Inflammatory myositis-associated interstitial lung disease can be distinguished from that associated with other connective tissue diseases

Introduction

Interstitial lung disease (ILD) increases the morbidity and mortality of the patients with connective tissue diseases (CTD), such as rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), Sjögren’s syndrome (SjS) and idiopathic inflammatory myopathies (IIM) (1).

IIM are a heterogeneous group of disorders characterized by muscle inflammation and weakness. The most common IIM in adults are dermatomyositis (DM) including clinically amyopathic dermatomyositis (CADM), polymyositis (PM) and inclusion body myositis (2). The antisynthetase syndrome (ASyS) is a distinct condition, which nowadays is also included in the IIM group (3).

The clinical presentation of any CTD-ILD can vary from an indolent disease course to an acute respiratory failure (4). Several cohorts have revealed that a high proportion of patients with IIM-associated ILD (IIM-ILD) presented an acute onset of disease (3,5-7), particularly in those patients with CADM and/or anti-melanoma differentiation-associated gene-5 (MDA5) positivity (7-9) and ASyS (10). However, a rapid disease onset has been described in other CTD-ILDs as well (11-13). More importantly, the IIM-ILD studies reporting high frequency of acute disease onset have lacked a control group consisting of other CTD-ILDs. Thus, it is unclear whether IIM-ILD has a distinct clinical presentation among CTD-ILDs.

Controlled comparative studies regarding to radiological findings and demographic data of IIM-ILD are also limited. One study has compared high-resolution computed tomography (HRCT) patterns of IIM-ILD and other ILDs, but the control group mostly consisted of idiopathic ILDs and less of CTD-ILDs (14). Thus, it is also unknown whether the radiological findings of IIM-ILD differ from other CTD-ILDs.

The aim of this study was to compare the clinical presentation and radiological findings between IIM-ILD and other CTD-ILDs. We present the following article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1219/rc).

Methods

Data sources and search

The study cohort consists of patients treated in the Kuopio University Hospital (KUH) pulmonology clinic between 1.1.2000–20.11.2019. The subjects for the study were searched from the KUH database using following International Classification of Diseases (ICD-10) codes: M05.X/M06.X/J99.0*M05.1 for RA, M32.X/J99.1*M32.1 for SLE, M33.X/J99.1*M33.9/J99.1*M33.2 for IIM, M34.X/J99.1*M34.8 for SSc, M35.0/J99.1*M35.0 for SjS, M35.1 for MCTD and M35.8/M35.9 for undifferentiated connective tissue disease (UCTD). We have previously published three studies of RA-ILD, in which the patient search reached to December 2014 (15-17). These patients are included in the present study cohort and the RA searches were further extended to 20.11.2019.

Altogether 2202 new patients were identified. First the patients were screened (HMN, VAEK, HMIJ) based on medical records and HRCT or other comparable computed tomography (CT) reports. If those did not suggest a presence of ILD, the patient was excluded, as were the cases for whom a proper CT scan allowing reliable analysis of the lung parenchyma was not available. The remaining 121 patients with suspected CTD-ILD, as well as our previous RA-ILD cohort of 60 patients, were further analyzed by an experienced rheumatologist (PKE) and two radiologists (HPK, SKS).

Re-analysis of the CTD diagnoses

A rheumatologist independently evaluated laboratory findings, clinico-radiological data and other necessary examinations and re-assessed the CTD diagnoses. Patients were included in the IIM subgroup if they fulfilled either (I) the probable or definite European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and their Major Subgroups (2), or (II) the Connor’s criteria for ASyS (18). Other CTD diagnoses were confirmed by using the current International classification criteria of each disease (19-27). Eight patients with dry eyes, dry mouth, and Sjögren’s-syndrome-related antigen A/B (SSA/SSB) antibodies were included to SjS subgroup as highly probable SjS, without objective tests for dryness of mouth or eyes, but with multiple signs and symptoms supporting the diagnosis. Twenty-three patients with autoantibodies or clinical features of CTD without meeting the criteria for any specific autoimmune disease were included as UCTD (28).

Radiological re-analysis

Two radiologists independently re-assessed the baseline HRCT scans according to the 2018 international statement as a definite usual interstitial pneumonia (UIP), probable UIP, indeterminate with UIP, or alternative diagnosis (29). In cases with alternative diagnosis, the 2013 idiopathic interstitial pneumonias (IIP) classification was applied to diagnose patients as having nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), desquamative interstitial pneumonia (DIP), diffuse alveolar damage (DAD) or unspecific radiological patterns (30). Some patients displayed NSIP/OP overlap pattern, as described in the previous literature (31). In 106 patients with available follow-up HRCTs, the final radiological diagnosis was determined based on the analysis of both CTs. In case of a disagreement, the final radiological categorization was reached via discussion between the investigators (HMN, HPK, SKS).

Gathering of demographic information

After the re-analysis of rheumatological and radiological diagnoses, 27 patients were excluded for not having confirmed CTD-ILD. Clinical information and laboratory test results (Table S1) were gathered from the patient records of KUH. The results of pulmonary function tests were gathered at baseline ± three months.

The order of CTD/ILD presentation was determined from the medical records. If the patient revealed both CTD- and ILD- related symptoms, signs, or findings on the first contact to either rheumatologist or pulmonologist, the disease onset was defined as simultaneous.

The disease onset was defined as acute if the patient needed hospitalization at the onset of ILD. These patients were further divided into those who were admitted to intensive care and those admitted to pulmonology ward. If the patient was managed on an outpatient setting, the disease onset was defined as subacute/chronic. In all cases with a possibility of an acute respiratory infection, appropriate microbiological samples were collected according to the clinician’s consideration. Bronchoalveolar lavage was performed in 63.4% of the patients with an acute onset disease to exclude infections.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). According to Finnish legislation, no consents for inclusion are needed in retrospective register-based study. The study protocol was approved by the Ethics Committee, Hospital District of Northern Savo [statement No. 151/2015 (17/2013)]. In addition, organizational permission of KUH was obtained, which enabled data collection from the hospital registries.

Statistical analysis

The continuous data is expressed as medians (range) and categorical variables as absolute numbers (valid percentages). Different variables were compared using Mann-Whitney U-test, Kruskal-Wallis test or chi-squared test, as appropriate. Missing data was excluded from these comparisons. Logistic regression of features associated with IIM-ILD was used for multivariate analysis. Results are presented as odds ratio (OR) ± 95% confidence interval (CI). A receiver operating curve (ROC) was constructed to evaluate the diagnostic performance of the final multivariate model. Of the variables utilized in the multivariate analyses, there were no missing data. A sensitivity analysis omitting the patients with RA was also performed. Survival time was calculated from the baseline to the date of death or December 10, 2021, when the vital status was ascertained. The Kaplan-Meier method and log-rank test were used to calculate and compare the survival curves. P values <0.05 were considered statistically significant. All data was analyzed using IBM Statistics SPSS software, version 26.0.

Results

Altogether 154 patients with confirmed CTD-ILD were identified. The most common CTDs were RA (78/50.6%), UCTD (23/14.9%), IIM (22/14.3%) and SSc (18/11.7%). Some patients fulfilled the diagnostic criteria of two different CTDs (Figure 1). The IIM-ILD subgroup consisted of 14 patients with ASyS, 5 with CADM, 2 with DM and 5 with PM of whom four fulfilled also criteria for ASyS.

Figure 1 Diagram showing the CTD diagnoses in the cohort of 154 patients. Eleven patients fulfilled the diagnostic criteria of two different CTDs. CTD, connective tissue disease; UCTD, undifferentiated CTD; SLE, systemic lupus erythematosus; MCTD, mixed CTD.

The demographics, lung functions and radiologic findings of different CTD-ILD subgroups are presented in Table 1. The IIM overlap patients are displayed in a separate column and thus the statistical comparisons in Table 1 involve only a subset of patients with IIM-ILD. The patients were mostly female and almost half of them had never smoked (Table 1). All but seven (95.5%) patients suffered from either cough or dyspnea. The median survival was 8.4 years. Comparing all the different CTD subgroups, patients with IIM-ILD had worse baseline FVC than patients with RA-ILD or MCTD-ILD (P values 0.004, 0.036, respectively, Table 1). Fever was more frequent in patients with IIM-ILD compared to RA-ILD (91.7% vs. 22.6%, P<0.001) or SSc-ILD (91.7% vs. 40.0%, P=0.022). In IIM-ILD patients the radiological NSIP/OP overlap pattern (Figure 2) was observed more commonly than in other subgroups.

Figure 2 Representative HRCT images of a patient with clinically amyopathic dermatomyositis. HRCT images display NSIP/OP overlap pattern with lower lobe predominance. There is GGO and reticulation without honeycombing or traction bronchiectasis on the right lower lobe (A). Milder GGO and reticulation are symmetrically distributed in the upper lobes (B). These changes are consistent with NSIP. On the left lower lobe (A) the main pattern is peribronchial consolidations with perilobular pattern (arrows), a finding consistent with typical OP pattern. HRCT, high-resolution computed tomography; NSIP/OP, nonspecific interstitial pneumonia/organizing pneumonia; GGO, ground glass opacity.

Dichotomous comparison between IIM-ILD patients, including the overlap ones, and other CTD-ILDs is shown in Table 2. The patients with IIM-ILD were younger and more often non-smokers with fever (Table 2). They displayed radiological NSIP/OP pattern more frequently whereas UIP pattern was less common. NSIP/OP overlap pattern showed a 27.3 sensitivity and 98.5 specificity for discriminating IIM-ILD from other CTD-ILDs (Table 2).

Over 90% of the IIM-ILD patients had ILD onset before or simultaneously with CTD presentation, whereas this was the situation in under half of the other CTD-ILDs (Table 3). Every fifth IIM-ILD patient was admitted to intensive care unit (ICU) at the disease onset, which was rare in other CTD-ILDs (22.7% vs. 2.3%, P<0.001). Of the five IIM-ILD patients admitted to ICU, two had CADM with MDA5 antibodies, two had PM + ASyS with positive Jo-1, and one had ASyS with positive PL-12. The median survival between IIM-ILD and other CTD-ILD patients did not differ statistically significantly (101.0 vs. 143.0 months, P=0.663) (Table 3).

In multivariate analysis, NSIP/OP overlap pattern, acute onset disease treated in ICU and ILD preceding or presenting simultaneously with CTD were significantly associated with IIM-ILD (Table 4). This model, supplemented with age, had excellent diagnostic performance identifying IIM-ILD [area under curve (AUC) 0.845] (Figure 3). The analyses were repeated utilizing the Solomon criteria for ASyS, which did not change the main results (data not shown).

Figure 3 A ROC curve for the multivariable model: (I) age, (II) NSIP/OP overlap pattern in HRCT, (III) acute onset treated in intensive care unit, (IV) ILD before CTD onset or simultaneously (Table 4). The model shows excellent diagnostic performance for identifying myositis-associated ILD from all CTD-ILDs with AUC value of 0.845. ROC, receiver operating characteristic; AUC, area under the curve; NSIP/OP, nonspecific interstitial pneumonia/organizing pneumonia; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; CTD, connective tissue disease.

In sensitivity analysis omitting the patients with RA, the IIM-ILD patients were still statistically significantly more likely to develop an acute onset of the ILD simultaneously or prior to CTD with more overlap NSIP/OP radiological appearance (Table 5). Among all subjects with acute onset ILD the most common radiological patterns were OP (41.5%), UIP/probable UIP (19.5%), NSIP (12.2%), and NSIP/OP overlap (12.2%).

Detailed data of each IIM-ILD patients diagnostics, treatment, outcome and given medications is described in supplementary Tables S2-S4.

Discussion

To our knowledge, this is the first study to directly compare IIM-ILD with other CTD-ILDs confirming that an acute disease onset was particularly associated with IIM-ILD. Further, NSIP/OP overlap pattern in HRCT, the simultaneous onset of both ILD and CTD symptoms, and younger age were associated with IIM-ILD. These findings are in line with the previous, but mostly uncontrolled studies.

An acute presentation of ILD have been observed in many uncontrolled IIM cohorts. For example, Obert et al. reported acute presentation of ILD in over half of the 48 IIM-ILD patients, defined as the presence of symptoms for less than 2 months (32). Fujisawa et al. examined 114 IIM-ILD patients and reported acute/subacute clinical presentation in 52% of the patients. The definition used for acute presentation was determined as rapidly progressive ILD with deterioration within 3 months (33). A high proportion (>50%) of acute disease onset has been described in many other IIM-ILD cohorts and case reports also (7,8,10), while others have reported smaller percentages of 9–30% (6,34). These controversies probably rise from the different patient selection, as some studies include also asymptomatic patients with an incidental finding of interstitial lung abnormalities (34). In our study, 96% of the patients suffered from either dyspnea or cough. Moreover, the definition of an acute onset varies in different studies as no official definition exists. In the present study, acute onset was based on the need for hospitalization.

We observed a high percentage (91%) of IIM-ILD patients in whom ILD had either preceded or developed simultaneously with IIM symptoms/signs. Almost as high percentages (75–78%) have been reported in many uncontrolled IIM-ILD studies (32,33). Another cohort of 33 IIM-ILD patients reported a simultaneous onset in 67% and ILD being first in 18% (6). In a Danish population-based CTD cohort however, ILD was diagnosed before CTD in only 39% of the IIM-ILD patients similarly as in other CTDs. A simultaneous onset was not reported (35). In that study, the order of presentations was derived from a national registry data without access to individual patient data, which may have affected this result (35).

Based on the previous literature and our results, it seems very common, that in IIM-ILD the respiratory and myositis-related symptoms and signs develop rather simultaneously. Therefore, it is crucial that pulmonologists are familiar with typical IIM features so that the necessary investigations are performed. The pulmonologists should look for the presence of symmetrical muscle weakness, myalgia, Gottron papules/sign, distal digital ulceration, nail fold bleeding, dysphagia, skin rashes, or Raynaud’s symptom (36,37).

Currently, autoimmune serology testing is recommended for all ILD patients (29) although it is unclear what auto-antibodies should be investigated (38,39). Universal screening for myositis-specific or myositis-associated antibodies in newly diagnosed ILD is controversial and currently suggested on a case-by-case consideration (29). However, especially those patients who present an acute/subacute respiratory failure with lung infiltrates, should be thoroughly examined keeping the possible IIM-ILD in mind, as stated by others also (4,38,40). Though myositis-specific and myositis-associated antibodies are useful in the diagnostics of these disorders (14), the delay of their laboratory analysis often necessitates the diagnosis on clinical grounds. Unfortunately it seems that critically ill patients are not commonly evaluated for IIM-ILD, since only 5% were tested for autoantibodies in the multinational Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) cohort with acute respiratory distress syndrome without an identified etiology (41).

According to previous literature, the most common HRCT patterns in IIM-ILD are NSIP or NSIP with OP (42), in line with our findings. In a study of 33 patients with ASyS, NSIP or mixed NSIP/OP patterns were seen in approximately 70% of subjects (43). In two recent studies of 52 PM/DM and 84 ASyS patients NSIP pattern was observed in 32–44%, OP pattern in 19–25% and NSIP/OP overlap pattern in 9-19% of the subjects (44,45). In a study of Enomoto et al., the HRCT patterns of 444 biopsy-proven patients with IIPs were re-assessed. They reported that the cumulative incidence of newly-developed CTD was similar in 21 (4.7%) patients with NSIP/OP overlap pattern and 44 (9.9%) with NSIP pattern, but the developing CTD was diagnosed as IIM in 100% of the patients with NSIP/OP overlap pattern and in 56% in those with NSIP pattern (46). One previous study has compared the radiological patterns of 12 IIM-ILD and 235 non-IIM-ILD subjects, the control group consisting of CTD-ILDs (n=52), IIPs (n=115) and other ILDs (n=68). They reported a statistically significant difference in the presence of NSIP/OP pattern between the groups (14). In our study, the NSIP/OP pattern was not sensitive, but highly specific to identify IIM-ILD patients. Combining this HRCT pattern to age, order of ILD and CTD presentations and an acute onset disease treated in ICU, we observed an excellent diagnostic performance (47) separating IIM-ILD from other CTD-ILDs. The best model of Jee et al. (14) with the highest AUC (0.96) consisted of myositis autoantibodies line immunoblot assay combined with age, gender, CTD-features, and radiological NSIP/OP pattern supporting our findings despite of the different control group.

Most of the limitations of the study rise from its retrospective nature. In the past, all autoantibodies including myositis-panel were neither yet available in clinical practice nor routinely investigated from all ILD patients, which probably has been the situation all over the world (41). Thus, there is some missing laboratory data. In addition, different symptoms and signs were not available from all patients, which may lead to some inaccuracies. However, gathering equally large CTD-ILD cohort prospectively would take several years given the rarity of the diseases. Another limitation is the fact that the IIM-ILD subgroup is fairly small and somewhat skewed towards ASyS and CADM, which might affect the results. A high proportion of RA-ILD patients could have caused a bias, but the sensitivity analysis omitting them did not change the main results. The classification criteria for ASyS are variable (3) and it is not clear which should be used in studies. We chose to use the Connors criteria, but the main results remained statistically significant using the stricter Solomon criteria.

The strengths of this rather large CTD-ILD cohort is that the data is collected comprehensively and that both pulmonologist, rheumatologist and two radiologists have re-analyzed the data.

Conclusions

In conclusion, IIM-ILD can be distinguished from other CTD-ILDs by clinical and radiological presentation. Compared to other CTD-ILDs, the patients with IIM-ILD are younger, they more often develop an acute onset dyspnoea and fever with simultaneous onset of the systemic disease, and display radiological NSIP, OP or NSIP/OP overlap pattern. When encountering this kind of patients, the clinician should suspect IIM-ILD and promptly test muscle enzymes and comprehensive autoantibody tests including myositis-panel.

Acknowledgments

Funding: This work was supported by Foundation of the Finnish Anti-Tuberculosis Association and the North Savo Regional Fund of the Finnish Cultural Foundation to HN.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1219/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1219/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1219/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1219/coif). HMN reports grants from the Foundation of the Finnish Anti-Tuberculosis Association and the North Savo Regional Fund of the Finnish Cultural Foundation during the current work. She also reports a grant from Duodecim for attending a congress; lecturers’ fees from Boehringer Ingelheim Finland Ltd. and Roche Ltd.; congress/travel support from Boehringer-Ingelheim Ltd., Sanofi-Genzyme Ltd. and Chiesi Ltd., all outside the submitted work. PKE reports a consulting fee from Abbvie Ltd.; congress/travel support form Mylan Ltd. and Pfizer Ltd.; participation on an Advisory Board for Astra Zeneca Ltd., all outside the submitted work. SKS owns stocks of CRISPR Therapeutics AG, Faron Pharmaceuticals Ltd. and Merck&Company, Inc. outside the submitted work. MKP reports lecturers’ fees from Boehringer-Ingelheim Finland Ltd. and Roche Ltd.; congress/travel support from Boehringer-Ingelheim Ltd. and Orion Pharma Ltd.; participation on an Advisory Board of Boehringer-Ingelheim Ltd.; personal grants from the Foundation of the Finnish Anti-Tuberculosis Association, the Jalmari and Rauha Ahokas foundation and the Kuopio region respiratory Foundation, all outside the submitted work. RLK reports lecturers’ fees from Boehringer-Ingelheim Ltd. and Roche Ltd.; congress/travel support from Roche Ltd. and Novartis Ltd.; participation on an Advisory Board of Boehringer-Ingelheim Ltd. and MSD Ltd.; being the President of the Finnish Respiratory Society between march 2017 and march 2020; grants for the study group from the Foundation of the Finnish Anti-Tuberculosis Association, the Research Foundation of the Pulmonary Diseases, the Research Foundation of North Finland, the Jalmari and Rauha Ahokas Foundation, and a state subsidy of the Oulu University Hospital, all outside the submitted work. HOK reports lecturers’ fee from Boehringer Ingelheim Finland Ltd.; congress/travel support from Astra Zeneca Ltd.; owning shares of Orion Pharma Ltd., all outside the submitted work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). According to the Finnish legislation, consents to participate are not required in retrospective register-based studies. The study protocol was approved by the Ethics Committee, Hospital District of Northern Savo (statement No. 151/2015 (17/2013)). In addition, organizational permission of KUH was obtained, which enabled data collection from the hospital registries.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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