to define the therapeutic role of the JAK-STAT inhibitors in DM.