Pulmonary complications cause significant morbidity and mortality in the idiopathic inflammatory myopathies. Advances in biomarker discovery have facilitated clinical phenotyping, allowing investigators to better define at-risk patient subsets and to potentially gauge disease activity. This serologic characterization has complemented more traditional assessment tools. Pharmacologic management continues to rely on the use of corticosteroids, often in combination with additional immunosuppressive agents. The rarity of myositis-associated interstitial lung disease and lack of controlled trials have limited analyses of treatment efficacy, mandating the development of standardized outcome measures and improvement of data sharing between disciplines.
Key points
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Up to 75% of patients with inflammatory myopathy develop pulmonary involvement in the form of interstitial lung disease (ILD). It is an independent predictor of mortality, and the number 1 cause of disease-related death in idiopathic inflammatory myopathies.
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Secondary pulmonary complications include aspiration pneumonia, opportunistic infections, spontaneous pneumomediastinum, pulmonary hypertension, ventilatory failure caused by neuromuscular weakness, and drug-induced pneumonitis.
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The antisynthetase syndrome is characterized by the presence of anti-ARS (anti–aminoacyl transfer RNA synthetase) antibodies in combination with ILD and/or myositis. Anti–Jo-1 is the most common anti-ARS antibody and is associated with a high risk of ILD.
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Nonspecific interstitial pneumonia is the most common histopathologic diagnosis, but ILD can also be in the form of usual interstitial pneumonia, cryptogenic organizing pneumonia, diffuse alveolar hemorrhage, and acute respiratory distress syndrome.
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Corticosteroids are the mainstay of therapy, but additional immunosuppressive agents are often required.
Introduction
The idiopathic inflammatory myopathies (IIMs) are immune-mediated, systemic inflammatory diseases that manifest with varying degrees of muscle inflammation. They primarily include polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). There are also patients with amyopathic dermatomyositis who present with the hallmark skin findings of DM, but lack significant muscle involvement. The presence of circulating antibodies in the serum of affected patients along with muscle tissue specimens containing T cells, macrophages, dendritic cells, B-lymphocytes, and plasma cells confirm that these diseases are immune mediated. Illustrating the systemic nature of IIM, these inflammatory processes often extend to other organ systems, most notably the lungs.
There are multiple secondary pulmonary complications associated with the inflammatory myopathies, but a significant number of patients are also affected with an intrinsic form of interstitial lung disease (ILD). Mills and Mathews first described ILD in a patient with dermatomyositis in 1956, and studies now estimate that 21% to 78% of patients with IIM have pulmonary involvement. ILD has not only been associated with a higher morbidity and mortality in this population, but has also proved to be an independent risk factor for death. In fact, pulmonary involvement is the leading cause of disease-related death among patients with IIM and therefore should be prioritized as part of ongoing management and future investigations.
Introduction
The idiopathic inflammatory myopathies (IIMs) are immune-mediated, systemic inflammatory diseases that manifest with varying degrees of muscle inflammation. They primarily include polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). There are also patients with amyopathic dermatomyositis who present with the hallmark skin findings of DM, but lack significant muscle involvement. The presence of circulating antibodies in the serum of affected patients along with muscle tissue specimens containing T cells, macrophages, dendritic cells, B-lymphocytes, and plasma cells confirm that these diseases are immune mediated. Illustrating the systemic nature of IIM, these inflammatory processes often extend to other organ systems, most notably the lungs.
There are multiple secondary pulmonary complications associated with the inflammatory myopathies, but a significant number of patients are also affected with an intrinsic form of interstitial lung disease (ILD). Mills and Mathews first described ILD in a patient with dermatomyositis in 1956, and studies now estimate that 21% to 78% of patients with IIM have pulmonary involvement. ILD has not only been associated with a higher morbidity and mortality in this population, but has also proved to be an independent risk factor for death. In fact, pulmonary involvement is the leading cause of disease-related death among patients with IIM and therefore should be prioritized as part of ongoing management and future investigations.
Secondary pulmonary complications
Although ILD affects many patients with inflammatory myopathy, there are secondary pulmonary complications to consider as well. These complications include aspiration pneumonitis/pneumonia, spontaneous pneumomediastinum, opportunistic infections, pulmonary hypertension, ventilatory failure caused by muscle weakness, and drug-induced pneumonitis ( Table 1 ).
| Secondary Pulmonary Complication | Prevalence in IIM (%) |
|---|---|
| Aspiration pneumonia/pneumonitis | 15–20 |
| Opportunistic infection | 11–21 |
| Pulmonary hypertension | ∼8 |
| Spontaneous pneumomediastinum | ∼8 |
| Ventilatory failure caused by neuromuscular weakness | Unknown |
| Drug-induced pneumonitis | Unknown |
Aspiration Pneumonitis
Among patients with PM/DM, the lung is the most common site of pyogenic infection, which is usually secondary to aspiration pneumonia. One study found that aspiration pneumonia occurs in up to one-fifth (15%–20%) of patients with PM/DM. Marie and colleagues studied 279 patients with inflammatory myopathy and found that two-thirds of pyogenic infections were related to aspiration pneumonia. One-fourth of these patients also had ILD on their chest imaging, and 17% of these patients died because of pneumonia-related complications within 1 year of PM/DM diagnosis. These findings suggest a high prevalence of aspiration that represents a potentially modifiable risk factor for worsening pulmonary outcomes.
Associated with this problem of aspiration pneumonitis that may be caused by nasopharyngeal dysfunction, studies have proved that patients with ILD have a higher prevalence of abnormal acid exposure in the proximal and distal esophagus compared to those without ILD. Although this problem does not seem to stem (directly) from the proximal esophageal dysfunction that can complicate inflammatory myopathy, it is likely prevalent among patients with IIM. Many of these patients do not have symptoms of gastroesophageal reflux ; although it is standard for proton pump inhibitor therapy to be given to help prevent microaspiration, future studies are needed to prove long-term benefit.
Opportunistic Infections
The treatment of active inflammatory myopathy includes immunosuppressive medications and, as a result, patients undergoing pharmacotherapy are more prone to infection. The opportunistic lung infections are most commonly caused by fungi, which accounted for about 40% of cases in a study conducted by Marie and colleagues in 2011. However, although the guidelines for Pneumocystis jiroveci pneumonia (PCP) prophylaxis are clear when it comes to patients with human immunodeficiency virus, they are not as straightforward for other immunosuppressed populations.
Steroids are the first-line therapy for active inflammatory myopathy and are often given in high doses to achieve a clinical response. Enomoto and colleagues conducted a retrospective analysis of 74 patients with idiopathic ILD to assess the incidence of PCP in those patients treated with corticosteroids. All of the patients received more than 0.5 mg/kg of prednisolone with or without additional immunosuppressants for more than 3 weeks. The mean dose of glucocorticoids was 37 mg daily. Seven out of 74 patients developed PCP, but none of those who were taking Bactrim as prophylaxis were affected. Multiple other studies have shown a significant risk of PCP in patients on biologic agents and disease-modifying antirheumatic drugs (complementing some of the older literature regarding the risk of PCP in patients with granulomatosis with polyangiitis/Wegener’s receiving a combination of corticosteroids and cyclophosphamide), indicating that primary prophylaxis should be considered in this population despite the lack of clear guidelines.
Congestive Heart Failure
Cardiac muscle tends not to be affected directly by the primary disease process because of inherent differences between cardiac and skeletal muscle. However, many of these patients have significant comorbidities at the time of diagnosis, or develop them during the course of disease. Congestive heart failure should therefore be considered in any patient presenting with dyspnea and bilateral interstitial infiltrates.
Pulmonary Hypertension
Pulmonary hypertension affects approximately 8% of patients with PM/DM and correlates independently with a lower 3-year survival rate. Although pulmonary hypertension can develop in the later stages of ILD secondary to significant fibrosis and chronic hypoxemia, at least one study showed that ILD was not significantly more prevalent in those with pulmonary hypertension than in those without, suggesting that there may be an intrinsic vascular component. A smaller case series of 20 patients showed that 20% had pulmonary arterial medial and intimal hypertrophy on biopsy, hinting at possible pathogenesis. Despite these considerations, studies have not yet proved any clear benefit to standard pulmonary vasodilator therapy in this patient population; nevertheless, the use of two-dimensional echocardiography to screen for pulmonary hypertension may be of some prognostic value.
Ventilatory Failure Caused by Muscle Weakness
In severe cases of inflammatory myopathy, patients may have pharyngeal and respiratory muscle weakness, which ultimately result in respiratory failure. Weakness of the respiratory musculature can be objectively assessed through measurement of the maximal inspiratory force (MIF) and maximal expiratory force (MEF). Although corticosteroids and other immunosuppressive agents are the mainstays of treatment of underlying myositis, not all patients respond. Maintenance therapy with noninvasive positive pressure ventilation improves quality of life, and, in severe cases, tracheostomy with home mechanical ventilation can be lifesaving.
Spontaneous Pneumomediastinum
Spontaneous pneumomediastinum is a rare complication of ILD that can result in free air around mediastinal structures. One study estimated its prevalence to be approximately 8.3% among patients with PM/DM, which is the most frequent connective tissue disease with which it is associated. This complication seems to occur more frequently in male patients, contrasting with the overall female gender predilection of PM/DM. Each case reviewed had concurrent ILD, suggesting that this is a risk factor for spontaneous pneumomediastinum. The overall mortality is thought to be near 34%, with almost one-fourth of cases resulting in death within 1 month of onset.
Drug-induced Pneumonitis
In patients with inflammatory myopathy, multiple different immunosuppressive agents are used, some of which can produce interstitial inflammation that is difficult to distinguish from ILD associated with the underlying disease. Methotrexate and cyclophosphamide are prime examples of medications that have been associated with drug-induced ILD.
Methotrexate-induced pneumonitis can occur at any dose and at any time during the course of treatment, although it most often occurs during the first year of therapy and usually resolves with discontinuation of the drug. Cyclophosphamide-induced pneumonitis presents in 2 different ways: either as an acute pneumonitis early in the course of treatment or as a chronic, progressive process after prolonged therapy. The chronic form tends to persist or advance despite discontinuation of therapy, whereas the acute form may improve gradually after drug discontinuation. Beyond methotrexate and cyclophosphamide, many of the newer antimetabolites (eg, leflunomide) and biologic agents have also been associated with pneumonitis, effectively highlighting the complexity of pharmacologic management in IIM.
Interstitial lung disease
Up to 75% of patients with inflammatory myopathy develop intrinsic pulmonary involvement in the form of ILD, a complication that is largely responsible for the morbidity and mortality of this disease. ILD can present insidiously or acutely, reflecting a variety of pathologic processes/histopathologic abnormalities.
Clinical Presentation
Most patients with ILD present with cough, dyspnea, and varying degrees of hypoxemia. This condition can develop gradually over weeks to months, or progress more rapidly with respiratory failure developing over days to weeks; in severe cases, patients present with acute respiratory distress syndrome. Overall, the relative frequency of acute versus chronically progressive disease seems to be evenly distributed in myositis-associated lung disease. ILD precedes the diagnosis of DM/PM in approximately 13% to 37.5% of patients.
Serum Biomarkers
Several clinical subsets of myositis associated with ILD exist as independent entities or as part of overlap syndromes defined by additional features of systemic lupus erythematosus, Sjögren syndrome, systemic sclerosis, or mixed connective tissue disease. In many instances, these clinical subsets are marked by antibodies directed toward various cytoplasmic and/or nuclear antigens. The nomenclature is variable, but includes myositis-associated antibodies such as ANA (52%), anti-SSA/SSB (12%), anti–U1-RNP (11%), anti-PM/Scl, and anti-Ku. Although these antibodies are not specific for PM/DM and can be found in other autoimmune disorders, other antibodies are more exclusive to myositis and are therefore referred to as myositis-specific antibodies (MSAs). MSAs encompass anti–signal recognition particle complex (anti-SRP), anti–Mi-2, anti–aminoacyl transfer RNA (tRNA) synthetase (anti-ARS), anti–CADM-140/MDA-5, and anti-155/140 (transcription intermediary factor 1 [TIF1γ]) antibodies ( Table 2 ).
| Antibody | Target | Subset | Phenotype |
|---|---|---|---|
| Jo-1 | Histidyl-tRNA Synthetase | PM/DM | Antisynthetase syndrome |
| CADM-140 | MDA-5 | DM | Amyopathic, ILD, cutaneous ulceration |
| SAE | SUMO | DM | ILD, dysphagia |
| Mi-2 | NuRD | DM | Shawl, V-neck, Gottron sign |
| MJ | NXP-2 | JDM | Calcinosis, ulceration |
| p155/140 | TIF1-γ | DM, JDM | Severe skin disease, malignancy a |
| SRP | 72 kDa and 54 kDa subunits of SRP | PM | Severe/refractory myositis |
Of the MSAs, antibodies targeting various tRNA synthetases are perhaps most strongly linked with the presence of ILD. Aminoacyl tRNA synthetases (ARSs) catalyze the binding of amino acids to corresponding transfer RNAs as part of ribosomally mediated protein translation in the cytoplasm. Although 20 different tRNA synthetases exist, only 8 have been identified as autoantibody targets to date: anti–Jo-1, anti–PL-7, anti–PL-12, anti-EJ, anti-OJ, anti-KS, anti-Zo, and anti–tyrosyl-tRNA synthetase ( Table 3 ). These antibodies collectively define the antisynthetase syndrome that is marked by the variable combination of myositis, arthritis, fever, Raynaud phenomenon, mechanic’s hands, and ILD.
| Antisynthetase Antibodies | Target Antigen | Prevalence in IIM (%) |
|---|---|---|
| Anti–Jo-1 | Histidyl-tRNA synthetase | 20–30 |
| Anti–PL-7 | Threonyl-tRNA synthetase | <5 |
| Anti–PL-12 | Alanyl-tRNA synthetase | <5 |
| Anti-EJ | Glycyl-tRNA synthetase | <5 |
| Anti-OJ | Isoleucyl-tRNA synthetase | <5 |
| Anti-KS | Asparaginyl-tRNA synthetase | <1 |
| Anti-Zo | Phenylalanyl-tRNA synthetase | <1 |
| Anti-YRS | Tyrosyl-tRNA synthetase | <1 |
Related posts:
Lung Disease in Rheumatic Diseases
Demystifying Lung Disease in the Rheumatic Diseases
Determining Respiratory Impairment in Connective Tissue Disease–Associated Interstitial Lung Disease
Lung Disease in Rheumatoid Arthritis
Interstitial Lung Disease in Scleroderma
Management of Connective Tissue Disease–associated Interstitial Lung Disease
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