|Ahead of print publication
Picking interstitial lung disease out of the myositis haystack
Jennifer Hannah1, Harsha Gunawardena2
1 Academic Rheumatology, King's College London; Department of Rheumatology, King's College Hospital NHS Foundation Trust, London, UK
2 Department of Rheumatology, North Bristol NHS Trust; Academic Rheumatology, University of Bristol, Bristol, UK
|Date of Submission||16-Jul-2020|
|Date of Acceptance||21-Jul-2020|
Department of Rheumatology, North Bristol NHS Trust, Southmead Hospital, Bristol, BS10 5NB
Source of Support: None, Conflict of Interest: None
Interstitial lung disease (ILD) is a common manifestation of the connective tissue disease (CTD) associated idiopathic inflammatory myopathies (IIM). Although patients may be diagnosed as having polymyositis (PM) or dermatomyositis (DM) under the IIM spectrum, it is quite clear that risk, pattern of ILD and disease course between subgroups of patients is different. The natural history may be asymptomatic and slowly progressive or stable, chronically progressive or fulminant rapidly progressive depending on ILD subtype. ILD can be the initial presenting feature and this can make recognition of an underlying CTD-IIM overlap more difficult with some patients initially misdiagnosed with idiopathic pulmonary fibrosis. Therefore, early recognition and characterization of patients can influence management and prognosis. It is clear than certain clinical and serological features phenotype patients into more specific CTD-IIM ILD subgroups. A number of myositis-CTD overlap associated antibodies and their clinical patterns have been described over the last few years. The hallmark CTD-IIM ILD subgroup is antisynthetase syndrome, characterized by autoantibodies to tRNA synthetases. Muscle weakness is not universally present and parenchymal lung disease can predominate. Anti-MDA5 DM has a distinct cutaneous pulmonary phenotype and is significantly associated with the development of ILD with different patterns seen in different ethnic groups. Other autoantibodies associated with ILD include those targeting nucleolar autoantigens such as anti-PM-SCL, again with characteristic syndromes. Picking ILD out of the “myositis haystack” can be complex. This heterogeneous disease group requires robust multidisciplinary collaboration between rheumatologists, pulmonologists, thoracic radiologists, and histopathologists to bring together clinical assessment to reach a diagnostic conclusion so optimal outcomes can be achieved.
Keywords: Autoantibodies, connective tissue disease, dermatomyositis, interstitial lung disease, myositis
| Introduction|| |
Connective tissue disease (CTD) idiopathic inflammatory myopathies (IIMs) are a broad and complex group of autoimmune disorders characterized by varying degrees of skeletal muscle and systemic inflammation. They are associated with a myriad of extra-muscular features including inflammation in skin, joints, heart, and lungs. Interstitial lung disease (ILD), a fibro-inflammation of the lung parenchyma, can present as chronic, slowly progressive dyspnea or cough, or more unusually as acute fulminant respiratory failure. An ILD diagnosis is reached through a combination of clinical history, physical examination, pulmonary function tests (PFT), and high-resolution computerized tomography (HRCT).
CTD-IIMs are rare diseases. The overall incidence is approximately 11 in 1,000,000 person years with a prevalence of 14 in 100,000. Estimates of the prevalence of ILD in retrospective cohorts of myositis patients vary widely, ranging from under 10% to over 60%.,,,, This is partly due to selection bias and differences in diagnostic methodologies. A recent prospective study indicated that as many as 65% of newly diagnosed myositis patients have evidence of radiological signs of ILD or a restrictive pulmonary defect, although a third of these were asymptomatic., The presence of ILD is one of the biggest predictors of mortality after excluding paraneoplastic IIM.,, A large US cohort study found patients with CTD-IIM ILD are twice as likely to die than those without ILD.
Many patients diagnosed with CTD-associated ILD will have a classifiable CTD at the time of diagnosis, however, in up to 25% of cases are undifferentiated but may transition to classifiable CTD over time. In idiopathic interstitial pneumonia without any CTD features, 19% subsequently developed a CTD, with IIM overlap and rheumatoid arthritis being the most common subsequent diagnoses. The historic approach of dividing patients into polymyositis (PM), dermatomyositis (DM), and clinically amyopathic dermatomyositis (CADM) is an over simplistic starting point to help differentiate the natural history of the disease. Within these groups, clusters of patients will follow different disease courses that warrant separate consideration, for example, anti-synthetase syndrome and specific DM phenotypes. Patients have shared clinical features including muscle inflammation, weakness, skin features, and fatigue, but dominant features can vary significantly., Given the substantial impact on morbidity and mortality, early identification of those at risk of significant ILD as a complication of IIM, and ability to prognosticate based on IIM subgroup is beneficial to target therapy early against this potentially critical complication.
| Standard Assessment|| |
The natural course of lung disease in patients with myositis-associated ILD divides into three groups: those with acute onset, rapidly progressive symptoms, those with chronic, stable or slowly progressive symptoms, and those who remain asymptomatic but have abnormal chest imaging or PFTs.,, Respiratory symptoms or signs are not a reliable way of detecting early ILD. Mild pulmonary impairment may be asymptomatic for some time due to subconscious adaptations to reduce pace and intensity of exertion. The expected auscultatory findings of inspiratory crackles/rales are not always present. Almost 30% of patients with abnormal imaging or PFTs are asymptomatic, yet two-thirds of patients without any objective signs of ILD on HRCT or pulmonary function testing describe either cough or dyspnea.
Pulmonary function tests
The large proportion of initially asymptomatic patients means that it is important to actively search for lung involvement. PFTs typically demonstrate a restrictive ventilatory defect with reduced total lung capacity, residual volume, forced expiratory volume in 1 s (FEV1), and forced vital capacity (FVC). The FEV1/FVC ratio will be normal or high, and the diffusing capacity for carbon monoxide (DLco) will be low. Decreased DLco appears to be the most sensitive test, however, there is large interpersonal variability and therefore comparison to a historic baseline for the patient is the most reliable method. An isolated decreased DLco is not specific and may also be seen in other conditions such as pulmonary hypertension or congestive heart failure. PFTs are also a useful tool for monitoring progression in CTD-ILD. A study in systemic sclerosis-associated ILD showed that a decline in FVC of 10% and in DLco and KCO of 15% over 1 year was predictive of a poor outcome. We also recommend baseline and serial 6 min walk tests alongside PFT. Decline in predicted walk distance or desaturation on exertion can indicate disease progression and other coexistent pathology such as subclinical chronic thromboembolic disease and/or secondary pulmonary hypertension.
High-resolution computerized tomography
While plain chest radiographs may demonstrate reticular changes, HRCT scans are more sensitive and specific at detecting ILD and radiological patterns can predict histopathological subtype. In patients with normal or minimally abnormal radiographs, performing the HRCT (we recommend with prone views) improve the sensitivity further. Common HRCT findings include bilateral reticulations, irregular linear opacities, ground glass opacities, and consolidation. In more advanced fibrosis, honeycombing, reticulations, and traction bronchiectasis may be seen. HRCT can also be used to grade disease extent. In idiopathic pulmonary fibrosis and systemic sclerosis-associated ILD, extent of lung involvement has been used to create grading scores that correlate with short- and long-term mortality. However, in myositis-ILD, no association has been found with radiological extent and mortality. HRCT ILD categorization requires multi-disciplinary collaboration to combine radiological, clinical features, and in some cases pathological correlation to reach a diagnosis.
The role of lung biopsy?
Histopathological findings have previously been considered the reference standard for diagnosis of idiopathic pulmonary fibrosis. It is increasingly recognized that sampling error, observer variation and a lack of clear association of histopathological findings and survival rates means that they do not always provide a complete picture. The diagnostic ability of transbronchial lung biopsy is limited by the fact the lung bases are not accessible through this route and biopsy sizes obtained are small and distorted by crush artefact. Diagnostic yield from transbronchial lung biopsy is <30%. A newer technique of transbronchial lung cryobiopsy shows an improved yield of >70%, as a larger sample can be obtained and the tissue architecture is preserved, however, it is not yet widely used. Thoracotomy or videothoracoscopy is an alternative way to source surgical lung biopsies but carry a moderate complication risk including a 4% mortality risk in elective cases. Lung biopsy is not routinely indicated in myositis-associated ILD because with careful clinical recognition, robust antibody testing, and CT interpretation, diagnosis can usually be made confidently. Biopsy should be considered in atypical or refractory cases.
The role of bronchoalveolar lavage?
Patients with acute symptoms provide a concerning diagnostic challenge. Differential diagnoses include ILD progression, pulmonary edema, drug hypersensitivity, infection, and alveolar hemorrhage. Myositis patients may have multiple risk factors for infection including concurrent immunosuppressant medication, diaphragmatic weakness, and dysphagia leading to aspiration. Differentiating between rapid lung inflammation and other causes can difficult. Accurate diagnosis of patients approaching respiratory failure may require bronchoalveolar lavage (BAL) to exclude other pathology. Where bronchoalveolar lavage is performed, neutrophilia is associated with a poor prognosis. BAL with cellular differential can also be an useful tool in patients where it remains uncertain following HRCT review whether there is a potentially reversible inflammatory component (lymphocytic predominance on lavage) or fixed fibrosis.
| Interstitial Lung Disease (Interstitial Pneumonia) Subtypes in Connective Tissue Disease-Idiopathic Inflammatory Myopathies|| |
Nonspecific interstitial pneumonia
Up to 80% of biopsy proven myositis associated ILD is in a nonspecific interstitial pneumonia histological pattern. Nonspecific interstitial pneumonia (NSIP) can be divided into cellular or “fibrotic.” Cellular NSIP is characterized by alveolar septal infiltrates with a predominance of inflammatory lymphocytes and plasma cells, whereas fibrotic NSIP shows accumulation of collagen leading to expansion of the alveolar and intra-lobular septae, peribronchial interstitium, or visceral pleura. HRCT may demonstrate ground glass opacities and/or significant reticular patterns[Figure 1]a.
|Figure 1: (a) Non-specific interstitial pneumonia (b) Usual interstitial pneumonia (c) Organising pneumonia (d) Acute interstitial pneumonia|
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Usual interstitial pneumonia
UIP shows primarily fibrotic change with only moderate inflammatory component. There is heterogeneous collagen deposition with destruction of the underlying lung architecture. Fibroblastic foci and histologic honeycombing are seen. HRCT classically shows a basal predominance of subpleural coarse reticulations, honeycombing, and traction bronchiectasis with minimal ground glass opacities. Honeycombing described a pattern of clustered cystic airspaces with well-defined walls and variable diameters. Prognosis of UIP-CTD-associated ILD appears to be preferable to UIP-IPF, with stabilization of disease progression with immunomodulatory therapy (personal observation), but may be less responsive than NSIP [Figure 1]b.
Organizing pneumonia (OP) accounts for up to 20% of IIM-ILD cases and is associated with a good prognosis. OP can overlap with NSIP. In OP, there is focal granulation tissue in the alveoli and their ducts which can progress to block smaller airways. HRCT demonstrates patchy areas of ground glass opacification, consolidation in arcade pattern and later stages fibrosis [Figure 1]c.
Acute interstitial pneumonia/diffuse alveolar damage
Acute interstitial pneumonia (or diffuse alveolar damage) in IIM-ILD is uncommon, but associated with rapidly progressive disease with poor prognosis., There is diffuse interstitial inflammation with edema and hyaline membrane production resulting in organizing fibrosis. HRCT pattern demonstrates extensive bilateral, symmetrical ground glass opacities, air-space consolidation, and dilated airways. There can be parenchymal architectural distortion with traction bronchiectasis, which correlates with disease duration [Figure 1]d.
Approach to autoantibody testing
Anti-nuclear antibody (ANA) is commonly used as screening for the presence of CTD; however, detection and interpretation in myositis patients can be limited. Standard extractable nuclear antibody panels (ENA) will only show up a subgroup of patients for example those with anti-Jo1 or anti-U1RNP positivity. ANA testing must be combined with comprehensive history and examination for any associated dermatological features or muscle weakness in any cases of diffuse lung disease of unknown cause. Negative ANA (or positive ANA with negative ENA) should not deter further testing in those with clinical features of myositis or those with ILD with any associated CTD features. However, around 20%–30% of IIM patients have no identified associated autoantibody.
Robust autoantibody screening using indirect immunofluorescence (IIF) on human epithelial cell lines (HEp-2) should be used first line to allow description of the staining distribution, which provides further clues to aid identification of the specific autoantigen involved and thereby the likely clinical phenotype of the patient. Further identification using confirmatory immunoassays is required. Immunoprecipitation is the gold standard but is complex and expensive and only available in specialist research laboratories. It is not practical in hospital practice, where throughput and rapid detection are needed to aid clinical management. A number of commercial tests are now available including line blots, dot blots, and enzyme-linked immunosorbent assays (ELISAs). However, a small number of CTD-ILD-associated autoantibodies are not present on the line blot and many not available by ELISA. Moreover, studies have shown the reliability of these commercial assays to detect myositis or CTD-ILD antibodies is dependent specificity., Clinicians should be mindful that the staining pattern observed on HEp-2 IIF should correlate with the immunoassay result, because false positives on the latter platforms are common. For example, cytoplasmic stain on HEp-2 IIF for amino-acyl-tRNA synthetases or MDA5 and nucleolar pattern for proteins such as PM-scl100/75. Careful serological interpretation with clinical correlation is mandatory.
| [Figure 2]"> Connective Tissue Disease-Idiopathic Inflammatory Myopathies Interstitial Lung Disease Phenotypes [Figure 2]|| |
|Figure 2: Connective tissue disease-idiopathic inflammatory myopathies interstitial lung disease phenotypes|
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Clinical risk factors
Traditional risk factors for the development of myositis-ILD have also been evaluated and include ethnicity, those with amyopathic disease, systemic features such as fevers and marked acute phase response at presentation. CTD-IIM patients with ILD are more likely to have nailfold capillaroscopic microangiopathy showing enlarged capillary loops. Statistically significant association has not been found with sex, age, presence of muscle or dermatological manifestations, esophageal dysfunction, or Raynaud's phenomenon between patients with and without ILD. Older age at onset (>45 years) is an independent risk factor for developing ILD excluding the autoantibody group. The presence of arthritis/arthralgia has also been associated with ILD, but this may be related to autoantibody subtype and not an independent risk factor.,
Anti-synthetase syndrome is a well-defined subset of CTD-IIM overlap, hallmark features are ILD, fever, nonerosive inflammatory arthritis, Raynaud's phenomenon, and mechanic's hands., Currently, 8 anti-synthetases have been described: anti-Jo1 (anti-histidyl, anti-PL7 (anti-theronyl), anti-PL12 (anti-alanyl), anti-OJ (anti-isoleucyl), anti-EJ (anti-glycyl), anti-KS (anti-asparaginyl), anti-Zo (anti-phenylalanyl), and anti-Ha (anti-tyrosyl). Anti-Jo1 is the most commonly identified, but in part this may be due to the natural history of anti-synthetase syndrome, which is not universal and dependent on their initial presenting manifestation. For example, a Japanese study demonstrating the heterogeneity within anti-synthetase syndrome found that muscle inflammation associates with anti-Jo-1, anti-EJ, and anti-PL7. Heliotrope rash and Gottron's lesions were seen more in anti-Jo1, anti-EJ, anti-PL12, and anti-PL7, whereas Raynaud's phenomenon was more common in anti-PL7 and anti-PL12 patients.
The concept of “pre or limited” anti-synthetase syndrome (seen in up to 25% of patients) needs to be appreciated, where ILD is the first presentation and may dominate the clinical picture so that the associated clinical features are not recognized., Isolated ILD at diagnosis is associated with poor survival. This could be due to patients being labeled as IPF, where clinical features such as mechanic's hands are subtle and hence over-looked. Studies have demonstrated that anti-PL12 and anti-PL7 are associated with more prevalent and severe lung involvement, frequently without any muscle involvement., These patients can have more of a UIP pattern on HRCT and thus can be misdiagnosed at presentation with IPF, which can adversely affect prognosis. The identification of anti-Ro60/52 in ILD only cohorts can also alert the treating physician to look for limited anti-synthetase syndrome. The dual positivity has also been shown to be associated with severe ILD as measured by CT scoring and FVC% and DLco%. Overall survival is reportedly poorer in anti-synthetase syndrome than in other IIM groups, which is likely to be related to their higher incidence of ILD, highlighting the important of early recognition and intervention.
Anti-MDA5 – a cutaneous pulmonary syndrome
Anti-MDA5 antibodies are found in a subgroup of CTD-IIM who are largely clinically amyopathic (CADM). Several studies have linked CADM to worse outcomes, which may be due to a high rate of this autoantibody amongst CADM patients.,, Anti-MDA5 has been shown to be associated with rapidly progressive ILD and high mortality rates in multiple Asian studies. The role of anti-MDA5 in ILD progression is further evidenced by the demonstration of an autoantibody titer-related response. The mean pretreatment titer of anti-MDA5 in patients with rapidly progressive ILD was lower in patients who responded to therapy and survived than in those who did not respond and died. The titer has also been demonstrate to reduce in responders. Other markers of severe lung damage in this group of patients include significant acute phase response with hyperferritinemia, and serum interleukin-18 concentrations. These findings have not been replicated in the European and American studies, but lung disease patterns appear to be different and less aggressive with higher rates of muscle involvement. NSIP and/or OP appears more prevalent with favorable prognosis suggesting anti-MDA5 patients are a heterogeneous group, influenced by genetic or environmental factors.,,
Anti-MDA5 patients have a distinct mucocutaneous phenotype associated with severe vasculopathy. It is common to see mucous membrane or skin ulceration, tender palmar papules, and Gottron's papules., They can also present with features in common with anti-synthetase patients such as inflammatory arthritis, Raynaud's, and fever. Therefore, the possibility of anti-MDA5 disease should be considered in anyone presenting with rapidly progressing ILD or CTD-IIM ILD patients with ulcerative skin disease.
Anti-PM-Scl syndrome (myositis-systemic sclerosis overlap)
Anti-PM-Scl antibodies are found in 20%–25% patients with overlap features with systemic sclerosis, and less frequently in isolated IIM (5%–8% cases). They are more commonly detected in European patients than in North American or Japanese groups. The clinical phenotype of anti-PM-Scl patients can be similar to anti-synthetase syndrome with mechanic's hands, Raynaud's phenomenon, and joint involvement being common features, and ILD occurs at a similar frequency., Linked with high rates of esophageal involvement, aspiration pneumonia is a frequent complication in this cohort. Studies have reported better ILD prognosis in anti-PM-Scl patients when compared to other systemic sclerosis subgroups.,, In addition, outcomes also appear favorable compared to anti-synthetase syndrome, with higher frequency of treatment responsive OP ± NSIP compared to fibrotic NSIP or UIP (personal observation).
Other overlap idiopathic inflammatory myopathies interstitial lung disease syndromes-anti-U3RNP and anti-RuvBL1/2
Antibodies against the U3RNP complex are seen in patients with features overlapping with diffuse cutaneous systemic sclerosis. They present younger with more progressive disease. These patients generally have inflammation within the muscles, and are also at risk of renal, cardiac, gastrointestinal complications with around one third developing ILD. Antibodies against the RuvBL1/2 proteins have been recently described in a cohort of SSc overlap patients with myositis features. ILD has been identified in approximately 50% of these patients. This group appear phenotypically different due to being older at time of onset, mostly male and with diffuse skin thickening.
Interstitial pneumonia with autoimmune features
The IPAF criteria were first described in 2015, sits on a continuum between IPF and CTD-ILD and aims to detect patients with non-IPF ILD., The criteria describe clinical, serological and morphological domains which highlight “undifferentiated” autoimmune CTD features in a patient with ILD. A recent study documented that patients with defined CTD-ILD were women, with overlap manifestations and presence of rheumatoid factor, anti-cyclic citrullinated peptide autoantibody, ANA positivity, or anti-MDA5 in comparison to IPAF. Of note, IPAF patients were more likely to present with respiratory symptoms. A clear benefit of the IPAF concept is to emphasize the importance of early detection to general pulmonologists and rheumatologists.
In our opinion, the construct IPAF describes patients whose predominate manifestation is lung disease and are simply a forms-frustes CTD. In this respect, traditional rheumatological CTD criteria appear limited. For example, a patient fulfilling IPAF criteria with once clinical domain (mechanic's hands), one serological domain (anti-PL12) and one morphological domain (UIP-ILD) have “pre or limited” anti-synthetase syndrome, a concept introduced earlier in this review. In addition, review of the current nomenclature, i.e., anti-synthetase autoantibodies are not “myositis-specific” but “CTD-ILD-specific” will further refine understanding. The key is collaboration between CTD and ILD physicians to bring together IPAF and traditional CTD diagnostic criteria.
Both CTD-ILD and IPAF patients have a better prognosis than those with IPF. IPAF patients have less ILD exacerbations and better mortality compared to IPF. Similar observations have been seen in CTD-ILD (anti-synthetase syndrome) compared to IPF survival, regardless if patients had coexistent myositis or not., In addition, UIP may have a better survival when associated with CTD compared to UIP-IPF. This again highlights why it is important to distinguish IPF from no-IPF ILD (CTD or IPAF), as natural history of disease and treatment approaches differ between subgroups.
| Summary|| |
The opportunity for multidisciplinary working to improve patient outcomes
CTD-IIM-associated ILD is a significant predictor of morbidity and mortality and it is therefore of vital importance it is identified and treated early. While there have been many suggestions regarding how to identify those at highest risk through their clinical phenotype, serological profile, radiological or histopathological findings, vigilance is essential in all myositis patients as early ILD can be asymptomatic. It is equally important to consider CTD-IIM in the presence of new ILD diagnoses, where other myositis associated features may be absent or subtle and masked by clinician and patient focus on the lung disease. This highlights the importance of moving away from the definitions of PM and DM to ensure we are considering CTD-IIM overlap-associated ILD even in patients not displaying classical proximal muscle weakness or DM skin signs. Clinical and serological association studies in different geographic areas and ethnic populations have shown some differences, which suggests genetics and environmental factors play a role in the development and severity of disease.,, This may lead to CTD-IIM ILD being underdiagnosed in different ethnic cohorts. The availability of collaborative working and specialist testing including robust ANA IIF HEp-2 alongside myositis-ILD autoantibodies may be limited in developing countries. Timely diagnosis is vital so that opportunities to start treatment with immunomodulatory medication are not missed. There is a real opportunity for clinicians to adopt a collaborative multidisciplinary approach to ensure optimal management for this group of patients [Figure 3].
|Figure 3: Collaborative multidisciplinary approach to connective tissue disease-idiopathic inflammatory myopathies interstitial lung disease|
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Anonymized HRCT images shown in [Figure 2] are obtained from Dr. Gunawardena's CTD-ILD patient cohort with permission.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]