Relapsing polychondritis (RP) is a rare inflammatory disease involving multiple organs, including the eyes, ears, nose, larynx, tracheobronchial tree, joints, kidneys, cardiovascular system, and nervous system. The pathogenesis of RP is currently unclear, although previous studies have indicated that both humoral and cell-mediated immune systems may be involved in its progression and development, and that cartilage-specific autoimmunity may play a critical role in the overall pathogenesis of RP (1, 2). Although RP can be present at any age, it develops most frequently between the ages of 40 and 60 years, with a male-to-female ratio of almost 1:1 (3). RP has an insidious and variable clinical presentation. In a previous study, French researchers identified three separate clusters in terms of clinical manifestations and prognosis, namely, hematologic, respiratory, and mild phenotypes, and suggested that cardiac involvement is a significant sign of poor prognosis in RP patients (4).

In clinical practice, it is commonly observed that cardiac involvement is generally insidious; however, cases of acute cardiovascular events have also been reported (5). We believe that the importance of cardiac involvement in RP may be underestimated and, in turn, has not received sufficient attention. To our knowledge, only one study has yet compared the differences in clinical presentation between patients with and without cardiac involvement, while studies comparing laboratory indices and detailed prognostic features are lacking. As such, current knowledge regarding RP with cardiac involvement remains insufficient.

The objective of this study was, therefore, to comprehensively clarify the risk factors of cardiac involvement. This is the most detailed large-scale study of RP cardiac involvement performed to date.

In the present study, we divided patients with RP into two groups based on the presence or absence of cardiac involvement. Subsequent comparison of the clinical differences between the two groups revealed several results worth discussing.

In our study, cardiac involvement in patients with RP was mostly subclinical, and patients were assessed for cardiac involvement by performing transthoracic echocardiography and electrocardiography. In our study, the incidence of cardiac involvement was 24.1%, while that of valvular involvement was 16.0%. These rates are similar to those found in previous studies (9, 10). Cardiac involvement is not unusual for RP; although the majority of patients have subclinical changes, given that cardiac involvement can lead to fatal cardiovascular complications (e.g., complete heart block, aortic valve rupture, and acute aortic valve insufficiency), regular ECG and echocardiography should be performed to monitor cardiac involvement (9).

To determine the clinical differences between the two more accurately, we selected the common clinical features and risk factors of cardiovascular disease for inclusion in univariate and multifactorial logistic regression, finding that cardiac involvement was positively associated with age, disease duration, CNS involvement, and NLR, and negatively associated with tracheobronchial involvement and chest wall involvement. Based on the above outcomes, a line graph was created to digitally assess the risk of cardiac involvement.

A retrospective study in Japan showed that the mean age of patients with and without heart involvement was 72 and 65 years, respectively (11). In this study, the mean age of onset was 51 years in the group with cardiac involvement, compared to 43 years in the group without cardiac involvement; the difference was significant (p < 0.001). These findings suggest that the risk of cardiac involvement increases with age. Previous studies have shown a higher incidence of cardiovascular events in men than in women (12), while Shimizu et al. found that men with RP are at greater risk for heart involvement (11). However, in this study, no significant difference was found in the incidence of cardiac involvement in RP patients in terms of sex. We further analyzed other common risk factors for cardiovascular disease, such as hypertension, diabetes, hypercholesterolemia, and obesity but found that none of them were statistically different.

Our data indicate that a longer disease duration is associated with a greater risk of cardiac involvement. As a flare-up and interventional disease, the amount and extent of tissue damage increases over time (13). Similarly, a case report previously reported a patient with RP who developed an acute aortic lesion despite long-term remission (14). In addition, one study showed that diagnosis of an ear biopsy can be useful even in the absence of ear symptoms during the non-inflammatory interval (15). This suggests that despite the absence of both subjective symptoms and evidence of systemic inflammatory activity in patients, inflammatory activity may be observed at the organ level. Assessments of RP disease activity often focus on clinical symptoms, systemic markers of inflammation (e.g., CRP and ESR), and radiological investigations. We recommend that careful cardiac investigations, such as echocardiography and electrocardiography, should be performed regularly in patients with RP, both in flare conditions and long-term remission states.

The NLR describes the ratio of two opposing but supplementary immune pathways. This reflects the key role of non-specific immune responses, as with specific immune responses in inflammation (16). NLR, a novel inflammatory marker, has been proven to be associated with the activity of diverse immune diseases, such as SLE, primary Sjögren’s syndrome, Behçet’s disease, ankylosing spondylitis, polymyalgia rheumatic (17–21). A previous study by our team also revealed an association between NLR and disease activity in RP (22). Inflammation is often implicated in the pathogenesis of cardiac pathology, and various inflammatory markers have been found to be associated with cardiac conditions. NLR also plays a prognostic role in the stratification and prognosis of various cardiovascular diseases (23, 24). NLR is associated with severe valve stenosis and the severity of rheumatic mitral valve stenosis, as demonstrated in previous studies (25–27). Additionally, NLR is considered to be associated with poor prognosis in arrhythmias and heart failure, including relapses and mortality (28, 29). We suspect that the NLR is a reasonable predictor of cardiac involvement in RP because of its role in RP and cardiovascular disease.

In our study, we found that patients with cardiac involvement were more likely to have CNS involvement. Cardiac involvement was negatively associated with tracheobronchial and chest wall involvement in univariate logistic regression. Based on the multiplicity of clinical manifestations and the close correlation between different tissue involvements in RP patients, the exploration of diverse phenotypes of RP patients has been a hot research topic in recent years. Dion et al. first classified 142 RP patients into hematologic, respiratory, and mild forms using cluster analysis, finding that cardiovascular involvement occurred primarily in the hematologic form, with less cardiovascular involvement in the respiratory form (4). Subsequently, Shimizu et al. advocated dividing patients into a respiratory involvement group, an ear involvement group, and an overlapping group of both, and few patients with cardiac involvement were found in the subgroup of patients affected by respiratory involvement (30). Overall, the results of prior studies support the findings of the present study. We propose that cardiac and CNS involvement may indicate RP disease severity and that clinicians should therefore focus on the heterogeneity of RP patients, who should be examined in greater detail during clinical treatment.

We observed an inter-relationship between cardiac, central nervous system, tracheobronchial and chest wall involvement in RP patients. Specifically, the nasal, chest wall, laryngeal, and tracheobronchial systems had similar patterns of involvement, as did the cardiac, CNS, ocular, and auricular systems. This corresponds well with the studies by Ferrada and Shimizu et al. (30, 31). Further, these results suggest that identifying the heterogeneity of RP patients at an early stage could help to promote timely diagnosis, assessment, and treatment, thereby reducing target organ damage.

In our study, we found no indications to suggest an adverse prognostic effect of cardiac involvement, which may be related to differences in the definition of poor prognosis, and may also be related to sample differences. In conclusion, we believe that the prognostic role of cardiac involvement needs to be further discussed.

The prognosis of RP is of significant concern to clinicians and patients. Although Dion et al. suggested that cardiac involvement was a risk factor for mortality (4), studies in both China and Japan failed to find any significant association between cardiac involvement, death, and relapse (10, 32). In our cohort, we focused on the association of cardiac involvement with remission, flare-ups, and death, none of which showed significant associations, suggesting that cardiac involvement was not associated with prognosis. Further prospective cohort studies are required to examine the correlation between cardiac involvement and prognosis.

This study has limitations. First, the single-center, retrospective design may have led to potential bias, caused by incomplete information in some medical records and insufficient follow-up time. As such, large retrospective or prospective studies need to be carried out to validate these results. Secondly, our study only included Chinese patients and no other races. Therefore, whether the current results can be generalized to other populations requires further study.

Overall, we found that four clinical factors, namely, age, CNS involvement, NLR > 6.41, and disease duration > 4 years were risk factors, while tracheobronchial involvement and chest wall involvement were adverse factors for cardiac involvement. Regular echocardiography and electrocardiography are essential for patients with RP due to their significant cardiac impact.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by The Ethics Committee of Peking Union Medical College Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

RY, YPH, and YH contributed to the conception and design of the study. MZ, DX, QW and ML collected clinical data. RY, WZ and FZ performed the statistical analysis. RY wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.