Can Mechanical Injury Really Trigger Relapsing Polychondritis? The First Report From A Large Case Series

Lei Zhang (  fcczhangl6@zzu.edu.cn ) Zhengzhou University First A liated Hospital https://orcid.org/0000-0003-4105-0824 Shuang Yun Zhengzhou University First A liated Hospital Tiange Wu Zhengzhou University First A liated Hospital Yujie He Zhengzhou University First A liated Hospital Jinyan Guo Zhengzhou University First A liated Hospital Lishuai Han Zhengzhou University First A liated Hospital Jiameng Lu Zhengzhou University First A liated Hospital Xiaojun Liu Zhengzhou University First A liated Hospital Rui Yang Zhengzhou University First A liated Hospital Shitao Zhang Zhengzhou University First A liated Hospital Tianfang Li Zhengzhou University First A liated Hospital Shengyun Liu Zhengzhou University First A liated Hospital


Introduction
Relapsing polychondritis (RPC) is a systemic in ammatory disease primarily affecting the cartilaginous tissues, including the ears, nose, larynx, tracheobronchial tree and joints, as well as non-cartilaginous tissues [1]. The rst case of relapsing polychondritis was described in 1923 by Jaksch-Wartenhorst, but little attention was given to the entity until the 1960s, when Pearson et al. introduced the name "relapsing polychondritis" [2].
The pathogenesis of RPC remains largely unknown [3,4]. However, it was postulated that it is an autoimmunity-mediated disorder and both cellular and humoral immunities are involved in the process. In addition, there is strong correlation between the RPC susceptibility and the presence of HLA-DR4 [5].
However, the triggers of this rare disorder are not fully characterized. Several case reports suggest that cartilage injury may initiate RPC process [6][7][8], while solid evidence from large case series is not available. In the present study, we retrospectively reviewed the history of mechanical injury, aiming to establish an association between mechanical injury and the onset of RPC.

Patients
This study included 127 RPC patients who were hospitalized and followed-up by rheumatologists at our hospital between January, 2008 and March, 2020. RPC was diagnosed based on traditional criteria proposed by Michet et al. [9] and Damiani et al [10]. Partial and limited RPC was also de ned as suggested by Mathew et al. [11] and our previous report [12]. Patients younger than 18 years and patients with positive anti-neutrophilic cytoplasmic antibody (ANCA) were excluded as suggested by Piette and colleagues [13]. The history of trauma or surgery was reviewed and con rmed. The sites and type of surgery or trauma and the intervals between these events and disease onset were recorded. Additionally, the demographic data, clinical manifestations, in ammatory index, survival data were all recorded during follow-up.

Statistical Analysis
Descriptive statistics were used to describe type of mechanical events and chronological occurrence, and all results were expressed as mean±standard deviation (SD), or percentage (%) where appropriate. Comparisons of continuous variables were performed using Student's t-test. Categorical data were compared using Chi-squared or Fisher's exact test. Kaplan-Meier curves were generated to estimate the survival rates. Statistical signi cance was de ned as two-sided P value < 0.05. Statistical analyses were performed using the SPSS version 17.0 software package (IBM).

Description of mechanical injuries
Out of the 127 RPC patients, 54 patients (42.5%) had 63 mechanical injuries, including 47 surgical procedures and 16 traumatic events, among which 9 patients experienced two mechanical or traumatic events (7 patients with two surgical procedures and 2 patients with one traumatic event and one surgical procedure each).
Trends of cartilage related and non-cartilage related injuries was showed in gure 1 in chronological order (Supplementary gure 1 for more details). The earliest mechanical injury occurred 40 years before disease onset, and there were only occasional mechanical injury until 5 years before disease onset. Mechanical injuries (both cartilage related and non-cartilage related) peaked in the preceding one year, especially 6 months, before disease onset. Thirty mechanical injuries in 28 patients occurred in the preceding one year before disease onset.
Characteristics of patients with mechanical injuries RPC patients with mechanical injuries (group A, n=54) presented similar features to those without injuries (group B, n=73) regarding clinical manifestations and mortality rate, except a signi cantly higher proportion of female gender in group A (59.3% vs 38.4%, P=0.002) (Figure 2A and Supplementary Table  1). In addition, there was no difference of the survival curve between these two groups of patients ( Figure  2C).

Discussion
This is the rst case series that describe mechanical injuries as triggering factors among relapsing polychondritis patients. Two fths of our patients ever had mechanical injuries while one fth had mechanical injury in the preceding one year before disease onset. RPC patients with cartilage-injury seem to be more severe than those without, since they had higher incidence of airway involvement and relative lower survival rate.
Several RPC cases triggered by auricular piercing have been reported [6,7]. However, most of our cartilageinjured patients experienced not only auricular injury, but also injury of nasal cartilage, laryngotracheal cartilage, voice cord, external auditory canal and mandible (tooth extraction), which expanded the triggering factors related to cartilage injury. Interestingly, some of our patients underwent surgical procedures or trauma that did not affect cartilaginous tissues, such as surgical procedures of intestinal tract, breast, thyroid, obstetric and ophthalmologic operations, which has never been reported. Our ndings suggest that both cartilage-related and non-cartilage-related injury may be triggers of RPC. One reasonable explanation is that these injured structures share the same antigens in extra-cellular matrix, including collagens, cartilage oligomeric matrix protein (COMP) and matrilins (see online supplementary  table 3 and supplementary text), which can be exposed after mechanical injury, causing activation of the immune system by multiple signaling pathways as hypothesized by Carlos A. C and colleagues [14].
Another point that should be stressed is that some mechanical injuries occurred many years before disease onset, which makes the link between mechanical injuries and PRC pathogenesis elusive. We postulated that these injuries may be the rst striking initiating low-grade immune response until reaching the threshold, and the second hits, which are not clear yet, may lead to the onset of RPC. Similar scenarios have been noticed in different autoimmune in ammatory disease, such as rheumatoid arthritis, in which autoantibodies preceded the disease onset many years ago [15,16]. As such, we postulate that the mechanical injuries may predispose these patients to the risk of developing RPC.
Three fths of our patients did not have mechanical injuries, which indicates that there may be other triggering factors apart from mechanical injuries. For example, infection [17,18] and some drugs [19,20] was reported to be associated with RPC.
Limitations of the present study derive from its retrospective nature inherent to all retrospective studies, which may resulted in incomplete information regarding the history of mechanical injury. However, we telephoned to patients that could be connected to con rm this, which may overcome this shortcoming in some extent.

Conclusions
In summary, we report that two fths of our patients ever experience mechanical injuries before disease onset, which may con rm the triggering role of these mechanical events in pathogenesis of RPC. We believe this is the rst report of relatively large case series focusing on this topic, and further prospective study is needed to con rm the causal relationship between mechanical injury and RPC and the pathogenesis need to be investigated deeply to identify novel effective targets for intervention.

Consent for publication
Not applicable.

Availability of data and materials
The datasets analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare no con ict of interest.

Funding
No speci c funding was received from any bodies in the public, commercial or not-for-pro t sectors to carry out the work described in this article.
Author's Contributions L.Z., S.L. and T.L. designed the study; LZ., S.Y. T.W., Y.H., J.G., L.H., J.L., X.L., R.Y. and S.Z. collected the data; L.Z. and S.Y. analyzed data, performed statistical analysis and wrote the manuscript; T.L. revised the manuscript. All authors read and approved the nal manuscript. Figure 1 Chronological order of mechanical injuries that occurred before RPC onset.

Figure 2
Comparison between different RPC patients. A. Characteristics compared between patients with injury(group A, n=54) and those without(group B, n=73). B. Characteristics compared between patients with cartilage injury(group C, n=17) and those with non-cartilage injury(group D, n=37).For more detailed data, please see supplementary tables. C. Comparison of Kaplan-Meier survival curves between patients with injury(group A, n=54) and those without(group B, n=73). D. Comparison of Kaplan-Meier survival curves between patients with cartilage injury (group C, n=17) and those with non-cartilage injury(group D, n=37). *Numerical difference but without statistical signi cance, P>0.05 **Difference with statistical signi cance, P<0.05 Notes: Ear, auricular chondritis; Nose, nasal chondritis; Eye, eye in ammation; Trachea, tracheobronchial involvement; Larynx, Laryngeal involvement; Costal, costal chondritis.

Supplementary Files
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