Phenotypic Clusters and Survival Analyses in Interstitial Pneumonia with Myositis-Specific Autoantibodies

Abstract Background: Interstitial pneumonia (IP) is one of the common pulmonary complications of idiopathic inflammatory myopathy (IIM), among which myositis-specific autoantibodies (MSA) are specific for IIM diagnosis and prognosis. However, IP patients with MSA (MSA-IP) have not been well described. The study aimed to explore the phenotypic clusters and prognosis of MSA-IP patients.Methods: A total of 124 MSA-IP patients were prospectively enrolled for analysis. Serum MSA were detected using immunoprecipitation. Radiographic patterns of IP were determined according to the classification of idiopathic IPs. The clusters of MSA-IP patients were identified using cluster analysis. Potential risk factors of acute onset and short-term prognosis were also analyzed. Results: There were four clusters of MSA-IP patients. Cluster 1 patients were elders with chronic onset and usual interstitial pneumonia pattern on CT scan. Cluster 2 patients were all positive for anti-aminoacyl-tRNA antibodies, predominantly females and had frequent respiratory symptoms. Patients of cluster 3 showed multi-system involvements with nonspecific interstitial pneumonia pattern. Patients of cluster 4 had severe respiratory symptoms with anti-MDA5. The patients of cluster 3 (OR 6.682, 95% CI 1.560–28.622, P=0.011) or cluster 4 (OR 6.057, 95% CI 1.715–21.388, P=0.005) were susceptible to acute onset. The patients of cluster 4 were prone to disease progression (HR 2.711, 95% CI 1.128–6.519, P=0.034), which was consistent with the Kaplan–Meier curves.Conclusions: Four distinctive clusters were determined by cluster analysis suggesting the characteristics, serological antibodies and prognosis of MSA-IP.

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Phenotypic clusters and survival analyses in interstitial pneumonia with myositis-specific autoantibodies

10.21203/rs.3.rs-38365/v2 ◽

2020 ◽

Author(s):

Yihua Li ◽

Shiwen Yu ◽

Yali Fan ◽

Na Wu ◽

Yiran Wang ◽

...

Keyword(s):

Cluster Analysis ◽

Interstitial Pneumonia ◽

Respiratory Symptoms ◽

Inflammatory Myopathy ◽

Usual Interstitial Pneumonia ◽

Idiopathic Inflammatory Myopathy ◽

Acute Onset ◽

Pulmonary Complications ◽

Potential Risk Factors ◽

Predominantly Female

Abstract Background Interstitial pneumonia (IP) is one of the common pulmonary complications of idiopathic inflammatory myopathy (IIM), among which myositis-specific autoantibodies (MSAs) are specific for diagnosing and predicting the prognosis of IIM. However, IP patients with MSAs (MSA-IP) have not been well described. The study aimed to explore the phenotypic clusters and prognosis of MSA-IP patients. Methods A total of 124 MSA-IP patients were prospectively enrolled for analysis. Serum MSAs were detected using immunoprecipitation. Radiographic patterns of IP were determined according to the classification of idiopathic IPs. Clusters of MSA-IP patients were identified using cluster analysis. Potential risk factors for acute-onset disease and short-term prognoses were also analysed. Results There were four clusters of MSA-IP patients. Cluster 1 patients were elderly with chronic onset and a usual interstitial pneumonia pattern on computed tomography. Cluster 2 patients were all positive for anti-aminoacyl-tRNA antibodies, were predominantly female and had frequent respiratory symptoms. Patients in cluster 3 showed multi-system involvement with a nonspecific interstitial pneumonia pattern. Patients in cluster 4 had severe respiratory symptoms with anti-MDA5 antibodies. The patients in cluster 3 (OR 6.682, 95% CI 1.560–28.622, P =0.011) and cluster 4 (OR 6.057, 95% CI 1.715–21.388, P =0.005) were susceptible to acute-onset disease. The patients in cluster 4 were prone to disease progression (HR 2.711, 95% CI 1.128–6.519, P =0.034), which was consistent with the Kaplan–Meier curves. Conclusions Four distinctive clusters were determined by cluster analysis, suggesting the characteristics, serological antibodies and prognosis of patients with MSA-IP.

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Myositis-specific antibodies identify a distinct interstitial pneumonia with autoimmune features phenotype

European Respiratory Journal ◽

10.1183/13993003.01205-2020 ◽

2020 ◽

Vol 56 (6) ◽

pp. 2001205

Author(s):

Julia Graham ◽

Iazsmin Bauer Ventura ◽

Chad A. Newton ◽

Cathryn Lee ◽

Noelle Boctor ◽

...

Keyword(s):

Interstitial Pneumonia ◽

Clinical Features ◽

Treatment Approach ◽

Strong Predictor ◽

Inflammatory Myopathy ◽

Usual Interstitial Pneumonia ◽

Idiopathic Inflammatory Myopathy ◽

Free Survival ◽

Specific Antibodies ◽

Research Classification

Interstitial pneumonia with autoimmune features (IPAF) characterises individuals with interstitial lung disease (ILD) and features of connective tissue disease (CTD) who fail to satisfy CTD criteria. Inclusion of myositis-specific antibodies (MSAs) in the IPAF criteria has generated controversy, as these patients also meet proposed criteria for an antisynthetase syndrome. Whether MSAs and myositis-associated antibodies (MAA) identify phenotypically distinct IPAF subgroups remains unclear.A multicentre, retrospective investigation was conducted to assess clinical features and outcomes in patients meeting IPAF criteria stratified by the presence of MSAs and MAAs. IPAF subgroups were compared to cohorts of patients with idiopathic inflammatory myopathy-ILD (IIM-ILD), idiopathic pulmonary fibrosis and non-IIM CTD-ILDs. The primary end-point assessed was 3-year transplant-free survival.269 patients met IPAF criteria, including 35 (13%) with MSAs and 65 (24.2%) with MAAs. Survival was highest among patients with IPAF-MSA and closely approximated those with IIM-ILD. Survival did not differ between IPAF-MAA and IPAF without MSA/MAA cohorts. Usual interstitial pneumonia (UIP) morphology was associated with differential outcome risk, with IPAF patients with non-UIP morphology approximating survival observed in non-IIM CTD-ILDs. MSAs, but not MAAs identified a unique IPAF phenotype characterised by clinical features and outcomes similar to IIM-ILD. UIP morphology was a strong predictor of outcome in others meeting IPAF criteria.Because IPAF is a research classification without clear treatment approach, these findings suggest that MSAs should be removed from the IPAF criteria and such patients should be managed as an IIM-ILD.

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SAT0529 CLINICAL CHARACTERISTICS AND TREATMENT PATTERNS IN A PATIENT GROUP WITH INTERSTITIAL LUNG DISEASE.

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5812 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1222.2-1222

Author(s):

R. Ortega Castro ◽

P. S. Laura ◽

F. U. Pilar ◽

J. Calvo Gutierrez ◽

A. Requejo-Jimenez ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Interstitial Pneumonia ◽

Smoking Habit ◽

Inflammatory Myopathy ◽

Usual Interstitial Pneumonia ◽

Treatment Patterns ◽

Common Symptom ◽

Radiological Pattern ◽

Mechanic’S Hands

Background:Diffuse interstitial lung disease (ILD) is frequently associated with connective tissue diseases (CTD) and is one of the main causes of morbidity and mortality in these patients. Recently, the concept of Interstitial Pneumonia with Autoimmune Features (IPAF) has been defined to characterize ILD associated with systemic manifestations limited to subtle serological and clinical autoimmune abnormalities and not fulfilling the international criteria for the diagnosis of a given CTD.Objectives:The objective of this study is to describe the clinical, serological and radiological characteristics, as well as the treatment patterns of patients with ILD referred to a Rheumatology Service for suspected CTDMethods:Observational, cross-sectional study of 43 patients with ILD referred for evaluation to the medical consultation of CTD of the Rheumatology service at the Reina Sofía Hospital. Patients were classified as patients with defined CTD, patient with IPAF and patients with other types of pneumopathy. We conducted a descriptive study of all patients and compared the clinical-analytical-radiological characteristics and treatment patterns of the first two groups.Results:Of the 43 patients, 67.40% were women with a mean age at diagnosis of 65.65 (10.42) years and 53.50% of smoking patientsOf the total of patients, 16 (37.2%) were included in the CTD group, 17 (39.5%) met criteria for IPAF and 10 (23.3%) had another type of pneumopathy.In the CTD group scleroderma was the most frequent disease (6/16), followed by inflammatory myopathy (4/16), Sjögren’s syndrome (3/16), rheumatoid arthritis (2/16) and polymyalgia rheumatic (1/16). In this group of patients, the most common symptom was Raynaud’s phenomenon (RP) (7/16), followed by arthritis (7/16) and mechanic’s hands (3/16). Regarding the most frequently antibodies were ANA (100%), anti-RO (41.7%), anti-citrullinated protein antibodies (30%) and rheumatoid factor (RF) (28.6%).In patients with IPAF, as in the CTD group, the most observed clinical criterion was RP (5/17), followed by arthritis (1/17) and mechanic’s hands (1/17). Among the serological criteria the most common antibodies were ANA (100%), followed by anti-RO (33.3%), anti-RNA synthetase (28.6%) and RF (22.2%).Regarding the radiological pattern, in both groups the most frequent was nonspecific interstitial pneumonia, followed by the indeterminate pattern and usual interstitial pneumonia (UIP) in third place. There were no significant differences by gender and age, between the group of CTD and IPAF, observing in both groups a predominance of women with a similar mean age, being the upper smoking habit in the IPAF group (70.6% vs 31.5%, p= 0.02). Regarding the treatment used, the use of immunosuppressants (IS) was more frequent in CTD group (56.3% vs 11.8%, p = 0.007).Conclusion:The clinical-serological and radiological characteristics were similar among patients with IPAF and CTD, which supports the notion of a similar pathophysiology in both groups. In our cohort patients with CTD received IS more frequently than IPAF group, however, future work would be necessary to assess whether the response to treatment is similar in these populations and if IS can benefit patients with IPAF to long term. In addition, it could be useful to include the UIP pattern within the IPAF classification criteria, not currently included, since it is the third most frequent radiological pattern.References:[1]Respirology, 21 (2016), pp. 245-258[2]Eur Respir J, 46 (2015), pp. 976-987Disclosure of Interests:Rafaela Ortega Castro: None declared, Pérez Sánchez Laura: None declared, Font Ugalde Pilar: None declared, Jerusalem Calvo Gutierrez: None declared, Antonio Requejo-Jimenez: None declared, Simona Espejo-Pérez: None declared, Teresa Gonzalez-Serrano: None declared, María del Carmen Castro Villegas: None declared, Gómez García Ignacio: None declared, Alejandro Escudero Contreras: None declared, Eduardo Collantes Estevez Grant/research support from: ROCHE and Pfizer, Speakers bureau: ROCHE, Lilly, Bristol and Celgene, Maria A Aguirre: None declared

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Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy

Journal of Experimental Medicine ◽

10.1084/jem.20041367 ◽

2005 ◽

Vol 201 (4) ◽

pp. 591-601 ◽

Cited By ~ 242

Author(s):

Livia Casciola-Rosen ◽

Kanneboyina Nagaraju ◽

Paul Plotz ◽

Kondi Wang ◽

Stuart Levine ◽

...

Keyword(s):

Inflammatory Myopathy ◽

Idiopathic Inflammatory Myopathy ◽

Antigen Expression ◽

Muscle Cells ◽

Autoimmune Response ◽

Normal Tissues ◽

Diagnosis And Prognosis ◽

Autoimmune Myositis ◽

Low Levels

Unique autoantibody specificities are strongly associated with distinct clinical phenotypes, making autoantibodies useful for diagnosis and prognosis. To investigate the mechanisms underlying this striking association, we examined autoantigen expression in normal muscle and in muscle from patients with autoimmune myositis. Although myositis autoantigens are expressed at very low levels in control muscle, they are found at high levels in myositis muscle. Furthermore, increased autoantigen expression correlates with differentiation state, such that myositis autoantigen expression is increased in cells that have features of regenerating muscle cells. Consistent with this, we found that cultured myoblasts express high levels of autoantigens, which are strikingly down-regulated as cells differentiate into myotubes in vitro. These data strongly implicate regenerating muscle cells rather than mature myotubes as the source of ongoing antigen supply in autoimmune myositis. Myositis autoantigen expression is also markedly increased in several cancers known to be associated with autoimmune myositis, but not in their related normal tissues, demonstrating that tumor cells and undifferentiated myoblasts are antigenically similar. We propose that in cancer-associated myositis, an autoimmune response directed against cancer cross-reacts with regenerating muscle cells, enabling a feed-forward loop of tissue damage and antigen selection. Regulating pathways of antigen expression may provide unrecognized therapeutic opportunities in autoimmune diseases.

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Respiratory failure in a patient with dermatomyositis

Multidisciplinary Respiratory Medicine ◽

10.4081/mrm.2013.503 ◽

2013 ◽

Vol 8 ◽

Author(s):

Ivano Salimbene ◽

Ilaria Leli ◽

Salvatore Valente

Keyword(s):

Respiratory Failure ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Interstitial Pneumonia ◽

Usual Interstitial Pneumonia ◽

Ventilatory Support ◽

Pulmonary Complications ◽

Gas Analysis ◽

Lower Limbs ◽

Arterial Blood

Since its original description in 1956 the association between interstitial lung disease and polymyositis (PM) and dermatomyositis (DM) has become well established. Interstitial lung disease (ILD) can be a significant complication in rheumatic diseases (RDs). Although most patients with RD do not develop clinically evident ILD, these systemic autoimmune disorders are estimated to be responsible for approximately 25% of all ILD deaths and 2% of deaths due to all respiratory causes. Radiologic abnormalities in DM are characterized by a high incidence of airspace consolidation. Non-Specific Interstitial Pneumonia (NSIP) is the most common form of lung disease, with a frequency in biopsies 4-fold greater than that of Usual Interstitial Pneumonia (UIP) in PM and a slightly smaller predominance in DM. We report a case of a female patient, 57 years old, no former smoker, whose clinical history was onset in November 2008 with asthenia with muscle and osteoarticular pain especially located in the upper limbs and then also expanded to the lower limbs. The EMG was compatible with dermatomyositis in the acute phase. The patient received therapy with steroids and tacrolimus, also making several rounds of treatment with immunoglobulin. Given the recurrence of myositis in association with signs of poorly controlled interstitial lung disease, immunosuppressive therapy with Rituximab was administered. The Computed Tomography (CT) scans showed "bronchiectasis and traction bronchiolectasis, hypodense areas consistent with the phenomena of air trapping. The pattern of interstitial lung disease with fibrotic evolution seems consistent with NSIP. The arterial blood gas analysis showed a pattern of hypoxic-hypercapnic respiratory failure (pH: 7,34, PaO2: 67 mmHg; PaCO2: 55 mmHg). As a result of an episode of marked desaturation unresponsive to supplemental oxygen at high flows we proceeded to noninvasive mechanical ventilation with Helmet for 24 hours/24. This ventilatory support was maintained for a week, with resolution of the respiratory failure. In this brief case report we want to highlight various pulmonary complications as a result of dermatomyositis. The progression of respiratory complications may also lead to a situation of respiratory failure, as in our patient, and require a noninvasive ventilatory treatment.

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Molecular Biomarkers in Idiopathic Pulmonary Fibrosis: State of the Art and Future Directions

International Journal of Molecular Sciences ◽

10.3390/ijms22126255 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6255

Author(s):

Anna Stainer ◽

Paola Faverio ◽

Sara Busnelli ◽

Martina Catalano ◽

Matteo Della Zoppa ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Interstitial Pneumonia ◽

Molecular Mechanisms ◽

Usual Interstitial Pneumonia ◽

Delayed Diagnosis ◽

Disease Course ◽

Diagnosis And Prognosis ◽

Clinical Biomarkers ◽

History Of

Idiopathic pulmonary fibrosis (IPF), the most lethal form of interstitial pneumonia of unknown cause, is associated with a specific radiological and histopathological pattern (the so-called “usual interstitial pneumonia” pattern) and has a median survival estimated to be between 3 and 5 years after diagnosis. However, evidence shows that IPF has different clinical phenotypes, which are characterized by a variable disease course over time. At present, the natural history of IPF is unpredictable for individual patients, although some genetic factors and circulating biomarkers have been associated with different prognoses. Since in its early stages, IPF may be asymptomatic, leading to a delayed diagnosis. Two drugs, pirfenidone and nintedanib, have been shown to modify the disease course by slowing down the decline in lung function. It is also known that 5–10% of the IPF patients may be affected by episodes of acute and often fatal decline. The acute worsening of disease is sometimes attributed to identifiable conditions, such as pneumonia or heart failure; but many of these events occur without an identifiable cause. These idiopathic acute worsenings are termed acute exacerbations of IPF. To date, clinical biomarkers, diagnostic, prognostic, and theranostic, are not well characterized. However, they could become useful tools helping facilitate diagnoses, monitoring disease progression and treatment efficacy. The aim of this review is to cover molecular mechanisms underlying IPF and research into new clinical biomarkers, to be utilized in diagnosis and prognosis, even in patients treated with antifibrotic drugs.

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Pulmonary Pathologic Manifestations of Anti-Alanyl-tRNA Synthetase (Anti–PL-12)–Related Inflammatory Myopathy

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2017-0010-oa ◽

2017 ◽

Vol 142 (2) ◽

pp. 191-197 ◽

Cited By ~ 2

Author(s):

Frank Schneider ◽

Samuel A. Yousem ◽

Chester V. Oddis ◽

Rohit Aggarwal

Keyword(s):

Lung Disease ◽

Interstitial Pneumonia ◽

Inflammatory Myopathy ◽

Idiopathic Inflammatory Myopathy ◽

Trna Synthetase ◽

Raynaud Phenomenon ◽

Nonspecific Interstitial Pneumonia ◽

Lung Biopsies ◽

Lymphoid Aggregates ◽

Mechanic’S Hands

Context.— Patients with anti–aminoacyl-tRNA synthetase syndrome (ARS), a subset of idiopathic inflammatory myopathy, have a high prevalence of lung involvement. Autoantibodies directed against alanyl-tRNA synthetase (anti–PL-12 Abs) represent 1 of the 8 autoantibodies currently described under the rubric of ARS. Objective.— To describe the clinical, radiographic, and pulmonary histopathologic findings in patients possessing anti–PL-12 autoantibodies. Design.— Patients with anti–PL-12 ARS were identified in the University of Pittsburgh Idiopathic Inflammatory Myopathy registry. Lung biopsies from 10 patients and lung explants from 2 patients with anti–PL-12 ARS were reviewed, together with chest computed tomography and clinical records. Results.— Patients primarily presented with dyspnea and variable combinations of cough, fever, mechanic's hands, Raynaud phenomenon, and skin and muscle involvement. Chest computed tomography most commonly showed lower lung zone-predominant reticular infiltrates and traction bronchiectasis, with or without honeycomb change. Surgical lung biopsies and pneumonectomies for lung transplantation revealed usual interstitial pneumonia in 8 of 12 cases (67%), nonspecific interstitial pneumonia in 2 of 12 cases (17%), and organizing pneumonia in 2 of 12 cases (17%). Lymphoplasmacytic interstitial inflammation with lymphoid aggregates was common. Conclusions.— Lung disease is often the first manifestation of anti–PL-12 ARS. There are no pathognomonic histopathologic features to distinguish anti–PL-12 ARS-related lung disease from idiopathic variants of diffuse interstitial lung disease. Increased inflammation, lymphoid aggregates, and nonspecific interstitial pneumonia–like areas in a biopsy, as well as clinical features of mechanic's hands, Raynaud phenomenon, arthritis, and fever, should prompt pathologists to suggest involvement by ARS.

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Interobserver Agreement of Usual Interstitial Pneumonia Diagnosis Correlated With Patient Outcome

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2016-0012-oa ◽

2016 ◽

Vol 140 (12) ◽

pp. 1375-1382 ◽

Cited By ~ 13

Author(s):

Mikiko Hashisako ◽

Tomonori Tanaka ◽

Yasuhiro Terasaki ◽

Toshimasa Uekusa ◽

Rosane D. Achcar ◽

...

Keyword(s):

Cluster Analysis ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Interstitial Pneumonia ◽

Latin American ◽

Interobserver Agreement ◽

Usual Interstitial Pneumonia ◽

American Thoracic Society ◽

European Respiratory Society ◽

Patient Prognosis

Context.— The histopathologic criteria for idiopathic pulmonary fibrosis were revised in the American Thoracic Society/European Respiratory Society/Japan Respiratory Society/Latin American Thoracic Association guidelines in 2011. However, the evidence of diagnosis based on the guidelines needs further investigation. Objective.— To examine whether the revised histopathologic criteria for idiopathic pulmonary fibrosis improved interobserver agreement among pathologists and the predicted prognosis in patients with interstitial pneumonia. Design.— Twenty, consecutive, surgical lung-biopsy specimens from cases of interstitial pneumonia were examined for histologic patterns by 11 pathologists without knowledge of clinical and radiologic data. Diagnosis was based on American Thoracic Society/European Respiratory Society guidelines of 2002 and 2011. Pathologists were grouped by cluster analysis, and interobserver agreement and association to the patient prognosis were compared with the diagnoses for each cluster. Results.— The generalized κ coefficient of diagnosis for all pathologists was 0.23. If the diagnoses were divided into 2 groups: usual interstitial pneumonia (UIP)/probable UIP (the UIP group) or possible/not UIP (the non-UIP group), according to the 2011 guidelines, the κ improved to 0.37. The pathologists were subdivided into 2 clusters in which 1 showed an association between UIP group diagnosis and patient prognosis (P < .05). Conclusions.— Agreement about pathologic diagnosis of interstitial pneumonia is low; however, results after division into UIP and non-UIP groups provided favorable agreement. The cluster analysis revealed 1 of the 2 clusters providing high interobserver agreement and prediction of patient prognosis.

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High-Resolution Computed Tomography and Lung Ultrasound in Patients with Systemic Sclerosis: Which One to Choose?

Diagnostics ◽

10.3390/diagnostics11122293 ◽

2021 ◽

Vol 11 (12) ◽

pp. 2293

Author(s):

Barbara Ruaro ◽

Elisa Baratella ◽

Paola Confalonieri ◽

Marco Confalonieri ◽

Fabio Giuseppe Vassallo ◽

...

Keyword(s):

Computed Tomography ◽

Systemic Sclerosis ◽

High Resolution ◽

Interstitial Pneumonia ◽

Lung Ultrasound ◽

Correct Diagnosis ◽

Usual Interstitial Pneumonia ◽

Pulmonary Complications ◽

High Resolution Computed Tomography

Imaging plays a pivotal role in systemic sclerosis for both diagnosis management of pulmonary complications, and high-resolution computed tomography (HRCT) is the most sensitive technique for the evaluation of systemic sclerosis-associated interstitial lung disease (SSc-ILD). Indeed, several studies have demonstrated that HRCT helps radiologists and clinicians to make a correct diagnosis on the basis of recognised typical patterns for SSc-ILD. Most SSc patients affected by ILD have a non-specific interstitial pneumonia pattern (NISP) on HRCT scan, whilst a minority of cases fulfil the criteria for usual interstitial pneumonia (UIP). Moreover, several recent studies have demonstrated that lung ultrasound (LUS) is an emergent tool in SSc diagnosis and follow-up, although its role is still to be confirmed. Therefore, this article aims at evaluating the role of LUS in SSc screening, aimed at limiting the use of CT to selected cases.

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