Clinical features of asthma with connective tissue diseases

The clinical features of asthma with connective tissue diseases (CTDs) are not well‐known. This study therefore aimed to investigate the clinical characteristics of asthma with CTDs.

Conclusions: Asthma with CTDs was related to lower lung function and low-T2 inflammation asthma.
K E Y W O R D S asthma, connective tissue diseases, lung function, rheumatoid arthritis, T2-low asthma 1 | INTRODUCTION Asthma is characterized by chronic airway inflammation, airway hypersensitivity and reversible airway obstruction. More than 330 million people around the world suffer from asthma, 1 and individuals with asthma can show a variety of comorbidities. 2,3 Some asthma comorbidities have been studied in detail, including allergic rhinitis (AR), sinusitis, chronic obstructive pulmonary disease (COPD) and obesity. In particular, COPD (asthma-COPD overlap: ACO) 4 and upper airway disease (AR and sinusitis; one airway, one disease) 5 have been intensively researched and are well-recognized comorbidities. Recently, relationships between asthma and connective tissue diseases (CTDs) have been reported 6-11 but remain relatively poorly characterized. Individuals with asthma have higher risks of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other collagen diseases. 6,[8][9][10][11] Conversely, an increased risk of asthma has been reported among individuals with RA. 7 Luo et al. reported RA as a risk factor for in-hospital mortality during asthma exacerbations. 12 However, the clinical features of asthma with CTDs are not well-known. The aim of this study was therefore to investigate the clinical characteristics of asthma with CTDs.

| PATIENTS AND METHODS
We retrospectively examined the records of adults (≥18 years old) with physician-diagnosed asthma who had been followed up for >1 year at our hospital between January 2010 and December 2019 (also defined as the study period). All subjects had been diagnosed by a pulmonologist and/or allergist at our hospital. To confirm the diagnosis of asthma, we only included subjects with follow-up >1 year. We collected data from spirometry, peripheral eosinophil counts and total immunoglobulin E (IgE) during a stable state of asthma within 2 years before or after the first visit of during the study period. We also collected findings from chest computed tomography (CT) if the subject underwent CT within 2 years before and/or after the start of the study period. Specific IgE status at diagnosis and/or during follow-up was also collected. We then compared clinical features between asthma with and without CTDs.
CTDs were diagnosed by rheumatologists independent of our study. We excluded vasculitides (antineutrophilic cytoplasmic antibody-related vasculitis and Behçet disease) and IgG4-related diseases from the investigated CTDs.
Because there is no consensus diagnostic criteria of COPD in asthma (ACO), 13,14 we made the diagnosis of concomitant of ACO with post-bronchodilator FEV1/ FVC < 0.7 and smoking history of ≥10 pack-year in ≥40-year-old subjects. Smoking history of ≥10 pack-year in ≥40-year-old was chosen based on previous studies. 13,14 Data are presented as median (range) unless otherwise specified. JMP version 11 software (SAS Institute, Cary, NC, USA) was used for all statistical analyses. Comparisons were made using t-tests or the Mann-Whitney U test for continuous variables. Categorical variables were compared using Pearson's chi-square test or Fisher's exact test. To detect whether CTDs is an independent risk factor for low FEV1 [percentage predicted forced expiratory volume in 1 s (%FEV1) < 80%] and low-T2 asthma, we performed multivariate analysis by logistic regression analysis for factors showing values of p < 0.1 in univariate analysis. Among the subjects who had the data of both eosinophils in peripheral blood and IgE, high-T2 asthma was defined as having eosinophils in peripheral blood ≥300 cells/μL and/or IgE ≥ 75 IU/mL. 15 Low-T2 asthma was defined as having eosinophils in peripheral blood <300 cells/μL and IgE < 75 IU/mL. Statistical significance was set for values of p < 0.05, and all tests were two-tailed.
This study was approved by the institutional review board of Yokohama City University Hospital (approval no. F210900006). Due to the retrospective nature of this study, the need to obtain written informed consent was waived by the institutional review board of Yokohama City University Hospital. All methods were carried out in accordance with relevant guidelines and regulations.

| DISCUSSION
This study investigated the clinical features of asthma with CTDs. Patients with asthma and CTDs showed lower lung function than patients with asthma without CTDs. With multivariable analysis, CTDs were independently associated with low FEV1 in asthma. Second, levels of markers for T2 inflammation were lower in asthma with CTDs.
Asthma subjects with CTDs showed lower FVC compared to those without CTDs. Interstitial lung diseases (ILDs) are often found with CTDs 16 and might lead to lower FVC and FEV1 in asthma with CTDs. However, whether ILDs related to CTDs, affected FVC was unclear in this study, because not all asthma subjects underwent CT to check for ILDs. In addition, ILD was found in only 19.4% of subjects with CTDs (Table S2). A %FVC < 80% is considered a risk factor for asthma exacerbation 17 and death in asthma subjects. 18 Managing asthma with CTDs requires special attention due to the lower FVC. FEV1 was also lower in asthma with CTDs. Airway diseases such as BE or bronchitis are often found in patients with CTDs. For instance, one study found that 30%-40% of individuals with RA had BE. 19 Airway diseases related to CTDs might result in a lower FEV 1 in asthma with CTDs. In fact, Wisher et al. reported that 20% of RA patients showed an obstructive pattern on spirometry. 20 In addition, asthma with CTDs required more intensive treatment than asthma without CTDs, as GINA step and the proportions of subjects using LABAs were higher in F I G U R E 1 Flow diagram for participation in the study.  Note: Data are presented as median (range) or number of patients (%). GINA treatment step and medication are presented as of the start of the study period. OCS used for reasons other than asthma was not included in evaluation of the treatment step of asthma. Allergic asthma was defined as at least one positive result for specific immunoglobulin E and/or symptom with exposure to allergens. Inhaled allergens associated with asthma are listed in the Supporting Information.
T17 inflammation, rather than T2 inflammation, are typical in RA, 23,24 the most common CTD in this study. T1 and T17 inflammation are implicated in low-T2 asthma. 25 This might be related to a lower proportion of peripheral eosinophils and low IgE level in asthma with CTDs. Further study is needed to validate these findings. Another point requiring attention in asthma with CTDs is immunosuppressive conditions in CTDs. Subjects with CTDs often receive systemic steroids, immunosuppressants and/or biologics, which result in varying degrees of immunosuppression. In fact, our previous study found that collagen vascular diseases were a risk factor for systemic corticosteroid use in asthma. 26 Respiratory tract infection is the most common cause of asthma exacerbation, 27 and prevention of such infections is important for asthma management. Moreover, asthma increases the risk of pneumonia. 28 One preventive measure is vaccination against influenza and Streptococcus pneumoniae. As vaccination rates remain unsatisfactory even among the elderly with comorbidities 29 or asthma, 30 this measure should be further encouraged.
In this study, 27.8% (10/36) of individuals with asthma and CTDs displayed BE on chest CT. BE in asthma is related to deteriorated lung function and exacerbation of asthma. 31 Whether BE is more frequent in asthma with CTDs remained unclear, because we had no control group. Further study is therefore warranted to clarify whether differences in the frequency of BE exist between asthma with CTDs and asthma without CTDs.
The aetiology of concomitant asthma and CTDs is under investigation. One cause is mucosal inflammation. Airway mucosal inflammation is related to the production of anti-citrullinated protein antibodies. 32 Zaccardelli et al. reported that asthma was associated with seropositive RA. 6 In addition, asthma and some CTDs share genetic susceptibilities. Common genetic risks have been reported between asthma, RA and SLE. 33,34 Another key player causing concomitant asthma and CTDs might be T17 inflammation. T17 cytokines and inflammation have been implicated in the pathogenesis of a variety of CTDs. 23,24 T17 is also involved in asthma. 35 Moreover, environmental factors such as smoking might also be relevant. 36,37 This study showed various limitations that should be considered. First, this was a retrospective study, and the diagnostic criteria for asthma were not predefined. In addition, not all subjects had data on peripheral eosinophils, IgE, lung function or CT within 2 years before and/or after the start of the study. However, asthma was diagnosed by an allergist and/or pulmonologist in all cases. About 90% of cases of asthma with CTDs underwent CT evaluation within 2 years before and/or after the start of the study. Second, diagnosis of asthma is challenging in subjects with CTDs, because some subjects with CTDs have obstructive lung function, which might be related to lung manifestations of CTDs. In addition, treatment for CTDs can affect asthma biomarkers. In this study, T2 inflammatory markers were lower in asthma with CTDs. However, some asthma patients with CTDs received systemic corticosteroids for the CTDs. Thus, low levels of Th2 inflammatory marker in asthma with CTDs may have been a result of therapeutic interventions. But the number of subjects receiving systemic steroids was low, it is unlikely to bias the results.
In conclusion, asthma with CTDs was related to low FEV1 and low-T2 inflammation asthma. Further study is needed to clarify the clinical features of asthma with CTDs.

AUTHOR CONTRIBUTIONS
Keisuke Watanabe contributed to the conception and design of the study; to the collection, analysis and interpretation of the data; and to drafting and finalizing the manuscript. Nobuyuki Horita, Yu Hara, Nobuaki Kobayashi and Takeshi Kaneko contributed to the interpretation of the data and to finalizing the manuscript. All authors reviewed the manuscript.

ACKNOWLEDGEMENTS
This study was partially supported by research grants from Teijin Pharma. Teijin Pharma had no role in this study.

DATA AVAILABILITY STATEMENT
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

ETHICS STATEMENT
This study was approved by the institutional review board of Yokohama City University Hospital (approval no. F210900006). Due to the retrospective nature of this study, the need to obtain written informed consent was waived by the institutional review board of Yokohama City University Hospital. All methods were carried out in accordance with relevant guidelines and regulations.
T A B L E 7 Factors related to low-T2 asthma with multivariable analysis.
Odds ratio (95%CI) p T A B L E 6 Factors related to low-T2 asthma.