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 Table of Contents  
Year : 2020  |  Volume : 15  |  Issue : 6  |  Page : 163-174

The evolving spectrum of interstitial lung disease in myositis—Management pearls

Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan

Date of Submission04-May-2020
Date of Acceptance29-Jul-2020
Date of Web Publication18-Jan-2021

Correspondence Address:
Dr. Takahisa Gono
Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo 113-8603
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_118_20

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Idiopathic inflammatory myopathies (IIMs) are characterized by muscle inflammation caused by exacerbated autoimmunity reactions. Patients with IIMs also have extramuscular lesions, such as skin rash, arthritis, interstitial lung disease (ILD), and cardiomyopathy. ILD is one of the leading causes of mortality in patients with IIMs. Thus, physicians need to manage patients with IIM-associated ILD (myositis-ILD) appropriately to prevent the development and progression of ILD. Predictive factors for morality should be considered at the time of making decisions on therapeutic strategies for myositis-ILD. There have been numerous prognostic factors associated with mortality or pulmonary dysfunction. According to the latest research, which contains the large database analysis enrolling 499 incident cases of myositis-ILD with the comprehensive measurement of myositis-specific autoantibodies (MSAs), the presence of anti-melanoma differentiation-associated gene 5 antibody, age ≥60 years, C-reactive protein ≥1 mg/dL, and pulse saturation oxygen <95% have been identified as independent risk factors for mortality. We should also consider the severity of ILD, such as lower values of vital capacity and extensive ILD, and disease behavior to. The clinical characteristics of myositis-ILD are highly diverse. Thus, the categorization of homogenous groups by MSAs and prognostic factors is required to offer appropriate therapeutic regimens to individual patients with myositis-ILD. This effort will contribute to improve the daily quality of life as well as the survival rate in patients with myositis-ILD.

Keywords: Biomarkers, interstitial lung disease, myositis, prognosis, therapeutics

How to cite this article:
Gono T. The evolving spectrum of interstitial lung disease in myositis—Management pearls. Indian J Rheumatol 2020;15:163-74

How to cite this URL:
Gono T. The evolving spectrum of interstitial lung disease in myositis—Management pearls. Indian J Rheumatol [serial online] 2020 [cited 2021 May 7];15:163-74. Available from:

  Introduction Top

Idiopathic inflammatory myopathies (IIMs) are characterized by muscle inflammation caused by exacerbated autoimmunity reactions. Patients with IIMs also have extramuscular lesions, such as skin rash, arthritis, interstitial lung disease (ILD), and cardiomyopathy. The leading causes of mortality in patients with IIMs are ILD, heart disease, malignancy, and infection.[1] Thus, physicians need to manage IIM patients appropriately to prevent the development and progression of these complications related to mortality. In this review, I will focus on IIM-associated ILD (myositis-ILD) and introduce emerging evidence regarding myositis-ILD.

The relevant literature from April 15, 2010, to April 15, 2020, was searched in PubMed. I used the following keywords to search for articles in PubMed: “polymyositis (PM),” “dermatomyositis (DM),” “myositis,” “ILD,” “therapeutics,” and “prognosis.” Non-English literature or literature before April 15, 2010, was excluded.

  Subtypes of Myositis-Interstitial Lung Disease Top

Clinical characteristics of ILD are highly variable among patients with myositis-ILD. The differences in clinical findings regarding myositis-ILD are closely associated with the clinical phenotype of IIMs, clinical course of ILD, myositis-specific autoantibodies (MSAs), high-resolution computed tomography (HRCT)-based lung imaging, and histopathological findings of ILD. I will describe these aspects.

Clinical phenotype of idiopathic inflammatory myopathies

Patients with myositis-ILD are usually presented with classic DM (cDM), amyopathic DM (ADM), or PM, which means that patients have no skin rashes associated with DM, such as Gottron's papules/sign and heliotrope rash. Patients with anti-aminoacyl-tRNA synthetase (ARS) antibody are occasionally presented with ILD alone. The prevalence of ILD was approximately 50% and 60% in PM and DM, respectively.[2],[3] The development of ILD was revealed in 13%–50% of patients with ADM. These frequencies are dependent on races and study design.[4],[5] PM patients with ILD were more likely to respond to conventional treatment, defined as the use of corticosteroids with at least one of azathioprine (AZA), methotrexate, or mycophenolate mofetil (MMF), than DM patients with ILD (67% vs. 35%, P = 0.013).[6] ILD with DM, especially ILD with ADM, may be more acute and severe and less responsive to therapy.[7] The 5-year survival rates of ILD were 82%, 71%, and 59% in patients with PM, those with cDM, and those with clinically ADM (CADM), respectively.[8] These differences in clinical outcome may be mainly attributed to differences in the pathophysiology and progression speed of ILD and responses to immunosuppressive therapy among PM, cDM, and ADM patients.

The overall survival of patients with anti-ARS antibody including ILD-alone cases was similar to that of idiopathic nonspecific interstitial pneumonia (NSIP).[9] The 5-year survival rate of ILD was approximately 90% in whole patients with anti-ARS antibody.[10]

Clinical course of myositis-interstitial lung disease

Idiopathic interstitial pneumonias (IIPs) are categorized into three groups based on the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of IIPs: (i) acute/subacute interstitial pneumonia (IP), such as diffuse alveolar damage (DAD) and organizing pneumonia (OP), (ii) chronic fibrosing IP, such as usual IP (UIP) and NSIP, and (iii) smoking-related IP.[11] The clinical course of myositis-ILD has been simply classified into two groups: (i) acute/subacute ILD with daily/weekly progression and (ii) chronic ILD with over 3 months of progression or no progression referring to the ATS/ERS classification.

The 5-year survival rates were 52% and 87% in patients with acute/subacute myositis-ILD and those with chronic myositis-ILD, respectively.[8] In terms of short-term outcome, in the first couple of years after diagnosis, acute/subacute myositis-ILD has a worse outcome because of rapidly progressive deterioration of pulmonary function, despite immunosuppressive therapy. On the other hand, acute/subacute myositis-ILD is better in terms of long-term outcome because acute/subacute myositis-ILD does not progress or ILD, in particular, ILD with anti-melanoma differentiation-associated gene 5 (MDA5) antibody, occasionally recurs even if the disease activity has reached the remission phase.[12],[13]

In the clinical setting, chronic myositis-ILD is subclassified into three subgroups: chronic ILD with stable or improving disease after immunosuppressive treatment, chronic-relapsing/progressive fibrosing ILD despite immunosuppressive therapy, and asymptomatic ILD with no progression and/or minimal changes in the lungs. Although there is a paucity of evidence regarding chronic myositis-ILD, 20%–30% of patients with chronic myositis-ILD suffered from the deterioration of pulmonary function for 10 years after disease onset.[9],[13] During the follow-up period, >10% decline in forced vital capacity or acute exacerbation on ILD developed in 25% of chronic ILD patients with anti-ARS antibody, leading to death in 20% of the whole patients.[3] The leading causes of death were acute exacerbation on ILD and infectious pneumonia.

Stratification by myositis-specific autoantibodies

The measurement of MSAs is a useful tool to support the diagnosis of IIMs; predict the clinical course, treatment response, and mortality; and evaluate disease activity with the titers of MSAs, especially anti-MDA5 antibodies.

The leading MSA associated with myositis-ILD is anti-ARS antibody. Thirty to forty percent of patients with myositis-ILD have anti-ARS antibody.[14],[15] The majority of patients respond well to initial immunosuppressive treatment and show favorable short-term survival, but the recurrence of ILD happens quite often while tapering the dose of prednisolone (PSL), resulting in unsatisfactory long-term survival.[16],[17] Patients with anti-Jo-1 antibody had a better prognosis than those with anti-no-Jo-1 synthetase antibody. The cumulative survival rates were 90% at 5 years and 70% at 10 years in patients with anti-Jo-1 but 75% at 5 years and 45% at 10 years in patients with anti-other synthetase antibody.[10] This phenomenon might be attributed to a delay in diagnosis in patients with anti-non-Jo-1 synthetase antibody, suggesting that patients with severe myositis are more likely to be treated sooner, whereas patients with isolated ILD remain asymptomatic for a longer time and may have been in a more severe condition at diagnosis.[18] In addition, anti-PL-7 or anti-PL-12 may be associated with more severe lung involvement than other kinds of anti-ARS.[19],[20],[21] In particular, the presence of anti-PL-7 was associated with rapidly progressive ILD (RP-ILD).[20] On the other hand, patients with anti-EJ had a comparable or better outcome in comparison of patients with anti-Jo-1.[20],[22]

Another leading MSA associated with ILD is anti-MDA5 antibody. Anti-MDA5 antibody was detected in 25%–40% of patients with myositis-ILD.[13],[14] Absent or mild muscular symptoms are common in patients with anti-MDA5 antibody. Almost half of adult patients with CADM had anti-MDA5 antibody.[23],[24] The distribution of cDM and ADM in adult patients with anti-MDA5 antibody varies among ethnic groups. Fifty to eighty percent of patients with anti-MDA5-ILD presented with RP-ILD.[24],[25],[26]

Recently, anti-small ubiquitin-like modifier-1 activating enzyme (SAE) antibody has been also closely related to myositis-ILD, particularly in Asian individuals. Fifty to eighty percent of patients with anti-SAE developed ILD, according to a literature review.[27] Thus, anti-SAE antibody is the third myositis-specific autoantibody associated with ILD. Myositis-ILD patients with anti-SAE antibody have more clinical course and better prognosis than those with anti-ARS or anti-MDA5 antibody.[17],[28]

Anti-Ro52 antibody is a common myositis-associated autoantibody detected in 20%–30% of myositis patients.[29] The disease course is more frequently chronic, remission is less common, and an increased number of medications is received in adult patients with anti-ARS or anti-MDA5 who have anti-Ro52 antibody, as well as juvenile patients.[30],[31],[32] Thus, the presence of anti-Ro52 antibody indicates the prediction of refractory myositis-ILD.

High-resolution computed tomographic patterns of myositis-interstitial lung disease

The leading patterns of HRCT of the lungs are NSIP pattern, such as reticulation, peribronchovascular ground-glass attenuation (GGA)/consolidation, traction bronchiectasis, lobar volume loss, and lower predominance, as well as organizing pneumonia (OP) pattern, such as subpleural nonsegmental consolidations with or without nonsegmental GGA.[33],[34] UIP pattern, such as honeycomb lung, is less likely found in myositis-ILD.[34],[35] Anti-MDA5-ILD is characterized by a consolidation or a GGA pattern in the lower lung lobes, a random GGA pattern, and the absence of intralobular reticular opacities on HRCT of the lungs, which is consistent with the findings in anti-ARS-ILD.[36] OP pattern is detected in greater than 50% of patients with anti-ARS, those with anti-MDA5, or those with anti-SAE. On the other hand, NSIP pattern is usually revealed in myositis-ILD patients with the other MSAs, such as anti-Mi-2, anti-SRP, anti-NXP2, and TIF1-γ.[34] NSIP with OP overlap pattern is also revealed in patients with anti-ARS or those with anti-MDA5. The presence of lower consolidation is significantly associated with the development of RP-ILD in patients with anti-ARS as well as those with anti-MDA5.[34]

Histopathological findings of myositis-interstitial lung disease

The most common histopathological pattern of myositis-ILD is NSIP (61%) followed by UIP (19%), OP (11%), and DAD (7%).[37] Based on the stratification by MSA, the histopathological hallmark is DAD in anti-MDA5, occasionally NSIP.[38],[39],[40] In terms of anti-ARS, DAD and UIP are common in anti-Jo-1 as a histopathological characteristic.[41] Radiological features are not always equated with histological patterns.[41] The characteristics of the histopathological findings in anti-no-Jo-1 synthetase antibody are as follows: DAD or UIP with a part of NSIP in anti-EJ; UIP, OP, or NSIP in anti-PL-7; NSIP with or without fibrosis or UIP in anti-PL-12; UIP, NSIP, or OP in anti-OJ; and fibrotic NSIP or UIP in anti-KS.[42],[43],[44],[45],[46],[47],[48] In fact, a combined feature of histopathological characteristics in DAD, OP, UIP, or NSIP, rather than a uniform histopathological feature of ILD, tends to be revealed in ILD with anti-ARS antibody.

  Clinical Outcomes Top

Mortality rate of myositis-interstitial lung disease

The mortality rates have been dependent on study designs or ethnic groups. According to a cohort study, the survival rates of patients with myositis-ILD were 97% at 1 year, 91% at 5 years, and 81% at 10 years during a median follow-up time of 4.5 years.[49] On the other hand, myositis patients without ILD have a better outcome with 90% at 10-year survival rates.[49] In another cohort, named the JAMI cohort, the 1-year, 5-year, and 10-year survival rates were 83%, 78%, and 75%, respectively. These cohort studies have suggested that 20%–30% of patients with myositis-ILD died. The leading cause of mortality was respiratory failure due to the progression of myositis-ILD, covering 82% of enrolled patients who died in the JAMI cohort.[13] Infection related to immunosuppressive therapy was occasionally problematic in the setting of fatal outcome.[50]

Association between myositis-specific autoantibodies and the mortality of myositis-interstitial lung disease

In terms of MSAs, patients with myositis-ILD who have anti-ARS antibody had a relatively preferable prognosis in the short term, with an over 90% survival rate in the first couple of years.[9],[13] The survival rate curve then gradually declined; eventually, 20%–30% of patients with anti-ARS antibody died in the long term, over 5–10 years.[9],[13] A decline in forced vital capacity or an initiation of long-term oxygen therapy during the disease course (odds ratio [OR], 5.34) and acute exacerbation (OR, 28.4) significantly increased the mortality risk in patients with anti-ARS antibody.[9]

On the other hand, approximately 30% of patients with myositis-ILD who have anti-MDA5 antibody died in 3 months due to respiratory failure.[13] Six months after the diagnosis of myositis-ILD with anti-MDA5 antibody, the survival rate curve plateaued. In myositis-ILD without anti-ARS or anti-MDA5, the survival rate curve behaved similar to that in those with anti-ARS antibody. However, patients without anti-MDA5 or anti-ARS had a relatively worse treatment response and prognosis than patients with anti-ARS antibody, even though they expressed milder pulmonary manifestations than those with anti-ARS antibody.[51]


Among a group of patients with myositis-ILD, ILD recurred in approximately 30% of patients with myositis-ILD.[52] The lower pulmonary vital capacity and glucocorticoid alone as a maintenance therapy were associated with early recurrence within 52 weeks. The late recurrence over 52 weeks was related to a positivity of anti-ARS antibody. Calcineurin inhibitors (CNIs) tended to decrease relapse incidences in patients with anti-ARS antibodies.[52]

In light of ILD with anti-MDA5 antibody, initially, the recurrence of ILD was considered rare, with 4% recurrence rates.[12] Recently, several reports regarding anti-MDA5 antibody-positive patients with relapsing ILD have emerged.[53],[54] Deliberate physical examinations and monitoring of anti-MDA5 antibody titers are important even after long-term remission is achieved.[53] Patients in the anti-MDA5 titer-sustained positive group relapsed earlier than those in the negative conversion group, suggesting that a decrease in anti-MDA5 antibody titers to the normal range during remission was associated with longer remission.[54] A re-increase in anti-MDA5 antibody titers is a warning sign for the relapse of ILD.

  Prognostic Factors for Myositis-Interstitial Lung Disease Top

Predictive factors for morality should be considered at the time of making decisions on therapeutic strategies for myositis-ILD. There have been numerous prognostic factors associated with mortality or pulmonary dysfunction. Actually, these prognostic factors are inconsistently reported among individual studies because the method of recruiting patients, statistical analysis measures, observational period, content of treatment, and ethnicity are different in each study. With precautions regarding these interpretations of prognostic factors, useful prognostic factors are introduced [Table 1].
Table 1: Prognostic factors for myositis-ILD

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Conventional predictors for poor prognosis

In terms of epidemiology and general clinical features, older age, male sex, presence of DM rash (a diagnosis of cDM or ADM), and a delay in diagnosis are associated with poor prognosis in patients with myositis-ILD.[8],[13],[55],[56],[57],[58] With regard to the clinical characteristics of ILD, acute/subacute ILD, clinically meaningful progression of ILD after 3 months, symptomatic ILD, lower values of forced vital capacity (FVC), increased alveolar-arterial oxygen gradient (A-aDO2), the extent of radiological abnormality, a pattern of UIP on lung HRCT or lung biopsy, the consolidation/GGA pattern in the lower lung lobes on lung HRCT, and corticosteroid-refractory ILD are predictors for mortality in patients with myositis-ILD.[13],[33],[50],[55],[56],[57],[59],[60] In biomarkers, elevated erythrocyte sedimentation rate, increased levels of C-reactive protein (CRP)/ferritin, lower levels of creatine kinase, high levels of KL-6 (e.g., >1000 U/mL), and the presence of anti-MDA5, anti-PL-7, or anti-Ro52 antibody were associated with poor prognosis.[13],[24],[50],[60],[61],[62],[63] On the other hand, a positive test for anti-Jo-1 antibody indicated better prognosis.[57]

According to the latest research, which contains the most reliable data because of the large database analysis enrolling 499 incident cases of myositis-ILD with the comprehensive measurement of MSAs, the presence of anti-MDA5 antibody (hazard ratio [HR] =7.5, 95% confidence interval [CI]: 2.8, 20.2), age ≥60 years (HR = 4.3, 95% CI: 2.4, 7.5), CRP ≥1 mg/dL (HR = 2.6, 95% CI: 1.5, 4.8), and pulse saturation oxygen (SpO2) <95% (HR = 2.0, 95% CI: 1.2, 3.4) have been identified as the independent risk factors for mortality.[13]

Experimental biomarkers

The macrophage–mannose receptor CD206 is a marker of alternatively activated macrophages. The levels of serum sCD206 were increased in anti-MDA5-ILD and are associated with poor prognosis.[64] The peripheral percentages of CD4+ CXCR4+ T-cells were significantly correlated with HRCT scores and pulmonary function impairments, such as the percentage of forced volume vital capacity. The peripheral percentages of CD4+ CXCR4+ T-cells ≥30% revealed a 6-month mortality as high as 47% in patients with myositis-ILD.[65] Higher levels of serum YKL-40 and lower percent-predicted forced vital capacity were independently associated with a poor prognosis. Immunohistochemical analysis demonstrated that YKL-40 expression was enhanced in aggregated intra-alveolar macrophages and hyperproliferative alveolar epithelial cells in patients with myositis-ILD.[66],[67] Serum progranulin, LIGHT, and high mobility group box 1 are associated with disease progression and severity in DM patients with ILD.[68],[69],[70] Serum levels of chemokines such as CCL2, CXCL10, and CXCL11 are also possible biomarkers of disease activity and prognosis in DM patients with ILD.[71]

  Pharmaceutical Treatment Top

The basis of treatment for myositis-ILD is primarily based on experienced expertise, not on randomized clinical trials. First, the mainstream treatment for myositis-ILD is systemic corticosteroids. The major drugs for myositis-ILD are shown in [Table 2]. A high dose of corticosteroids (dose of oral PSL equivalent to 0.8–1.0 mg/kg/day) is usually administered as a remission induction therapy, especially in RP-ILD or acute ILD. Some experts lower the initial dose of PSL (0.5–0.8 mg/kg/day) in nonsevere forms of chronic ILD. Additional treatment with intravenous methyl-PSL (mPSL) pulse therapy (250–1000 mg for 3 days) is considered for patients who suffer from dyspnea caused by extensive distribution of ILD or acute deterioration.
Table 2: Immunosuppressive agents in remission induction therapy for myositis-ILD

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A combination therapy of at least one immunosuppressant (IS) with PSL is recommended, in particular, for severe acute forms, such as RP-ILD, refractory/relapsing ILD with PSL therapy alone, or when tapering the dose of PSL is difficult. Virtually, the choice of IS is dependent on the experiences of physicians and the circumstances of available IA approved by the government in each country. Based on a retrospective review of treatment outcomes in steroid-resistant myositis-ILD, treatment with cyclophosphamide (CYC), AZA, or MMF was associated with the stabilization of pulmonary physiology, improved dyspnea, and a reduction in the steroid dose.[72] This effect was sustained after 12 months of therapy. There had been no significant outcome differences among CYC, AZA, and MMF, perhaps due to the small sample size and retrospective nature.

In RP-ILD or acute ILD, fundamental immunosuppressive therapy is generally required because patients face an urgent situation caused by hypoxia due to crucial pulmonary deterioration. In this severe situation, intravenous CYC therapy (IVCY) is usually administered on the basis of risk–benefit if the toxicities are tolerated. The intravenous dose of 300–800 mg/m2 body surface area (BSA) is given monthly in six courses according to an open-label study.[73] Recently, rituximab (RTX) has also been shown to be an effective IA for refractory patients with myositis-ILD as the second- or third-line therapy. As of now, the first randomized clinical trial, IVCY (intravenous dose of 600 mg/m2 BSA, 6 doses given 4 weekly) versus RTX (1 g given at baseline and at 2 weeks) for connective tissue disease-associated ILD (CTD-ILD) is ongoing.[74]

In RP-ILD with anti-MDA5 antibody, an intravenous dose of CYC was initiated at 500 mg/m2 BSA biweekly and then was gradually increased to a maximum of 1000 mg/m2 according to a protocol indicated in a Japanese study.[75] This protocol was implemented with the goal of a nadir leukocyte count of 2,000–3000/μL or a 50% reduction from the baseline. After the sixth administration of IVCY, the interval was extended to 4–8 weeks.[75] In this regimen, a combination therapy of PSL, IVCY, and CNI is considered an induction remission therapy for patients who have RP-ILD with anti-MDA5 antibody, especially patients who have several risk factors for mortality.

Cyclosporine A (CSA) and tacrolimus (TAC) are CNIs.[76],[77] CNIs are also considered a good therapeutic option for managing ILD with anti-ARS, not only in refractory patients but also as the first-line treatment.[78] The efficacy of CSA and TAC is comparable for myositis-ILD. The trough concentration of CSA (C0) is targeted at 100–150 ng/mL with administration twice daily (initial dose of 2–4 mg/kg/day) and 150–200 ng/mL for severe forms of ILD, such as RP-ILD.[79] A research paper has suggested that the concentration at 2 h after oral administration of CSA (C2) was important to increase the efficacy of immunosuppression with CSA, with the concentration sustained over 1000 ng/mL with administration once daily.[80] The measurement of CSA blood levels, especially C0 and C2, is useful to monitor both the clinical and adverse effects of CSA during combination therapy.[81] On the other hand, the C0 of TAC is 5–10 ng/mL with administration twice daily. Some experts set C0 at 10–15 ng/mL as an induction therapy for RP-ILD with anti-MDA5 because immunosuppression with TAC is intensified. A recent study has suggested that early therapeutic intervention in combination with glucocorticoids and initial high-trough level C0 TAC 10–15 ng/mL in the initial 3 months was effective for acute/subacute ILD with DM, although consideration of the risks of infection and renal damage is required.[82] Physicians should pay attention to adverse events such as increased blood pressure/blood sugar levels, renal dysfunction, and gastrointestinal symptoms to monitor the concentration of CNI.

MMF is also a potential effective IS for myositis-ILD.[83],[84],[85] However, there are few papers regarding the efficacy of MMF for myositis-ILD. MMF is also considered one of the PSL-sparing drugs useful for refractory patients with myositis-ILD.[86]

B-cell depletion salvage therapy by RTX is effective for refractory patients with anti-MDA5 as well as those with anti-ARS.[87],[88],[89],[90],[91] In refractory anti-ARS-ILD, the best outcome was observed in patients with a disease duration <12 months and/or acute onset/exacerbation of ILD.[92] Infections should be given attention.

The Janus kinase inhibitor tofacitinib has been reported as a potential effective agent for refractory ILD, such as RP-ILD with anti-MDA5 antibody or ILD associated with ADM.[93],[94] Plasmapheresis has also been considered a supplemental treatment for refractory ILD.[95],[96],[97],[98] The effective mechanism of plasmapheresis is supposed to remove pathogenic liquid factors such as cytokines, autoantibodies, and abundant autoantigens that stimulate the immune system via pattern recognition receptors. Basically, fundamental IS therapy is necessary, and the combination with plasma exchange could increase the efficacy of therapy and improve morality rates in refractory patients.

Antifibrotic agents have not yet sufficiently been shown in myositis-ILD. Previous data suggested that pirfenidone add-on immunosuppressive therapy may improve the prognosis of patients with subacute ILD associated with ADM.[99] There are also several reports of effectiveness regarding extracorporeal membrane oxygenation or lung transplantation.[100],[101],[102],[103],[104],[105] These therapeutic procedures are still limited to a part of tertiary referral hospitals.

  Evaluation and Remission Induction Therapy for Myositis-Interstitial Lung Disease Top

We should consider both the severity of pulmonary disease and predictive risk factors related to mortality to make decisions regarding the therapeutic regimen for myositis-ILD. A therapeutic flowchart of my personal opinion regarding therapeutic regimen decisions is shown in [Figure 1].
Figure 1: Evaluation and therapeutic flowchart for myositis-interstitial lung disease. ADM: Amyopathic dermatomyositis, X-ray: radiography, ILD: Interstitial lung disease, HRCT: High-resolution computed tomography, RP-ILD: Rapidly progressive ILD, MDA5: Melanoma differentiation-associated gene 5, CRP: C-reactive protein, SpO2: Pulse saturation oxygen, PSL: Prednisolone, IVCY; Intravenous cyclophosphamide therapy, CNI: Calcineurin inhibitor, RTX: Rituximab, mPSL: Methyl-PSL, ARS: Aminoacyl-tRNA synthetase, FVC: Forced vital capacity, AZA: Azathioprine, MMF: Mycophenolate mofetil

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First, after physicians diagnose patients with IIMs, they should check for lung involvement by chest radiography (X-ray) and take a medical history regarding respiratory symptoms, such as cough and dyspnea at rest or on exertion. Chest HRCT, blood gas analysis with estimated A-aDO2, and pulmonary function testing (forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide [DLco]) should be performed to confirm the development of ILD if lung disease is apparently found or suspected in patients with IIM.

Next, if the presence of ILD is confirmed in patients with IIM, we should classify myositis-ILD into two subgroups: an acute/subacute form, in which ILD develops in days or weeks within 3 months, or a chronic form, in which ILD progresses gradually over 3 months, or remains stabilized, with no remarkable progression. Then, we predict prognosis by risk factors and stratify therapeutic regimens based on the predictions for each form of ILD.

In acute/subacute ILD, we should consider the following prognostic factors: the presence of anti-MDA5 antibody, 60≥ years old, CRP ≥1 mg/dL, and hypoxia (SpO2<95%) at the diagnosis of myositis-ILD.[13] A high dose of PSL initially combined with one kind of IS, such as IVCY, CNI, or RTX, is considered an induction therapy. In patients with severe acute/subacute ILD in whom there are several factors out of those four poor prognostic factors, immunosuppressive therapy should be intensified with the initial administration of mPSL pulse therapy; the choice of IVCY or an increasing dose of IVCY; or triple therapy with PSL, IVCY, and CNI.

For chronic ILD, [Figure 1] shows my opinion regarding prognostic factors. An intermittent dose or high dose of PSL (0.5–0.8 mg/kg/day) is administered, with the adjustment of the initial dose of PSL based on the consideration of the severity of ILD, prognostic factors related to myositis-ILD, and anticipated adverse effects of PSL. IS is also administered initially to regulate the disease activity of ILD and for a PSL-sparing effect. The choice of IS is dependent on the severity and clinical course, such as progressive shrinking lung and poor response to PSL, and the presence or absence of anti-ARS antibody. In refractory or expected-refractory patients, CNI, IVCY, or MMF might be considered as a treatment option. CNI or RTX is also considered for patients with anti-ARS antibody. AZA is considered one option for myositis-ILD, similar to myositis. However, AZA might not be preferable as an induction therapy for severe ILD but rather appropriate as a PSL-sparing agent or maintenance therapy.

In patients with stabilized ILD with no progression or minimal changes in ILD, physicians need to follow-up respiratory symptoms, SpO2, chest X-ray, FVC/DLco, and biomarkers, such as CRP and KL-6, cautiously in 3–6 months.

  Monitoring Disease Status of Interstitial Lung Disease After the Initiation of Remission Induction Therapy and during Maintenance Therapy Top

We need to evaluate how the disease status of ILD improves, remains stable, or is aggravated after treatment or during the follow-up period without intervention by immunosuppressive therapy. Physicians comprehensively evaluate the disease status of ILD in consideration of patients' symptoms, lung imaging, pulmonary function testing, and biomarkers [Table 3]. In particular, chest X-ray and pulmonary function testing, such as FVC and DLco, should be evaluated regularly at 3–6 months during maintenance therapy or follow-up without initiation intervention of immunosuppressive therapy in accordance with an official ATS/ERS/JRS/ALAT statement for idiopathic pulmonary fibrosis.[106] Serum biomarkers related to myositis-ILD are useful for the evaluation of disease activity and severity. Serum ferritin, neopterin, sIL-2R, and KL-6 are reported to be useful in monitoring the response to therapy for myositis-ILD.[107],[108],[109],[110] Anti-MDA5 titers decreased in parallel to below the cutoff level with the correlation of disease activity. It is useful to quantify anti-MDA5 antibodies for monitoring disease activity in patients with anti-MDA5-ILD.[12],[111]
Table 3: Monitoring disease status of myositis-ILD after treatment

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Of these biomarkers, KL-6 is relatively specific for lung as a pneumoprotein, although it occasionally increases in patients with lung adenocarcinoma, pancreatic cancer, or breast cancer. In anti-ARS-ILD, the levels of KL-6 are useful as predictors of relapse in ILD. The relapse rates after 104 weeks were significantly higher in patients with KL-6 levels ≥2400 U/mL before treatment, ≥600 ng/mL after 6 months, and ≥470 U/mL after 12 months.[112] In an ILD group consisting of a relapse group and a nonrelapse group, baseline serum KL-6 was significantly different between the groups.[59],[113] The level of serum KL-6 is a promising biomarker in clinical practice to assess clinical response to treatment.[114],[115] Serum TARC/CCL17, α-defensin 1, and a disintegrin and metalloprotease-17 are also the potential biomarkers related to myositis-ILD as the experimental biomarkers.[116],[117],[118]

  Perspective Top

We need to produce durable evidence regarding the treatment of myositis-ILD much more right now. To realize this, a large, worldwide prospective cohort database is required. We are also asked to provide personalized medicine for patients with myositis-ILD. Decision-making on therapeutic regimens depends on precise prediction of clinical course, response to drugs, and mortality rates. In the future, these predictors should be clarified, and therapeutic modeling by risk stratification should be organized by a multicenter cohort study.

  Conclusions Top

The clinical characteristics of myositis-ILD are highly diverse. The categorization of homogenous groups is helpful for the stratification of therapy regarding myositis-ILD. We should offer appropriate therapeutic regimens to individual patients with the prediction of future outcome of myositis-ILD. This effort will contribute to improving the daily quality of life as well as the survival rate in patients with myositis-ILD.

Financial support and sponsorship


Conflicts of interest

T. G. received honorarium from Astellas and MBL.

  References Top

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  [Figure 1]

  [Table 1], [Table 2], [Table 3]


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