Review

Idiopathic inflammatory myopathies related lung disease in

adults
Sameep Sehgal*, Aditi Patel*, Soumya Chatterjee, Anthony P Fernandez, Carol Farver, Ruchi Yadav, Yuebing Li, Sonye K Danoff, Didem Saygin,
Julio A Huapaya, Erin M Wilfong, Kristin B Highland

Lancet Respir Med Interstitial lung disease (ILD) is common in idiopathic inflammatory myopathies in adults, especially in patients with
2025; 13: 272–88 antisynthetase syndrome and anti-MDA5 antibody-associated dermatomyositis. Pulmonary manifestations can range
Published Online from subclinical ILD to rapidly progressive respiratory failure. Coexistent myositis, characteristic skin lesions,
November 29, 2024
arthritis, and Raynaud’s phenomenon are common. However, 16–65% of patients present with isolated lung disease.
https://doi.org/10.1016/
S2213-2600(24)00267-4 Detection of myositis-specific and myositis-associated antibodies can aid in diagnosis and disease characterisation.
*Contributed equally Chest imaging and pathology most commonly show non-specific interstitial pneumonia and organising pneumonia
Department of Pulmonary and
patterns. Immunosuppression is the mainstay of management with aggressive combination treatment for rapidly
Critical Care Medicine, progressive disease and incremental escalation as needed for chronic ILD. The addition of antifibrotic agents is an
Integrated Hospital Care option in progressive fibrotic disease, and lung transplantation can be considered in severe, end-stage disease. Most
Institute (S Sehgal MD, patients respond to treatment, but short-term mortality remains high for patients with rapidly progressive disease
K B Highland MD), Department
of Rheumatologic and
associated with anti-MDA5 antibody ILD.
Immunologic Disease
(A Patel MD, S Chatterjee MD), Introduction skin, lung, and joint disease. With clinical features,
Department of Dermatology,
Idiopathic inflammatory myopathies are a heterogeneous serology, and muscle pathology, currently six main pheno-
Medical Specialty Institute
(A P Fernandez MD PhD), group of diseases primarily characterised by the common types have been described in adults. Each phenotype has
Department of Pathology feature of immune-mediated inflammation of muscle a distinct typical presentation (table 1).2
(A P Fernandez, C Farver MD), fibres and surrounding tissues. The annual incidence of First, antisynthetase syndrome is the presence of anti-
Department of Diagnostic
idiopathic inflammatory myopathies ranges from 0·2–2·0 aminoacyl-tRNA synthetase antibodies with interstitial
Radiology, Diagnostic Institute
(R Yadav MD), and Department per 100 000 person-years, with a prevalence ranging from lung disease (ILD), inflammatory myopathy, arthritis, or
of Neurology, Neurological 2–25 per 100 000 people.1 However, these systemic diseases mechanic’s hands. Dermatomyositis manifests as typical
Institute (Prof Y Li MD), can manifest with a combination of inflammatory muscle, skin findings with muscle weakness. A subgroup of
Cleveland Clinic, Cleveland, OH,
patients have skin findings with no clinical muscle
USA; Division of Pulmonary
and Critical Care Medicine, disease and are characterised as having clinically
Johns Hopkins University, Key messages amyopathic dermatomyositis. Overlap myositis is inflam-
Baltimore, MD, USA
• Interstitial lung disease (ILD) is common in patients with matory myopathy with simultaneous presence of features
(Prof S K Danoff MD); Division
idiopathic inflammatory myopathies, especially those of other autoimmune diseases, such as systemic
of Rheumatology and Clinical
Immunology, University of with antisynthetase syndrome and anti-MDA5 antibody. sclerosis, mixed connective tissue disease, or Sjögren’s
Pittsburgh, Pittsburgh, PA,
• The clinical presentation of idiopathic inflammatory syndrome. Immune-mediated necrotising myopathy
USA (D Saygin MD); Critical Care describes myopathy with muscle biopsy features of
Medicine and Pulmonary myopathy-associated ILD can vary from mild asymptomatic
Branch, National Heart, Lung, disease to acute respiratory failure. Nonspecific interstitial myonecrosis without a considerable number of inflam-
and Blood, Institute, National pneumonia and organising pneumonia are the most matory cells. Inclusion body myositis is asymmetric
Institutes of Health, Bethesda,
common patterns observed on imaging and pathology. myopathy at disease onset presenting with quadricep
MD, USA (J A Huapaya MD); weakness and finger flexor weakness at diagnosis or later
Division of Rheumatology and • Extrapulmonary manifestations of myositis, skin rash,
Immunology, Division of arthritis, and Raynaud’s phenomenon are common. Lung in the disease course. Muscle biopsy shows endomysial
Pulmonary and Critical Care disease might present in isolation or precede inflammatory infiltrate and muscle fibres with rimmed
Medicine, Vanderbilt University
extrapulmonary disease. The presence of myositis-specific vacuoles and eosinophilic muscle fibre inclusions.
Medical Center, Nashville, TN, Patients with inclusion body myositis usually do not
USA (E M Wilfong MD) and myositis-associated antibodies can help to establish
the diagnosis and characterise the clinical disease. respond to immunosuppression treatment. Lastly, poly-
Correspondence to
• Immunosuppression is the mainstay of treatment for myositis is a rare subtype defined as myositis with the
Sameep Sehgal, Department of
Pulmonary and Critical Care pulmonary and extrapulmonary manifestations of absence of features that would classify patients in
Medicine, Integrated Hospital
idiopathic inflammatory myopathies. Early, high-potency the other subgroups.
Care Institute, Cleveland Clinic, Idiopathic inflammatory myopathies can affect
Cleveland, OH 44195, USA combination treatment is used with a step-down
[email protected] approach in rapidly progressive disease. Conversely, slow, multiple compartments of the respiratory system
incremental escalation of immunosuppression is including lung parenchyma (resulting in ILD),
preferred for chronic ILD in a step-up approach. pulmonary vasculature (leading to pulmonary hyperten-
• Most patients improve or stabilise on treatment; sion), and respiratory muscles. Aspiration pneumonitis
however, mortality remains high for rapidly progressive or pneumonia from dysphagia is also seen. ILD is the
disease. Lung transplantation is an option for severe, most common pulmonary manifestation, with an
progressive disease in a subgroup of patients. overall estimated prevalence of 40–50%. However, in
patients with anti-melanoma differentiation-associated

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 Review

Lung Muscle Skin Characteristic features

Dermatomyositis (classic dermatomyositis rash with or without myositis)
Anti-MDA5 Rapidly progressive ILD Mild to amyopathic Cutaneous ulcerations High mortality; mediastinal emphysema
Anti-SAE No known association Typically absent initially and Classic dermatomyositis rash Severe skin rashes
developed later
Anti-Mi2 Infrequent Markedly elevated creatine Classic dermatomyositis rash Good response to therapy
kinase level
Anti-NXP-2 No known association Severe muscle disease at onset Dermatomyositis rash; calcinosis; oedema High malignancy risk
Anti-TIF1γ Infrequent Mild to amyopathic Severe dermatomyositis rash; calcinosis High malignancy risk
ASyS (antisynthetase antibody plus combination of lung, muscle, or skin involvement)
Anti-Jo-1 (most common Frequent (80–86%) Frequent (90%) Dermatomyositis-associated skin rashes; Arthralgia; fever; puffy hands
antisynthetase syndrome antibody) mechanic’s hands; Raynaud’s phenomenon
Anti-PL-12 Frequent (88–90%) Myositis or myalgia (52%) Mechanic’s hands Arthralgia
Anti-PL-7 Always present Frequent Mechanic’s hands; Raynaud’s phenomenon Can have rapidly progressive ILD

Anti-OJ Frequent Infrequent Infrequent Isolated ILD

Anti-EJ Frequent Frequent Gottron’s sign Better outcomes of the antisynthetase
antibody
Anti-KS Frequent Rare Mechanic’s hands; Raynaud’s phenomenon Isolated ILD
Overlap myositis (myositis with concomitant features of other connective tissue disease)
Anti-PM/SCL antibody At onset of disease (10%), Frequent Sclerodactyly; Raynaud’s phenomenon; Muscle disease associated with severe
eventually 60% developed ILD dermatomyositis rashes; calcinosis disease phenotype
Anti-Ku Prevalence of ILD (35%) Mild muscle disease Limited systemic sclerosis features; Can have severe steroid-resistant ILD
Raynaud’s phenomenon
Anti-U1-RNP Prevalence of ILD (50%) Myopathy can be seen Raynaud’s phenomenon; digital ulceration; Mixed connective tissue disease;
puffy fingers pericarditis and glomerulonephritis
Anti-U3/RNP Prevalence of ILD (38%) Myopathy can be seen Diffuse systemic sclerosis features Pulmonary hypertension; high mortality
Anti-Ro52 Higher ILD rates if seen with Frequent Dermatomyositis rashes; cutaneous lupus Most common myositis-associated
antisynthetase syndrome antibody; can be seen with
antisynthetase syndrome

Anti-SRP ILD more prevalent Severe myopathy Not commonly reported Cardiac involvement; dysphagia; can have
refractory disease
Anti-HMGCR No known association Severe myopathy No association Associated with statin use
Inclusion body myositis
Anti-cN1A No known association Asymmetric myopathy with Has been reported with systemic sclerosis Poor response to immunosuppression
distal weakness and systemic lupus erythematosus
ILD=interstitial lung disease.

Table 1: Clinical phenotypes of immune-mediated myositis and associations with antibodies

protein 5 (MDA5)-dermatomyositis and antisynthetase Pathobiology

syndrome, the prevalence is more than 80%.3 The preva- The underlying mechanism of antisynthetase syndrome
lence of anti-MDA5-dermatomyositis is higher in Asian and dermatomyositis is postulated to be chronic
cohorts than European cohorts.4,5 ILD in idiopathic inflammation caused by both innate and adaptive
inflammatory myopathies can be progressive and immune activation triggered by interactions between
carries high morbidity and mortality. Treatment refrac- genetic and environmental risk factors (figure 1).
tory and rapidly progressive disease has been associated Several HLA and non-HLA genetic associations have
most with anti-MDA5-dermatomyositis.6,7 been shown in idiopathic inflammatory myopathies.8
This Review will discuss pulmonary and extrapulmo- Epidemiological studies have reported smoking as
nary clinical manifestations, diagnostic evaluation, a risk factor for antisynthetase syndrome.9 Preceding
treatment options, management approach, and future respiratory and gastrointestinal infections are associ-
directions in adult patients with idiopathic inflammatory ated with idiopathic inflammatory myopathy onset,
myopathy-associated ILD (IIM-ILD). We focus on specifically Coxsackievirus for dermatomyositis and
antisynthetase syndrome and dermatomyositis; however, anti-MDA5 dermatomyositis.8,10 Recently, SARS-CoV-2
the principles can apply to any idiopathic inflammatory infection has been associated with idiopathic inflam-
myopathy lung disease phenotype. matory myopathy onset.11 Medica­tions such as statins,

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 Review

A B C D
Immune activators Immune response Systemic manifestations

Gene susceptibility Danger signal pathway activation

MDA5
Microparticle release
HLA alleles APC TCR Innate immune Lungs
Type-1 IFN activation (lungs)
WDFY4
DCs CD8
CD4 NK cell

Environmental factors Alveolar Cytokine release Granzyme B

CD8+
CD4+ macrophage (lymph nodes)
Cytotoxic • IFNα
Helper B cell Aminoacyl-
Infection T cell • IL-6 • IL-10 • TNF-α Cleaved form
activation tRNA
• IL-17 (immunogenic) Skin
(lymph nodes) • Ferritin • TGF-ß synthetase
• IL-22
Smoking Plasma cell Extracellular HisRS generation Muscle
Fibroblast fibres
Anti-aminoacyl-
Anti-MDA5 tRNA synthetase
UV exposure Pulmonary fibrosis Neoantigen formation NETosis
antibodies antibodies

Figure 1: Proposed pathobiology of myositis-associated ILD

(A) Immune activators and environmental factors can trigger aberrant immune responses in a genetically susceptible individual. (B) Anti-MDA5 dermatomyositis is
caused by infected cells that activate MDA5, which triggers type-1 IFN production. Virus induced cell injury and lysis, causes release of viral-MDA5 complexes that are
recognised by antigen-presenting cells (macrophages) with subsequent activation of helper T cells (CD8) and B cells (CD4). As a result, there is production of
anti-MDA5 autoantibodies and release of interleukins, TNF-α, and other inflammatory cytokines. (C) Antisynthetase syndrome is caused by cellular stress from
epithelial injury that leads to cell death with microparticle release and danger signal pathway activation. APCs bind to TCRs on CD8+ T cells. Along with NK cell
activation, proteolytic enzymes (granzyme B) are produced, which leads to HisRS generation. The release of HisRS antigen in the extracellular milieu leads to
inflammatory response activation, cytokine release, and production of HisRS autoantibodies. (D) Immune activation can lead to multisystem inflammation and
fibrosis in the lungs, muscle, and skin. APC=antigen-presenting cell. DC=dendritic cell. HisRS=histidyl-tRNA-synthetase. IFN=interferon. ILD=interstitial lung disease.
MDA5=melanoma differentiation-associated protein 5. NETosis=neutrophil extracellular traps and cell death. NK=natural killer. TCR=T-cell receptor. TNF-α=tumour
necrosis factor-α.

immune checkpoint inhibitors, d-penicillamine, inter- A subtype of dermatomyositis associated with

ferons, and anti-TNF agents are also potential anti-MDA5 antibody is strongly associated with rapidly
triggers.12–14 A seasonal distribution with higher preva- progressive ILD. MDA5 is a cytosolic sensor that
lence of anti-MDA5 dermatomyositis in colder months recognises viral double stranded RNA as a danger
could be related to infections.15 A higher prevalence of signal and triggers the transcription of genes encoding
antisynthetase syndrome and dermatomyositis has IFN-1 production, leading to suppression of viral repli-
been noted with a latitudinal gradient, suggesting an cation. Viral infections might incite autoimmunity
association with increased intensity of ultraviolet via several possible mechanisms. Viral induced MDA5
radiation.16 activation in genetically predisposed individuals
Antisynthetase syndrome is characterised by the followed by excessive cellular apoptosis could lead to
development of autoantibodies directed against different a tolerance breach with lungs being the primary
tRNA-synthetase enzymes. Activation of adaptive triggering and affected organ.22,23 Considering the role
immune cells and tolerance breakdown leads to antigen of IFN-1 signalling pathway in anti-MDA5 dermatomy-
presentation, CD8+ T cell priming, and CD4-T cell–B cell ositis, JAK inhibitors have been used to treat anti-MDA5
crosstalk. Release of type I and type II interferons, dermatomyositis.
B lymphocyte stimulator, and other cytokines lead to the
production of anti-tRNA synthetase autoantibodies.17–19 Clinical presentation and diagnostic testing
The resultant aberrant immune activation of T cells The classical presentation of idiopathic inflammatory
(including CD8+ and CD4+ T cells), is thought to play myopathy includes a combination of muscle, skin,
a central role in disease pathogenesis. Activated lung, and joint disease. However, patients can initially
CD8+ T cells release granzyme B, which cleaves several manifest symptoms affecting any of these systems
aminoacyl-tRNA synthetases in the lungs.20 Active in isolation. The disease can become progressive and
T cells, B cells, and autoantibodies enter the systemic affect other organs after initial presentation.24
circulation and encounter the altered auto­antigens in A multidisciplinary collaboration between pulmonol-
the lungs, resulting in lung injury. Most of the 20 known ogy, rheumatology, dermatology, and neurology plays
aminoacyl-tRNA synthetases could become autoanti- an important role in the diagnosis and management
genic; however, commercially available tests only of these patients. Knowledge of the subtle signs of
measure antibodies against some of them.21 The most systemic manifestations of idiopathic inflammatory
common antibodies are anti-histidyl-tRNA-synthetase myopathy by specialists can help in early and accurate
antibody or anti-Jo-1 antibody. diagnosis.

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 Review

Serology group, those with ILD as the first clinical manifestation

Autoantibodies in idiopathic inflammatory myopathy are represent a more challenging subgroup that requires eval-
closely linked to clinical phenotypes. In patients with uation by a multidisciplinary team of experts in IIM-ILD.
suspected IIM-ILD, antibody testing can help establish Currently, standard assays only identify the eight most
a diagnosis, predict outcomes, and play a role in determin- common antisynthetase antibodies that have been associ-
ing treatments. The group of antibodies specific for ated with IIM-ILD. However, there are other tRNA
idiopathic inflammatory myopathy manifestations are synthetases whose corresponding autoantibodies are not
known as myositis-specific antibodies and those frequently yet identified by standard assays. Immunoprecipitation is
found in other connective tissue diseases, which can also particularly useful in this population of myositis-specific
cause myositis, are grouped into myositis-associated anti- antibody-negative IIM-ILD, as it could reveal an
bodies. Myositis-specific antibodies include antibodies for immunoprecipitation band representing an unidentified
dermatomyositis (ie, anti-MDA5, Mi-2, TIF-1γ, NXP-2, and autoantibody. In our practice, we have observed that a con-
SAE), antisynthetase syndrome (ie, anti-Jo-1, EJ, OJ, PL-7, siderable number of patients negative for myositis-specific
PL-12, Ha, Zo, and Ks), immune-mediated necrotising antibody are positive for anti-Ro-52 autoantibody; however,
myopathy (ie, anti-HMGCR and anti-SRP), and inclusion studies to validate these findings are warranted. Sclafani
body myositis (ie, anti-cN1A). Myositis-associated antibod- and colleagues reported that 50 patients with ILD only
ies include anti-PM/Scl, anti-U1RNP, anti-U3RNP, positive for anti-Ro-52 autoantibody had similar outcomes
anti-Ku, anti-cN1A, and anti-Ro52. Details of common compared with those with co-positivity of anti-Ro-52 and
clinical manifestations associated with the various myosi- a myositis-specific antibody.27 This finding highlights the
tis-specific antibodies are reviewed in table 1. potential role of the anti-Ro-52 autoantibody in the evalua-
Anti-nuclear antibody testing is often used to screen for tion of patients with suspected IIM-ILD, particularly those
connective tissue disease. Indirect immunofluorescence negative for myositis-specific antibody. These patients
using human epithelial type 2 cells as a substrate, is the exhibit a higher mean percent-predicted forced viral
standard screening for anti-nuclear antibodies with quan- capacity (FVC) and lower total chest CT scores than
tification of the titre and anti-nuclear antibody staining patients with the anti-Jo1 autoantibody. Yoshifuji and col-
pattern. Most myositis-specific antibodies show positive leagues reported that patients negative for myositis-specific
cytoplasmic staining and a negative nuclear staining antibody had similar lung function, lower ILD recurrence,
pattern, which can lead to a negative anti-nuclear antibody and a lower response to steroids than those who tested
test. Therefore, anti-nuclear antibody is not useful for positive for myositis-specific antibodies.28 Larger studies
screening for the presence of a myositis-specific antibody. and the use of novel immunoassays that can detect other
Several single and multiplex commercial assays are antisynthetase antibodies will help to better characterise
available for detecting most myositis-specific antibodies. this group.
These assays include ELISA, addressable laser bead
immunoassays, immunoblotting techniques, and RNA or Pulmonary manifestations
protein radio-immunoprecipitation. ELISA are the most Interstitial lung disease
used assay worldwide.25 Currently, the gold standard for ILD is the most common pulmonary manifestation
myositis autoantibody testing is the radio-immunoprecipi- of idiopathic inflammatory myopathy, affecting over
tation assay, which is not commonly available. In 80% of patients with antisynthetase syndrome and
a multinational study evaluating real world antisynthetase anti-MDA5 dermatomyositis.29–31 Other idiopathic inflam-
antibody measurement, the local or commercial measure- matory myopathy subtypes often present with muscle
ment of anti-Jo1 antibody was reliable compared with the disease and have a much lower prevalence of and milder
gold standard RNA radio-immunoprecipitation measure- ILD. Lung disease preceding extrapulmonary symptoms
ment. The measurement of non-Jo1 antisynthetase is seen in 16–65% of patients, often by several months.31
antibodies (anti OJ, EJ, PL-12, and PL-7) were less reliable.26 Three distinct clinical presentations of IIM-ILD are fre-
Thus, the clinician should be aware of the limitations of quently encountered. First, rapidly progressive ILD can be
the test being used and be mindful of the possibility seen in an acute exacerbation of previously undiagnosed
of false-positive or false-negative results. ILD or in patients with considerable worsening of ILD
Based on our experience, we suggest starting with within 1–3 months of diagnosis. Acute hypoxic respiratory
a panel that includes all eight available antisynthetase failure is commonly associated with anti-MDA5-dermato-
antibodies, anti-MDA5, and anti-Ro52, which are antibod- myositis and antisynthetase syndrome, particularly with
ies that have been associated with ILDs. Other antibodies, anti-Jo1, anti-PL7, and anti-PL12 antibodies. Development
such as anti-HMGCR, anti-SRP, or anti-CN1A can be of spontaneous pneumo­mediastinum is a poor prognostic
ordered if clinically indicated. sign.32 Second, chronic ILD manifests as insidious onset
of dyspnoea and cough, which can be associated with
Myositis-specific antibody-negative IIM-ILD extrapulmonary symptoms of idiopathic inflammatory
Patients can present with clinical features consistent with myopathy. Chronic ILD is the most common presenta­
IIM-ILD without myositis-specific antibody. Within this tion in patients with antisynthetase syndrome. Lastly,

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 Review

sub-clinical ILD can be seen on imaging with minimal or predominant reticulation and ground-glass opacities with
no symptoms, particularly in patients with anti-SAE, sub-pleural sparing.31 Organising pneumonia pattern is
anti-SRP, and anti-TIF1γ antibodies, which are asso- characterised by patchy peripheral or peribronchovascular
ciated with severe myositis.33 Occasionally, patients with consolidation and ground-glass opacities. The presence of
antisynthetase syndrome might be in this category when an organising pneumonia pattern on imaging is associ-
extrapulmonary symptoms are predominant.31 ated with a good response to immunosuppression
Chest imaging is important for establishing a diagnosis, and better outcomes. Concomitant presence of both
choosing therapy, and estimating the prognosis of non-specific interstitial pneumonia and organising
IIM-ILD (figure 2). A high-resolution CT scan (<1·5 mm pneumonia patterns are often observed in IIM-ILD.35
slices) with volumetric scanning of the chest with inspira- A usual intestinal pneumonia pattern is characterised
tory, and expiratory images can help characterise by sub-pleural, predominantly basilar fibrosis, hon-
parenchymal disease. Prone images can assist with subtle, eycombing, and the absence of ground-glass opacities.
sub-pleural changes and distinguish from compression Usual interstitial pneumonia has been reported in
atelectasis or dependent oedema.34 Non-specific interstitial 10–30% of patients with antisynthetase syndrome, usually
pneumonia is the most common pattern in chronic ILD in advanced disease.31 A usual interstitial pneumonia
and is seen in more than 50% of patients with IIM-ILD pattern is rare in anti-MDA5 dermatomyositis and is seen
and is characterised by peripheral and lower lobe in less than 1% of patients.36 Additional radiographic
features have been associated with usual interstitial
pneumonia due to connective tissue disease and include
A C the concentration of fibrosis in the anterior upper lobes,
exuberant honeycomb-like cysts in the fibrotic paren-
chyma, and lower lobe predominant fibrosis with sharp
demarcation with normal lung in the craniocaudal plane.37
The diffuse alveolar damage pattern consists of diffuse
ground-glass opacities and consolidation, and is
commonly seen during an acute exacerbation of chronic
ILD or in rapidly progressive ILD, particularly in patients
B
with anti-MDA5 dermatomyositis. Usual interstitial
pneumonia and diffuse alveolar damage patterns are
associated with poor response to treatment and worse
outcomes. The imaging patterns can overlap, evolve, and
progress.38,38
PET scans can show an increase in fluorodeoxy­
glucose uptake in both fibrotic and inflammatory ILD.
D E

Figure 2: Chest CT findings and evolution

(A) Patient with rapidly progressive ILD due to anti-MDA5 dermatomyositis.
A1- Axial thin-section CT with centrilobular ground-glass opacities at
presentation. Axial (B) and coronal images (C) over the course of next 30 days
show progressive diffuse ground-glass opacities with lower lobe predominant
F G airspace consolidation suggestive of diffuse alveolar damage along with
pneumomediastinum (blue arrow). Patient with anti-MDA5 antibody associated
dermatomyositis. Axial thin-section CT (D) shows multifocal subpleural airspace
opacities. Subsequent post-treatment chest CT (E) shows improvement with
residual subpleural curvilinear opacities. Patient with antisynthetase syndrome
(anti-PL7 antibody) axial CT (F) shows lower lobe predominant airspace
opacities with ground-glass changes suggestive of organising pneumonia.
Follow-up CT images on treatment (G) show the evolution to a fibrotic
non-specific interstitial pneumonia imaging pattern (lower lobe predominant
ground-glass opacities with traction bronchiectasis). (H) Patient with
H I antisynthetase syndrome (anti-Jo-1 antibody). Coronal CT image shows a usual
interstitial pneumonia pattern (subpleural and lower lobe predominant coarse
reticulation with architectural distortion, traction bronchiectasis, traction
bronchiolectasis, and honeycombing). (I) Patient with antisynthetase syndrome
(anti-Jo-1 antibody). Coronal CT shows upper lobe predominant bullous
emphysema with lower lobe predominant usual interstitial pneumonia pattern
(subpleural reticulation, traction bronchiectasis, traction bronchiolectasis, and
honeycombing). ILD=interstitial lung disease. MDA5=melanoma
differentiation-associated protein 5.

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In patients with IIM-ILD, an increased fluorodeoxy­ Respiratory muscle disease

glucose uptake (>2·5 standardised uptake value) is Respiratory muscle (diaphragm and intercostal muscle)
more prevalent in anti-MDA5 ILD than in patients who weakness can present with dyspnoea and orthopnoea and
are negative for anti-MDA5, and has been associated can progress to hypercapnic respiratory failure if severe.
with worse outcomes.40,41 PET scans are not used Isolated respiratory muscle involvement is rare. However,
in routine practice, but could potentially have a role in subclinical diaphragm weakness is common and can be
prognostication.42 seen in up to 75% of patients, often with mild symptoms
A restrictive pattern (ie, low total lung capacity and normal PFTs. Low activity levels due to myopathy
and FVC) along with a low diffusion of carbon could account for the absence of dyspnoea in some
monoxide (DLCO) is the most common finding on patients.48 Dyspnoea in the absence of parenchymal or
pulmonary function tests (PFTs). Patients with mild pulmonary vascular disease should trigger tests for muscle
disease can have an isolated mild reduction in DLCO weakness. Diaphragmatic ultrasound is a promising,
with normal FVC. Concomitant ILD and emphysema non-invasive method to assess diaphragm function by
or pulmonary hypertension might lead to a reduction measuring diaphragm dome excursion and diaphragm
in DLCO, which is out of proportion to the reduction in thickness. This technique can accurately measure
FVC. In patients with respiratory muscle weakness, PFTs diaphragm function in other neuromuscular diseases, but
usually reveal a decreased FVC, normal DLCO, a greater clinical use in idiopathic inflammatory myopathy is yet to
than 20% drop in FVC when laying supine, decrease in be established.49
maximum voluntary ventilation, and decreased maximal
inspiratory and expiratory pressures. Aspiration
Lung biopsy is rarely needed to establish a diagnosis of Dysphagia can occur due to pharyngeal muscle weakness
IIM-ILD with classical clinical, radiographic, and sero- or oesophageal dysmotility. In the EuroMyositis registry,
logical presentations (appendix p 1). Occasionally, lung 26% of patients with antisynthetase syndrome and See Online for appendix
biopsy might be needed to rule out malignancy. Non- 53% of those with overlap myositis reported dysphagia,50
specific interstitial pneumonia is the most common which can lead to aspiration pneumonia or pneumonitis.
pathological finding.43 A usual interstitial pneumonia Video-fluoroscopic swallowing study and manometry can
pattern is seen in a few patients. Both non-specific inter- be used to evaluate dysphagia.51
stitial pneumonia and usual interstitial pneumonia
might be associated with an acute pathology, either Respiratory infections
diffuse alveolar damage, or organising pneumonia. Respiratory infections are common in patients on immu-
nosuppression treatment and can mimic rapidly
Pulmonary hypertension progressive ILD or trigger an acute ILD exacerbation.
Pulmonary hypertension has been reported in 8–10% of The range of respiratory infections in an immunocom-
patients with antisynthetase syndrome with most promised individual is wide and risks depend on the
patients (81%) having severe disease at diagnosis. degree and type of immunosuppression.52 High dose
Pulmonary hypertension is most commonly associated corticosteroids and combination immunosuppression
with concomitant advanced ILD (World Symposium for increases the risk of opportunistic infections such as
Pulmonary Hypertension [WSPH] group 3 disease).30 pneumocystis pneumonia. Seasonal and community
However, pulmonary arterial hypertension (WSPH acquired viral infections (eg, SARS-CoV-2 or influenza)
group 1) in the absence of ILD or out of proportion to the can lead to severe and persistent disease in patients on
degree of ILD has also been reported in antisynthetase B cell depleting therapy.53 Infections related to environ-
syndrome and other idiopathic inflammatory myopa- mental exposures (fungal pathogens), nosocomial
thies.44 Pulmonary hypertension in the absence of ILD is infections, or reactivation of latent pathogens should be
rare in anti-MDA5 dermatomyositis and data are limited to considered based on the patient’s risk factors. Ruling out
case reports.45 Occasionally, pulmonary hypertension can infection and identifying the causative pathogen is both
be a consequence of myocarditis, inflammatory infiltration essential and challenging. While bronchoalveolar lavage
in the cardiac conduction system, and replacement fibrosis is an effective tool, the risk of respiratory decompensa-
(WSPH group 2). Patients can present with angina, dys- tion in patients with a tenuous respiratory status needs to
rhythmias, or congestive heart failure. Cardiac MRI is be considered. Non-invasive testing (ie, sputum, urine
a sensitive technique that can detect mild inflammation in antigen, nasopharyngeal swab, or serological next gener-
the myocardium.46,47 Echocardiogram is used as a screening ation sequencing) with empirical antimicrobials for
test to establish if further investigations for pulmonary common pathogens might be the only option in some
hypertension are warranted, but the clinician needs to patients.54
maintain a high clinical suspicion as echocardiography in
patients with parenchymal lung disease can be inaccurate. Constitutional symptoms
The diagnosis of pulmonary hypertension requires confir- Fever is the presenting symptom in 25% of patients with
mation by right heart catheterisation. antisynthetase syndrome and is seen in 40% of patients

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during their disease course. Antisynthetase syndrome Arthritis or arthralgia is seen in 90% of patients with
should be on the differential diagnosis for fever of idiopathic inflammatory myopathy and is the presenting
unknown origin. Weight loss can be associated with symptom in 30% of patients with antisynthetase
disease activity, although other important causes, such as syndrome.63 Three general patterns of joint involvement
an underlying neoplasm, should also be considered.55 are seen: (1) symmetrical, non-erosive, polyarthritis
affecting the hand joints and knees (seen in around 60%);
Musculoskeletal manifestations (2) isolated joint arthralgia (25%); and (3) subluxing-
Myopathy is a hallmark feature of idiopathic inflamma- arthropathy affecting the distal interphalangeal
tory myopathy (appendix p 2). The characteristic joints (15%).64 Plain radiographs typically show a non-
presentation is symmetric—proximal muscle weakness destructive arthropathy, although erosive arthritis has
with hip and thigh muscles being the most frequently been occasionally reported.65
affected areas. Common symptoms are difficulty
standing from a seated position, climbing steps, or Skin manifestations
raising arms overhead. Neck extensor muscle weakness The presence of classical skin findings, on history or
can cause head drop and pharyngeal muscle weakness examination, can be helpful in establishing a diagnosis;
might result in dysphagia and voice change. Myalgia and however, the appearance of skin manifestations can be
muscle tenderness are common with antisynthetase affected by the patient’s skin tone (figure 3). Several
syndrome. A detailed neurological examination is crucial pathognomonic dermatomyositis skin findings have been
in determining the severity and distribution of muscle described and can be seen in various combinations in idi-
weakness and to rule out myositis mimics. opathic inflammatory myopathy. These include heliotrope
In patients with antisynthetase syndrome, lung disease rash (periorbital violaceous erythema commonly with
in the absence of or preceding myositis by months is oedema), Gottron’s papules (erythematous-to-violaceous
typical.6 The absence of myopathy is most often seen in papules and plaques, overlying metacarpo-phalangeal and
anti-MDA5 dermatomyositis, but can also be associated interphalangeal joints), Gottron’s sign (erythematous
with other myositis-specific antibodies. Clinically, macules or patches over extensor surfaces of the fingers,
patients with amyopathic dermatomyositis are at higher elbows, and knees), Shawl sign (erythema over posterior
risk of developing ILD than patients with classic dermat- shoulders, neck, and upper back), V sign (erythema over
omyositis, and clinically amyopathic dermatomyositis is lower anterior neck and upper chest), nailfold changes
considered a predictor of rapidly progressive ILD.56–58 (Periungual nailfold erythema, telangiectasia, and
The diagnostic investigations for myopathy include punctate cuticular haemorrhage), Holster sign (symmetric
a variable combination of muscle enzymes, muscle MRI, poikiloderma of hips and lateral thighs), and mechanic’s
electromyography, and muscle biopsy. Creatine kinase is hands (non-pruritic, hyperkeratotic eruptions on the
the most sensitive and measurable muscle enzyme and lateral surface of fingers, and common in patients with
can be used to monitor treatment responses and relapses. antisynthetase syndrome).
Other non-specific biomarkers of muscle injury include Most of these skin lesions are pruritic or burning and
aldolase, lactate dehydrogenase, and aminotransferases.59 some can be photosensitive. Skin hypopigmentation or
Bilateral thigh MRI using a myositis protocol hyperpigmentation, atrophy, and telangiectasia resulting
(T1-weighted imaging, fluid-sensitive T2W with fat sup- in poikiloderma can occur, especially on the upper chest
pression, or short-tau inversion recovery sequence) can and lateral upper arms. Patients with anti-MDA5
be used to identify early stages of myositis and target dermatomyositis can develop specific skin features,
areas for a muscle biopsy. Findings include oedema of including skin erosions, ulcerations over joints or on
muscle fibres, alteration in muscle signal intensity, and, digits, and tender palmar papules.
in later stages, presence of fatty infiltration, fibrosis, or Lesional skin biopsies can be helpful in diagnosing
muscle atrophy. These changes are not specific to patients with clinically amyopathic dermatomyositis and
myositis and can also be seen in injuries, muscle infarc- could prevent the need for muscle biopsy in patients with
tion, denervation, or rhabdomyolysis.52,60 other idiopathic inflammatory myopathies. Characteristic
Electromyography can distinguish myopathy from histological findings include interface dermatitis with
neuropathic causes of weakness. Myopathy is character- dyskeratosis, increased dermal mucin, chronic perivas-
ised by polyphasic motor unit action potentials that are of cular inflammation, and vascular dilatation or damage.
short-duration, low amplitude on voluntary activation, Although these histological characteristics are essentially
and with prominent muscle membrane irritability at identical to those seen in patients with lupus erythemato-
rest. Electromyography is not diagnostic of myositis, as sus, correlation of these histological findings with
similar findings can occur in infectious, toxic, metabolic, serological test results and the clinical pattern and mor-
or degenerative myopathies. Electromyography can phology of skin lesions typically allows clinicians to easily
guide muscle biopsy, but biopsy should not be performed arrive at the correct diagnosis.
on a muscle that has recently undergone electro­ Nailfold capillaroscopy can aid in diagnosis and
myography testing.61,62 prognostication. Findings include enlarged capillaries,

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A B C

D E F

G H I

Figure 3: Dermatological manifestations of idiopathic inflammatory myopathy

MDA5-associated dermatomyositis: (A) chest and neck ulceration, (B) livedo changes and scar around elbow, and (C) Palmar papules and ulcers. Antisynthetase
syndrome: (D) Gottron’s sign, (E) mechanic’s hands, (F) Hiker’s feet, (G) periorbital erythema, (H) arms and back pigmentation, and (I) dyspigmentation in V-neck
areas. MDA5=melanoma differentiation-associated protein 5.

disorganised vascular array, capillary loss, and sclero- common forms. The risk and screening strategies vary
derma-like patterns.66 Improvement in nailfold considerably based on the disease phenotype and antibody
capillaroscopy findings has been seen in response to profile. Patients with dermatomyositis (anti-TIF1γ and
immunosuppression and might be helpful in evaluating NXP-2 antibodies) older than 40 years at idiopathic inflam-
disease activity and response to treatment.67–69 matory myopathy onset, dysphagia, and cutaneous
necrosis are at the highest risk for having an underlying
Cancer-associated myositis malignancy followed by patients with polymyositis,
Adult onset idiopathic inflammatory myopathy is associ- immune-mediated necrotising myopathy, or clinically
ated with an increased risk of malignancy, particularly amyopathic dermatomyositis who are at intermediate
within the 3 years before and 3 years after onset.70 risk. Patients with antisynthetase antibody (anti-Jo1 or
Furthermore, cancer is a leading cause of death in adults non-Jo1 antibody), myositis-associated antibodies, or
with idiopathic inflammatory myopathy.71,72 Various anti-SRP antibody with features of Raynaud’s phenome-
cancers including lung, ovarian, colorectal, breast, non, inflammatory arthropathy, and ILD are at low risk.
lymphoma, and nasopharyngeal are among the most Patients can be risk-stratified based on demographics,

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 Review

Bohan and Peter (1975)74,75 Connors (2010)76 Solomon (2011)77 EULAR/ACR (2017)78
Classification criteria Classified into definite, probable, and Positive antisynthetase antibody and Diagnosis of antisynthetase antibody Web based calculator; assigns total score and
possible polymyositis or any one of the following: myositis by based on major and minor criteria; probability; sub-Classification in immune
dermatomyositis; exclude other Bohan and Peter criteria, presence of antisynthetase antibody positive and mediated myositis subtypes
causes of myopathy ILD, presence of arthritis, unexplained two major criteria or one major plus
and persistent fever, Raynaud’s two minor criteria
phenomenon, or mechanic’s hands
Muscle Symmetrical muscle weakness; Myositis by Bohan and Peter criteria Polymyositis or dermatomyositis per Symmetrical muscle weakness; elevation of
manifestations elevation of muscle enzymes; muscle Bohan and Peter criteria (major) muscle enzymes; muscle biopsy findings
biopsy evidence of myositis;
electromyography findings of
myopathy
Skin manifestations Characteristic dermatomyositis rash Mechanic’s hands; Raynaud’s Mechanic’s hands (minor); Raynaud’s Heliotrope rash; Gottron’s papules; Gottron’s
phenomenon phenomenon (minor) sign
Lung manifestations Not included ILD ILD (major) Not included
Serology Not included Antisynthetase antibody (required) Antisynthetase antibody (required) Anti-Jo-1 antibody
Other manifestations ·· Arthritis; unexplained fever Arthritis (minor) Oesophageal dysmotility
Method Retrospective review of 153 cases Expert opinion Expert opinion Analysis of data from 976 patients with
immune-mediated myositis and 624 patients
with non-immune-mediated myositis
Comments Most widespread criteria for Widely used for isolated lung disease; Widely used for isolated lung disease; Based on large dataset and externally
dermatomyositis or polymyositis for includes all antisynthetase antibodies includes all antisynthetase antibodies; validated; does not include isolated lung
40 years; does not include antibody includes amyopathic immune- disease or non-Jo-1 antibody
testing; isolated lung disease mediated myositis patients
ACR=American College of Rheumatology. EULAR=European League Against Rheumatism. ILD=interstitial lung disease.

Table 2: Evolution of classification criteria for immune-mediated myositis

clinical features, and antibody status. Enhanced cancer There are active efforts for establishing a revised classifi-
screening is recommended in patients who are at inter- cation criteria for idiopathic inflammatory myopathy and
mediate or high risk, which includes CT scans, pelvic separate classification criteria for antisynthetase syndrome
ultrasound, mammography, cervical cancer screening, that incorporate the presence of ILD. Currently, criteria
and cancer biomarkers. A whole-body PET scan should be suggested by Solomon and colleagues77 and Connors and
considered in patients at high risk where other investiga- colleagues76 based on expert opinion, are widely used to
tions have not detected a malignancy.73 establish a diagnosis of antisynthetase syndrome. The
presence of anti-synthetase antibodies with any one or
Classification criteria for idiopathic inflammatory two clinical features (ILD, idiopathic inflammatory
myopathy myopathy, Raynaud’s phenomenon, or skin changes) can
Bohan and Peter provided classification criteria for der- be considered adequate for diagnosing antisynthetase
matomyositis in 1975, which was widely used for 40 years syndrome.
(table 2).74,75 They included characteristic dermatomyositis
rashes and the need to exclude other causes of myopathy, Management
but did not mention pulmonary manifestations. Patients Immunosuppression is the mainstay of treatment for
with anti-Jo-1 antibody were recognised as having a distinct IIM-ILD targeting several pathways. As with most rare
phenotype termed antisynthetase syndrome in the diseases, few clinical trials exist, and treatment varies
early 1990s.79,80 Since then, idiopathic inflammatory myo- based on clinical presentation and centre preference.81
pathies have been further classified based on clinical Patients with rapidly progressive ILD need early,
manifestations and antibody profiles. In 2017, the first aggressive, combination anti-inflammatory therapy.
validated classification criteria of idiopathic inflammatory Patients with chronic ILD can be treated with a step-up
myopathy by the American College of Rheumatology and escalation of therapy over several months. Patients
European Alliance of Associations for Rheumatology with subclinical disease can be monitored without
(EULAR) were developed and included the probability of therapy but require close follow-up. Treatment
having idiopathic inflammatory myopathy.78 The criteria decisions are based on expert opinion, experience, the
include age of onset, pattern of muscle weakness, muscle clinical gestalt of individual treatment teams and
enzyme elevation, muscle biopsy findings, presence of require multidisciplinary collaboration. A summary
rash, and the presence of anti-Jo-1 antibody. The criteria of our recommendations on initial dosing, common
do not include ILD or non-Jo-1 antibodies. The adverse events, and monitoring of immunomodulators
criteria also do not define antisynthetase syndrome as commonly used in patients with IIM-ILD are detailed
a distinct idiopathic inflammatory myopathy subtype. in the appendix (pp 3–6).

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Corticosteroids recommend testing for thiopurine methyltransferase

Corticosteroids have been the first-line treatment for deficiency in patients taking azathioprine as thiopurine
pulmonary and extrapulmonary manifestations of methyltransferase intermediate metabolisers require
idiopathic inflammatory myopathy for decades. A meta- lower doses, and patients who are low metabolisers
analysis of patients with IIM-ILD (45% antisynthetase should not receive azathioprine.
syndrome and 40% dermatomyositis), reviewed the effect Methotrexate has been efficacious in treating myositis
of various treatment strategies. Six studies in the analysis and has a steroid-sparing effect; however, data for ILD
included 124 patients who received corticosteroid mono- are scarce.86 Casal-Dominguez compared methotrexate
therapy.82 Clinical improvement was reported in 112 (89%) with azathioprine monotherapy in 102 patients with
of the 124 patients. However, the meta-analysis had antisynthetase syndrome.87 Both drugs led to improve-
several limitations and none of the included studies were ment in muscle strength, reduced corticosteroid dose
controlled. Most studies evaluating other therapies for requirement, and had a similar rate of adverse effects. In
IIM-ILD have patients on background corticosteroids, this cohort, two (4%) patients developed methotrexate
thus limiting the data available on using a steroid-free pneumonitis. The reported incidence of pneumonitis is
approach. variable depending on the definition and cohort studied,
In clinical practice, most patients are started on with no reports of pneumonitis in clinical trials in
corticosteroids at the time of diagnosis either as a single patients with rheumatoid arthritis since 2001.88 While the
agent or in combination with a steroid-sparing agent. In use of methotrexate remains a viable alternative to other
patients with rapidly progressive-ILD, high dose intrave- antimetabolites drugs, clinicians should be aware of the
nous steroids (500–1000 mg methylprednisolone for clinical risk of pneumonitis.
3 days) in combination with other immunomodulators
are started. Advantages of using corticosteroids include Calcineurin inhibitors
quick onset, low cost, and physician experience. However, The calcineurin inhibitors, tacrolimus and cyclosporine,
long-term use of corticosteroids carries considerable restrict T cell function by inhibiting the enzyme calcineu-
morbidity, including steroid myopathy. Given the mor­ rin and impairing transcription of cytokines such as IL-2.
bidity associated with long-term corticosteroids, we In a randomised controlled trial, Fujisawa and colleagues
advocate to start them in conjunction with a steroid- compared the use of tacrolimus with cyclosporine as
sparing agent early in the course of disease. first add-on agents in 58 patients with IIM-ILD: 14 (24%)
with clinically amyopathic dermatomyositis, ten (33%)
Antimetabolites with dermatomyositis, and six (20%) with polymyositis.
Mycophenolate mofetil (MMF), methotrexate, and aza- Patients in both groups showed similar improvement in
thioprine block lymphocyte activation and proliferation percentage predicted FVC (12% tacrolimus and 14%
by inhibiting DNA synthesis via various mechanisms. In cyclosporine) and percentage predicted DLCO (23%
patients with IIM-ILD, antimetabolites are commonly tacrolimus and 23% cyclo­ sporine). This trial showed
used as first-line steroid-sparing agents due to good efficacy of calcineurin inhibitors as first-line agents with
patient tolerance and favourable adverse effect profiles. corticosteroids, but was not designed to compare them
However, data are limited to retrospective studies. with other treatments.89 Therefore, calcineurin inhibitors
In a single-centre, retrospective study of 125 patients can be used either as first-line or second-line steroid-
with connective tissue disease-associated ILD (32 [25·6%] sparing agents. The choice between tacrolimus and
with idiopathic inflammatory myopathy), MMF treat­ cyclosporine is physician dependent, with no evidence of
ment led to improvement or stabilisation of disease superiority for either agent.
across various underlying connective tissue diseases.
Patients with usual interstitial pneumonia pathology Rituximab
showed stabilisation and those with non-usual interstitial Rituximab is an anti-CD20 monoclonal antibody that
pneumonia had improvement in lung function.83 In causes peripheral B cell depletion. The RECITAL ran-
a retrospective review of patients with IIM-ILD, both domised controlled trial compared rituximab with
MMF and azathioprine led to improvement or stabilisa- cyclophosphamide as second-line agents in 101 patients
tion of lung function (FVC improvement of 3·6% in with connective tissue disease-associated ILD (44 [43·6%]
MMF group and 3·3% in azathioprine group) and a sig- with IIM-ILD).90 Both rituximab and cyclophosphamide
nificant reduction in prednisone dose (6·9 mg in MMF increased the median FVC at 24 weeks (94 mL rituximab
group and 15 mg in azathioprine group) at 24 months. and 99 mL cyclophosphamide) and 48 weeks (112 mL
The rate of adverse effects was slightly higher in the rituximab and 138 mL cyclophosphamide). DLCO, 6-min
azathioprine group.84 Mira-Avendano and colleagues walk distance, and quality of life also improved in both
compared cyclophosphamide, azathioprine, and MMF groups. The cyclophosphamide group had more total
as second-line agents in steroid-refractory IIM-ILD adverse effects, but both had a similar number of serious
and reported that all three led to an improvement in adverse events. This randomised control trial showed
FVC, DLCO, and dyspnoea scores at 12 months.85 We that most patients treated with second line rituximab or

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 Review

cyclophosphamide improve, both with similar efficacy.90 dermatomyositis, with decreased disease activity
Retrospective studies have shown similar efficacy of compared with placebo.99 In IIM-ILD, data are limited.
cyclophosphamide and rituximab and a better adverse In a retrospective study, 17 patients with antisynthetase
effect profile with rituximab.91 In a systematic review of syndrome (14 [80%] with refractory disease) were treated
patients with anti-MDA5 ILD, 71% of patients responded with IVIg for 6 months and followed up for 2 years; FVC
to rituximab as a second-line or third-line agent.92 and DLCO percentages increased, and prednisone dose
Rituximab can be used as a second-line agent in refrac- decreased.100 Most patients were on concomitant immu-
tory disease. nosuppression. The absence of a control group limits
the ability to conclude IVIg efficacy. The main indication
Cyclophosphamide for IVIg in idiopathic inflammatory myopathy is to treat
Cyclophosphamide is an alkylating agent, commonly used extrapulmonary disease and as second-line or third-line
for cancer chemotherapy, which is used for induction in therapy in rapidly progressive ILD. The side-effect
life-threatening autoimmune conditions due to its rapid profile of IVIg and absence of immunosuppression
and profound immune suppression. In addition to data makes it an attractive add-on therapy for patients with
from the RECITAL randomised controlled trial, similar severe lung disease or in patients where active infections
findings were seen in a systematic review of five studies have not been ruled out.
analysing cyclophosphamide use in patients with IIM-ILD
(55% with anti-Jo-1 antibodies). In the review, 71% of Antifibrotic therapy
patients had improvement in FVC, 69% had improvement Nintedanib and pirfenidone have shown efficacy in
in DLCO, and 67% had improvement in chest CT treating idiopathic pulmonary fibrosis (IPF). The
findings.81 Cyclophosphamide can be administered up to INBUILD randomised control trial studied the efficacy
6 months in severe or rapidly progressive ILD, with transi- of nintedanib in 663 patients with progressive
tion to less toxic agents once the disease is in remission. pulmonary fibrosis. In the study, 170 (25%) of the
patients had connective tissue disease-associated ILD.
JAK inhibitors Nintedanib slowed the rate of progression in the entire
Tofacitinib is a JAK inhibitor that preferentially inhibits cohort. Data from patients with IIM-ILD were not
JAK1 and JAK3. Tofacitinib suppresses the interferon reported separately.101 In a single-centre, prospective
pathway and various cytokines that are implicated in the study of patients with IIM-ILD, 39 patients on
pathogenesis of anti-MDA5-dermatomyositis. Thus, nintedanib were compared with those receiving stand-
currently available data mainly focus on tofacitinib use in ard-of-care therapy. Patients in the nintedanib group
anti-MDA5 dermatomyositis. had a lower rapidly progressive ILD risk and better
In a single-centre, open-label trial with retrospective survival compared with the control group102 In the 2022
controls, Chen and colleagues studied the efficacy of American Thoracic Society guidelines for progressive
tofacitinib as a first-line steroid-sparing agent in pulmonary fibrosis, nintedanib is recommended for
18 patients with anti-MDA5 ILD, compared with patients with progressive pulmonary fibrosis.103
32 historical controls.93 The 6-month survival was 100% Pirfenidone did not meet its primary endpoint in
in the tofacitinib group compared with 78% in controls. patients with progressive pulmonary fibrosis in the
They reported an improvement in FVC, DLCO, and RELIEF trial. Furthermore, the study had to be stopped
chest CT scores in the tofacitinib group. Fan and col- due to poor recruitment and futility.104
leagues compared tofacitinib with tacrolimus in Determining disease progression can be challenging in
a retrospective study of patients with anti-MDA5 der- ILD, particularly in IIM-ILD.105 Based on the authors’
matomyositis. More than 50% of patients had rapidly experience, we suggest a trial of adequate immunosup-
progressive ILD. Lower mortality in the tofacitinib group pression treatment with step-up as indicated after the
was seen at 6 months (38·5% tofacitinib vs 62·9% tac- initial diagnosis and before adding an antifibrotic.
rolimus) and 1 year (44·0% tofacitinib vs 65·7%
tacrolimus).94 Tofacitinib has also shown efficacy in Therapeutic plasma exchange
patients with disease refractory to other agents.95,96 Therapeutic plasma exchange can decrease the levels of
Tofacitinib is orally dosed and can be used as a second- autoantibodies, cytokines, and immune complexes.
line or third-line agent for anti-MDA5 dermatomyositis. Data for therapeutic plasma exchange in IIM-ILD is
The use of other JAK inhibitors such as baricitinib have restricted to case series. In a retrospective study of
been reported in a case series with clinical trials 11 patients who underwent therapeutic plasma exchange
ongoing.97,98 for anti-MDA5 ILD, survival was ten (90%) in the thera-
peutic plasma exchange group compared with four (50%)
Intravenous immunoglobulin of eight patients in the non-therapeutic plasma exchange
Intravenous immunoglobulin (IVIg) is purified from group.106 With scarce data, therapeutic plasma exchange
pooled human plasma consisting of monomeric IgG. continues to be used as a salvage therapy for rapidly pro-
IVIg has shown efficacy in treating patients with gressive ILD.107

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Lung transplantation Management of chronic ILD

Lung transplantation is an option for selected patients
with end-stage lung disease. Patients with progressive First-line immune modulators All patients:
Corticosteroids; mycophenolate or azathioprine Pulmonary
disease despite appropriate therapy, need for supplemen- rehabilitation;
tal oxygen, progressive fibrotic disease, and rapidly monitor for
Progression, lack of considerable medication adverse
progressive ILD should be considered for transplant improvement, or relapse of disease effects; pneumocystis
evaluation.108 In addition to standard issues of candidate pneumonia
selection, extrapulmonary manifestations of idiopathic prophylaxis†
Second-line immune modulators
inflammatory myopathy can affect candidacy and Rituximab; tacrolimus or cyclosporine; intravenous immunoglobulin
WSPH group 3
post-transplant outcomes.109 Active myositis can affect Progression or relapse of disease
pulmonary
hypertension:
rehabilitation potential, ventilator weaning, and the risk Inhaled treprostinil
of aspiration. Therefore, myositis needs to be quiescent
Antifibrotic for Third-line immune Lung transplant Respiratory muscle
before transplant referral. Patients with considerable pulmonary modulators evaluation weakness:
respiratory muscle weakness are not considered candi- function tests* Cyclophosphamide Need for Non-invasive
dates for lung transplantation. Nintedanib (after an supplemental oxygen mechanical ventilation
adequate trial of
Post-transplant outcomes in IIM-ILD are similar to those immunosuppression)
for other indications in US and European cohorts.110,111
Timely referral to an experienced transplant centre can Management of rapidly progressive ILD
help improve the likelihood of a successful transplant.
First-line combination therapy All patients:
Corticosteroid pulse (500-1000 mg per day for 3 days) Monitor for
Pulmonary rehabilitation AND one or two agents depending on severity: tacrolimus or medication adverse
cyclosporine; cyclophosphamide (maximum 6 months); rituximab; effects; pulmonary
Pulmonary rehabilitation is a comprehensive interven-
tofacitinib; IVlg rehabilitation;
tion for patients with chronic lung disease that includes pneumocystis
exercise training and education, usually in an outpatient Progression or lack of significant pneumonia
improvement prophylaxis†
setting. A Cochrane review of 16 trials in patients with
ILD showed that pulmonary rehabilitation helped to WSPH group 3
pulmonary
improve 6-min walk distance, dyspnoea, and quality of Salvage Lung transplant evaluation
hypertension:
life with no significant adverse effects.112 This treatment Therapeutic plasma exchange (if isolated respiratory failure)
Inhaled treprostinil
and IVlg
modality remains underutilised despite its high reward Evaluate ECMO candidacy
and low risk profile. Referral should be considered in all (bridge to recovery or transplant in
acute respiratory failure)
symptomatic patients with IIM-ILD.

Figure 4: Management algorithm for chronic and rapidly progressive ILD

Infection prevention and prophylaxis
ILD=interstitial lung disease. ECMO=extracorporeal membrane oxygenation. IVIg=intravenous immunoglobulin.
Patients on immunosuppression treatment are at increased WSPH=World Symposium on Pulmonary Hypertension. *Fibrotic disease with more than 10% fibrosis on imaging
risk for infectious complications. Prophylaxis for pneumo- and progression defined by any two or three criteria (ie, worsening respiratory symptoms, worsening pulmonary
cystis pneumonia with trimethoprim–sulfamethoxazole physiology, absolute decline in FVC >5% or absolute decline in DLCO >10%, or progression of disease on radiology).
†Pneumocystis pneumonia prophylaxis in patients on two immunosuppressive medications or those on high-dose
or an alternate regimen should be started in patients
corticosteroids (>20 mg per day prednisone for 1 month).
on two immunosuppression medications or those on
high-dose corticosteroids (>20 mg per day prednisone for increase 31 m), improve biomarkers of right heart failure
1 month). Age-specific and location-specific immunisa- (nt-pro BNP), and decrease the incidence of clinical
tions before initiating immunosuppression treatment and deterioration (22% treprostinil vs 33% control).114
seasonal annual immunisation is strongly recommended
by the authors. Management of respiratory muscle weakness
Aggressive immune modulation with high-dose steroids,
Management of pulmonary hypertension IVIg, and other agents should be initiated depending on
In patients with WSPH group 1 pulmonary arterial the degree of muscle weakness. Patients need to be
hypertension, treatment according to the latest WSPH monitored closely for worsening disease with measure-
guidelines for group 1 disease should be pursued. ments of negative inspiratory force and vital capacity.
Immunosuppression has been reported to be beneficial A negative inspiratory force of less than 30 cmH2O and
in observational studies in patients with systematic lupus FVC of less than 20 mL per kg might warrant monitoring
erythematosus and mixed connective tissue disease- in an intensive care unit setting. Patients might progress
associated pulmonary hypertension.113 However, there is to respiratory failure and could require non-invasive or
no supporting data in patients with idiopathic inflamma- invasive mechanical ventilation. Management in this
tory myopathy-related pulmonary hypertension. situation is similar to other neuromuscular diseases
In patients with WSPH group 3 pulmonary hyperten- affecting the respiratory system.115 Non-invasive ventila-
sion due to ILD, inhaled treprostinil is recommended as tion can help improve hypercapnia, sleep quality, and
it is shown to increase 6-min walk distance (mean quality of life in patients with chronic hypoventilation.

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Monitoring corticosteroids (prednisone 0·5–1·0 mg per kg), with

The goal of ongoing monitoring is to assess response to tapering over 2–3 months to the lowest tolerated dose.
therapy, progression of disease, medication toxicity, Depending on severity, an antimetabolite is often started
infections, and comorbidities. The frequency is based on within weeks. We use rituximab or calcineurin inhibitors
the severity, rate of disease progression, and comorbidi- as second-line agents either alone or in combination
ties, and is altered to individual patient needs. In patients with IVIg. Cyclophosphamide can be used as a third-line
with chronic ILD, patients should be evaluated agent in refractory disease. Antifibrotic medications are
1–3 months after initiating or altering therapy. Patients added in progressive pulmonary fibrosis if there is pro-
with rapidly progressive ILD and anti-MDA5 dermato- gression on optimal anti-inflammatory therapies.
myositis are often admitted to hospital for rapid initiation In patients with rapidly progressive ILD, aggressive
of combination therapy. Post-hospital discharge visits are therapy is started early to induce remission, followed
often every 2–4 weeks initially. Repeat imaging can help by a step-down approach once the disease is quiescent.
in assessing response to therapy by evaluating the The favoured regimen varies based on experience and
inflammatory findings from imaging. Once the disease institution, but includes a combination of high-dose
is deemed quiescent, patients with stable disease should corticosteroids and one or two immunomodulators
be evaluated every 3–6 months. (eg, calcineurin inhibitors, cyclophosphamide, rituximab,
In addition to assessing symptoms and medication IVIg, or tofacitinib). Lung transplantation should be
toxicity, PFTs are checked (spirometry and DLCO) every considered early in patients with single-organ disease
3–6 months and a chest CT scan performed as needed. and respiratory failure. Several retrospective studies have
At any time, worsening symptoms or hospitalisation reported the use of combination immunosuppression in
should trigger a detailed re-evaluation, which includes patients with anti-MDA5 ILD.117
investigations for infection or pulmonary hypertension. Our approach seems to be in line with guidelines from
Disease can be considered progressive if there are the American College of Rheumatology, British Thoracic
worsening symptoms, a drop in FVC (>5%), a drop in Society, Japanese Respiratory Society, and Japan College
DLCO (>10%), worsening oxygenation, or worsening of Rheumatology published in the past few years. There
parenchymal disease on imaging.104 Progressive disease is also an ongoing European Respiratory Society and
is common and is reported in 18% of patients in the EULAR clinical practice guideline taskforce for manage-
first year.116 ment of connective tissue disease-associated ILD.118–120

Treatment approach Prognosis

Our management approach is based on our experience, The estimated 1-year survival in patients with IIM-ILD
disease acuity, severity, and comorbidities (figure 4). In is greater than 90% and 10-year cumulative survival is
patients with incidental, mild, or subclinical disease with around 80%.121 When compared with patients with IPF,
no symptoms and normal pulmonary physiology, a wait survival is considerably better in IIM-ILD. Patients
and watch approach can be adopted. Patients should be with anti-MDA5 dermatomyositis continue to have
closely monitored for the development of symptoms and a high short-term mortality, with 75% having a 1-year
PFT should be measured every 3–6 months for any signs survival.81,122,123 Acute exacerbations of ILD carry a high
of progression. short-term mortality irrespective of the underlying idio-
In patients with chronic ILD, a step-up approach pathic inflammatory myopathy. The overall age-adjusted
should be used starting with a single agent, monitoring mortality rate for IIM-ILD in the USA has been stable for
response, and stepping up treatment over weeks or the past two decades.124 Factors associated with lower
months. First-line therapy includes moderate dose survival are anti-MDA5 and anti PL-7 antibody positivity,
older age at onset, rapidly progressive ILD, poor response
to therapy, elevated inflammatory markers, usual inter-
Search strategy and selection criteria stitial pneumonia pattern, malignancy, and concomitant
We searched MEDLINE and PubMed for original articles about pulmonary hypertension.125–127
idiopathic inflammatory myopathy-associated interstitial
lung disease published from Jan 1, 1980, to March 1, 2024. Conclusions
Both human and animal studies were considered. We used Idiopathic inflammatory myopathies are a common
the terms “polymyositis” OR “dermatomyositis” OR cause of chronic and rapidly progressive ILD, often with
“antisynthetase” AND “interstitial lung disease”. We screened isolated lung disease. Recognition of idiopathic inflam-
the reference lists of the articles identified for studies that matory myopathy as a cause of ILD is essential since
fulfilled the search criteria that were not identified during the most patients respond to initial immunosuppression
initial search. No measures were used to exclude any studies treatment.
in the literature search for this Review. Only English language The widespread availability of myositis-associated
papers were considered. antibodies and testing can help improve diagnosis and
phenotyping of this disease. Notably, there is an absence

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of reliable biomarkers to guide therapy and monitor the 3 Sun KY, Fan Y, Wang YX, Zhong YJ, Wang GF. Prevalence of
clinical response. Furthermore, better diagnostic interstitial lung disease in polymyositis and dermatomyositis: a meta-
analysis from 2000 to 2020. Semin Arthritis Rheum 2021; 51: 175–91.
criteria for idiopathic inflammatory myopathy should 4 Chen Z, Hu W, Wang Y, Guo Z, Sun L, Kuwana M. Distinct profiles
recognise isolated IIM-ILD (ie, pneumomyositis) and of myositis-specific autoantibodies in Chinese and Japanese
antisynthetase syndrome. patients with polymyositis/dermatomyositis. Clin Rheumatol 2015;
34: 1627–31.
Several treatments continue to be investigated in patients 5 Betteridge Z, Tansley S, Shaddick G, et al. Frequency, mutual
with idiopathic inflammatory myopathy, with many exclusivity and clinical associations of myositis autoantibodies in
ongoing clinical trials. Immunomodulators targeting a combined European cohort of idiopathic inflammatory myopathy
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various pathways are being repurposed for use in IIM-ILD. 6 Pinal-Fernandez I, Casal-Dominguez M, Huapaya JA, et al.
Case reports have shown the benefits of daratumumab A longitudinal cohort study of the anti-synthetase syndrome:
(anti-CD38 antibody), basiliximab (IL-2 receptor antago- increased severity of interstitial lung disease in black patients and
patients with anti-PL7 and anti-PL12 autoantibodies.
nist), tocilizumab (IL-6 antagonist), abatacept (selective Rheumatology 2017; 56: 999–1007.
co-stimulation modulator), anakinra (IL-1 receptor antago- 7 Xie H, Zhang D, Wang Y, et al. Risk factors for mortality in
nist), and ruxolitinib (JAK inhibitor) among others.128,129 patients with anti-MDA5 antibody-positive dermatomyositis:
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recognise CD19+ B cells can lead to their depletion and an 8 Miller FW, Lamb JA, Schmidt J, Nagaraju K. Risk factors and disease
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Contributors
who have died. JAMA Neurol 2021; 78: 948–60.
SS and AP were responsible for conceptualisation, literature search,
12 Liu SW, Velez NF, Lam C, et al. Dermatomyositis induced by
writing the initial draft, critical review, and revision. SC, APF, CF, RY,
anti-tumor necrosis factor in a patient with juvenile idiopathic
YL, SKD, DS, EMW, and JAH were responsible for critical review and
arthritis. JAMA Dermatol 2013; 149: 1204–08.
commentary. KBH was responsible for conceptualisation, critical review,
13 Jones JD, Kirsch HL, Wortmann RL, Pillinger MH. The causes of
and revision of the manuscript. drug-induced muscle toxicity. Curr Opin Rheumatol 2014; 26: 697–703.
Declaration of interests 14 Somani AK, Swick AR, Cooper KD, McCormick TS. Severe
APF received grants and contracts from Mallinckrodt, Novartis, Corbus, dermatomyositis triggered by interferon beta-1a therapy and
Alexion, Priovant, and Pfizer; consulting fees from Biogen, AbbVie, associated with enhanced type I interferon signaling.
Novartis, Bristol-Myers Squibb, and UCB; is on the speakers’ bureau for Arch Dermatol 2008; 144: 1341–49.
AbbVie, Mallinckrodt, Kyowa Kirin, and Novartis; is on the Board of 15 So H, So J, Lam TTO, et al. Seasonal effect on disease onset and
Directors for American Society of Dermatopathology; is the Director at- presentation in anti-MDA5 positive dermatomyositis.
large for the Rheumatologic Dermatology Society; and is on the Front Med 2022; 9: 837024.
OMERACT Shared-Decision Making Committee. YL received consulting 16 Hengstman GJD, van Venrooij WJ, Vencovsky J, Moutsopoulos HM,
fees from Argenx, Immunovant, and UCB; and grant support from van Engelen BGM. The relative prevalence of dermatomyositis and
polymyositis in Europe exhibits a latitudinal gradient. Ann Rheum Dis
Argenx. SKD received grants and contracts from Boehringer Ingelheim
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and United Therapeutics; is on steering committees for Avalyn and
17 Gayed C, Uzunhan Y, Cremer I, Vieillard V, Hervier B.
Bristol-Myers Squibb; is an educational speaker (non-branded) for
Immunopathogenesis of the anti-synthetase syndrome.
Merck; and received royalties from UpToDate. EMW has grants from the Crit Rev Immunol 2018; 38: 263–78.
National Institutes of Health (K08AR080808); serves as a consultant for
18 Lo WS, Gardiner E, Xu Z, et al. Human tRNA synthetase catalytic
AstraZeneca, Cabaletta Bio, Capstan Therapeutics, and Merck; and nulls with diverse functions. Science 2014; 345: 328–32.
receives royalties from UpToDate. KBH received grants or contracts
19 Howard OM, Dong HF, Yang D, et al. Histidyl-tRNA synthetase
from aTyr Pharmaceuticals, Boehringer Ingelheim, Gossamer Bio, and asparaginyl-tRNA synthetase, autoantigens in myositis,
Merck (Acceleron), and United Therapeutics; consulting fees from activate chemokine receptors on T lymphocytes and immature
aTyr Pharmaceuticals, Boehringer Ingelheim, Gossamer Bio, Merck dendritic cells. J Exp Med 2002; 196: 781–91.
(Acceleron), United Therapeutics, Johnson and Johnson (Actelion, 20 Casciola-Rosen L, Andrade F, Ulanet D, Wong WB, Rosen A.
Janssen), and Mistsubishi Pharmaceuticals; is on the speakers’ bureau Cleavage by granzyme B is strongly predictive of autoantigen
for Bayer Healthcare, Boehringer Ingelheim, Johnson and Johnson status: implications for initiation of autoimmunity. J Exp Med 1999;
(Actelion, Janssen), Merck (Acceleron), and United Therapeutics; is on 190: 815–26.
the steering committee for Boehringer Ingelheim, Gossamer Bio, 21 Preger C, Notarnicola A, Hellström C, et al. Autoantigenic
Johnson and Johnson (Actelion, Janssen), Merck (Acceleron), and United properties of the aminoacyl tRNA synthetase family in idiopathic
Therapeutics; and is the co-founder of Zafer Therapeutics. RY is an inflammatory myopathies. J Autoimmun 2023; 134: 102951.
educational speaker for Boehringer Ingelheim. All other authors declare 22 Rodero MP, Crow YJ. Type I interferon-mediated monogenic
no competing interests. autoinflammation: the type I interferonopathies, a conceptual
overview. J Exp Med 2016; 213: 2527–38.
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