Relapsing polychondritis: tracheobronchial involvement and differential diagnoses

Introduction

Relapsing polychondritis (RP) is a rare auto-immune disease, characterized by inflammatory flare-ups of cartilaginous tissues, associated with systemic manifestations. It has been first described in 1923 (1), but has really been highlighted in 1960 by Pearson et al. (2). The aim of our review is to update the knowledge of RP on clinical and therapeutical aspects, and to emphasize the differential diagnoses of a tracheobronchial involvement, in the context of recent description of a new entity, the Vacuoles, E1-enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome (3).

Epidemiology

RP mainly affects adults, with a mean age at diagnosis of 40 to 50 years old, but extreme ages of diagnosis have been described, ranging from 2 to 84 years (4,5). With a sex-ratio of two males for three females, there is a slight female predominance. However, it could be biased by the fact that VEXAS syndrome almost exclusively affects males, so the sex-ratio for RP could be closer to one male for three females (3,6-8). A study in the United Kingdom showed a prevalence of nine cases per million population between 2010 and 2012, with an overall incidence between 1990 and 2012 of 0.71 cases per million population (9).

Pathophysiology and histology

The cause of RP is still unknown. Genetic predispositions probably exist, with controversial findings regarding overrepresentation of some HLA genes, either HLA-DR4 alleles, either HLA-B*67:01, HLA-DRB1*16:02 or HLA-DQB1*15:02 (10-12). Recently, a whole-exome sequencing study has revealed variants in the DCBLD2 genes in two families of patients, with five carriers (13). Moreover, in the same study, RP patients had a higher plasma level of DCBLD2 protein compared to control patients, suggesting a possible role of this protein in the overall pathophysiology.

Histological analysis of chondritis during inflammatory phases shows a perichondral pleiomorphic infiltrate composed of lymphocytes T CD4⁺ and antigen-presenting cells. Immunoglobulins and C3 fraction deposition can be observed in active lesions. As the disease progresses, the inflammatory milieu and proteolytic enzymes lead to chondrocytes apoptosis. Total destruction of cartilaginous tissue leads to fibrous development even gelatinous involution or calcifications (11).

Antigenic targets are not well known. However, autoantibodies against cartilage components may be detected in RP patients (14). Mouse and rat models of immunization have shown the development of cartilage inflammation following exposure to cartilage components. All of this suggests that autoimmunity is involved in the natural history of the disease in several ways (15).

Clinical manifestations

During inflammatory phases, systemic symptoms such as altered general condition, sometimes associated with fever (15-18) are often reported. However, beyond being a sign of infectious complications, fever may also be a sign of another autoinflammatory disease, such as VEXAS syndrome (6-8).

Respiratory manifestations

Tracheobronchial chondritis

Found in 60% of RP patients, with a time to onset of 2.5 years if absent at diagnosis (18), tracheobronchial chondritis is characterized by cough and progressive dyspnea, inspiratory or expiratory, depending on the severity of obstruction. Less than 50% obstruction may not be noticed by patients, leading to late diagnosis. Chest auscultation during inflammatory flare-ups may detect stridor or wheezing, indicating severe airway diseases, depending on the site of inflammation (15-18). Inflammation and destruction of cartilaginous tissue results in loss of rigidity of the tracheobronchial tree, leading to either malacia, stenosis, and/or bronchiectasis, creating the conditions for infectious complications, particularly with immunosuppressive therapies (19-21). As described by Dion et al. (18) in their cluster 2, tracheobronchial involvement leads to 25% of intensive care admission, making this manifestation one of the most severe in RP patients, in relation to its frequency.

Laryngeal chondritis

Laryngeal chondritis is observed in 40% of cases (15-18,21), with various manifestations such as dry cough, hoarseness, dysphonia/aphonia, or thyroid cartilage pain. The inflammatory aspect of the larynx can be visualized by flexible nasendoscopy or bronchoscopy, with edema of the supraglottic region or the appearance of false vocal cords (19,20). The evolution can be severe with laryngomalacia or laryngeal stenosis, responsible for inspiratory dyspnea, leading to respiratory failure, requiring tracheostomy (15,16,20-22).

Costochondritis

Costochondritis is responsible for chest wall pain, parasternal or lateral pain, or back pain for floating ribs, increasing on palpation. It can also affect ventilatory mechanisms, especially during inspiratory phases (16,17,20).

Other clinical manifestations

Among the whole range of manifestations of RP, we can list the following ones:

• Auricular chondritis is almost pathognomonic of RP, occurring in approximately 90% of cases during the natural history of the disease, and its presence can be reported within 2 years of diagnosis in 25% of cases (9). It is characterized in the acute phase, by pain on palpation or pressure, associated with redness and swelling, localized to the cartilaginous tissues, sparing the earlobe. The sequelae include damage and distortion of the auricular relief, with an aspect called “cauliflower ear” (15-18,21).
• Nasal chondritis is less symptomatic and more common, with a prevalence of 60% cases, and is characterized by inflammation of the nasal cartilage, with symptoms of pain, nasal discharge, or obstruction. A deformity of the nasal bridge may be observed over time, known as “saddle nose” (15-18,21). This deformity can be seen in granulomatosis with polyangiitis (GPA), which is usually preceded by more pronounced symptoms.
• Joint manifestations can be isolated at the onset of RP. They are characterized by oligo- or polyarthritis, intermittent, migratory and asymmetric, without destruction. Large joints may be affected as well as small ones, such as metacarpophalangeal and interphalangeal joints, knees, ankles, or wrists (15-18,21).
• Ocular involvement is observed in 60% of cases and often precedes other manifestations (9). Various manifestations have been described, but the most common are episcleritis, scleritis, and conjunctivitis (15-18,21).
• Cochleo-vestibular manifestations are described in 20% to 45% of cases (15-18,21), dominated by sudden or progressive hearing loss, sometimes associated with vestibular dysfunction.
• Skin involvement is polymorphic with either recurrent buccal aphtosis, erythema nodosum-like nodules, purpura, or livedo (15-17,21).
• Cardiovascular involvement with aortic valve regurgitation, often combined with ascending aortic root dilatation, and/or mitral regurgitation (which may be present alone). Thoracic and/or abdominal aortitis can also be observed during RP history, with an evolution up to aneurysm. Other clinical manifestations include myocarditis, pericarditis, and atrio-ventricular block. There is also an increased risk of venous thrombosis (15-18,21,23).
• Neurologic manifestations, mainly of the central nervous system, with encephalitis or aseptic meningitis (15-18,21).

Diagnosis

The first diagnostic classification was made by McAdam in 1976 focusing essentially on clinical aspects, followed by one made by Damiani including histologic evidence or therapeutic response to corticosteroids and/or dapsone (24,25). It was thus abandoned in favor of Michet’s criteria, proposed in 1986 (26) (Table 1), which is the last known classification. Cartilage biopsy should not be performed as histology is not necessary to confirm the diagnosis.

Biological investigations

Specific markers of RP for diagnosis or activity do not exist at this time. An increase in C-reactive protein (CRP) can be observed during flares (17,18,21), but its normality cannot be used to exclude the diagnosis. It should also raise the question of an infectious complication or a differential diagnosis such as VEXAS syndrome (6-8). Auto-immunity testing may detect antinuclear antibodies without specificity, rheumatoid factor, or anti-neutrophil cytoplasmic antibodies (ANCAs) with atypical fluorescence (17,18,21). However, ANCA positivity with anti-proteinase 3 (PR3) specificity must orient the diagnosis to GPA.

Autoantibodies to cartilage components such as type II collagen, matrillin-1 (for tracheobronchial involvement), or cartilage oligomeric matrix protein (COMP) can be detected but should not be used in routine practice due to their low specificity and sensibility. Other biomarkers have been studied, such as serum soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), but none have been shown to be useful in diagnosis (14,27).

Evaluation of tracheobronchial involvement

Thoracic computed tomography (CT)

The first test to assess airway compromise is a cervico-thoracic CT scan. It should include the cervical portion of the trachea in addition to the thorax, with thin slices during the inspiratory and expiratory phases, and dynamic slices, to assess stenosis, tracheobronchomalacia (TBM), and small airway involvement. CT scan is also useful in the follow-up of the disease. The following abnormalities may be observed, at different stages of the disease (20,28-32):

• Tracheal anterior wall thickening, isolated or associated with bronchial wall thickening, with a threshold of 2 mm. Isolated bronchial thickening has never been described. Absence of posterior tracheal wall involvement is often described but may not be sufficient to diagnose RP. In fact, circumferential thickening may also be observed during flare-ups or after complete destruction of the tracheal structure. Furthermore, the evaluation of the anterior wall is difficult, with low inter-observer reproducibility. The density of the thickening is variable, corresponding either to fatty remodeling or to subsequent calcifications. Tracheal wall thickening can result in focal stenosis or a homogenous and extensive reduction of the tracheobronchial lumen, defined by a 25% caliber reduction (Figures 1,2).
• TBM on the expiratory and dynamic sections, corresponding to the complete destruction of the cartilaginous support (Figure 3).
• Small airway involvement by mosaic attenuation of lung parenchyma with air trapping, on expiratory slices, with a significance level of 25% of lung parenchyma affected.
• Bronchiectasis, but less frequent than other respiratory tract abnormalities.
• The role of magnetic resonance imaging has not been defined yet. Correlation between respiratory symptoms and airway damage at acquisition has been found, but its routine use should not be retained (20,30).

Figure 1 Thoracic CT scan, transverse section, non-injected, mediastinal window. Anterior tracheal wall thickening (arrow). CT, computed tomography.

Figure 2 Thoracic CT scan, transverse section, non-injected, mediastinal window. (A) Circumferential thickening of tracheal wall, responsible for tracheal stenosis (arrow). (B) Circumferential thickening of main left bronchus wall, responsible for bronchial stenosis (arrow). CT, computed tomography.

Figure 3 Thoracic CT scan, transverse section, non-injected, parenchymal window. Dynamic sections in inspiration (A) and expiration (B), showing a bronchial collapse during expiratory time, signaling a bronchomalacia. CT, computed tomography.

Positron emission tomography (PET)

18-Fluorodesoxyglucose (FDG)-PET scan is still a debatable place. Hypermetabolism can be found in ear, upper airway, tracheobronchial, costal, and articular cartilage, and can guide diagnosis in cases of asymptomatic involvement (33,34). When PET is helpful, at least two cartilaginous regions are involved in 80% of cases, with a median maximum standardized uptake value (SUVmax) between 4.94 and 6.47 (33,34). The correlation between clinical data and radiologic data seems to be excellent for the respiratory tract. Lei et al. described that 89.5% of patients with respiratory symptoms had hypermetabolism, and conversely, 89% of patients with hypermetabolism had respiratory symptoms (33). Hypermetabolism may also be a target for measuring treatment response (33,34) (Figure 4).

Figure 4 Tracheobronchial hypermetabolism during RP. Thoracic CT scan (A) related to 18-FDG PET scan (B) transverse section showing bronchial wall hypermetabolism (arrow). Thoracic CT scan (C) related to 18-FDG PET-CT (D) coronal section showing tracheobronchial wall hypermetabolism (arrows). RP, relapsing polychondritis; CT, computed tomography; 18-FDG, 18-fluorodesoxyglucose; PET, positron emission tomography.

Fiberoptic bronchoscopy

Fiberoptic bronchoscopy allows mapping of airway damage and should be performed with caution, in patients with respiratory symptoms. The endoscopic aspect is unspecific, associating mucous edema and inflammation (19,20,35). RP-associated stenoses are localized to the trachea, with a vocal cords distance of approximately 4 cm and a mean length of 4 cm (31) (Figure 5). Changes in endotracheal and endobronchial caliber during breathing and coughing allow a good evaluation of TBM with a good correlation with CT scan data (19,20,35). The risk of respiratory failure seems to correlate with inflammatory flare but has never been fully evaluated (20,36,37). However, spirometry parameters seem to correlate with an excess risk of respiratory failure, especially a low percent predicted forced vital capacity (38). Thus, flexible bronchoscopy should be discussed on a case-by-case basis, with the goal of mapping airway damage prior to treatment initiation, investigating infectious complications, or following up after a rigid bronchoscopy procedure. A temporary preventive increase in corticosteroids before bronchoscopy could be a solution to prevent inflammatory flare-ups.

Figure 5 Bronchoscopic views of tracheal stenosis.

Pulmonary function tests (PFTs)

PFTs are essential in the initial assessment and during follow-up. Spirometry is the minimum test required, combined with inspiratory maneuvers. Obstructive ventilatory impairment may be observed, with a lack of response to bronchodilators, due to a reduction in bronchial size or a diffuse bronchiolar involvement. Proximal obstruction can also be observed on spirometry, with different phenotypes, depending on localization and compliance: isolated inspiratory limitation [laryngeal or compliant extra-thoracic tracheal stenosis, with a decrease in forced inspiratory vital capacity (FIVC) and forced inspiratory flow at 50% of the vital capacity (FIF₅₀), and a FIF₅₀/forced expiratory flow at 50% of the vital capacity (FEF₅₀) ratio <1], isolated expiratory limitation [compliant intra-thoracic tracheal stenosis, with a decreasing in forced expiratory volume in the first second (FEV₁) and FEF₅₀] or both inspiratory and expiratory limitation (fixed tracheal stenosis) (20,39-42). The correlation between measurements and stenosis size is not perfect, but the temporal evolution is an essential element in the follow-up of RP.

Impulse oscillometry can be also used. Oscillometry can measure mechanical properties of the respiratory system in a passive manner, without the need to hold breath. Pressure oscillation is generating by a loudspeaker (or piston-type device or pneumatic valves) at specific frequencies (between 5 and 40 Hz). Flow modifications monitored by the sensor reflect the whole impedance of the respiratory system which can be linked to the resistance and the reactance of the respiratory system (43,44). It has already been used mainly in pediatrics. Recently, a Japanese study (45) found a correlation between radiological data of tracheal obstruction and lung function tests by spirometry and impulse oscillometry. It showed that FEV₁ and peak flow could be correlated to tracheal volume, tracheal volume/tracheal length, and minimal tracheal cross-section area. In addition, impulse oscillometry, particularly 5 Hz resistance, 20 Hz resistance, and 5 Hz reactance, could be correlated with tracheal volume.

Finally, the severity of obstruction could lead to hypercapnia and ultimately to hypoxemia, due to alveolar hypoventilation. It should be noted that pulmonary diffusion capacity is not affected by the disease.

Differential diagnoses

VEXAS syndrome

First described in 2020 by Beck et al. (3) in male patients with autoinflammatory symptoms and hematological abnormalities, VEXAS syndrome is associated with a mutation on UBA1 gene, located on the X chromosome. Its mutation leads to inactivation of the enzyme-1 protein, which is responsible for protein degradation through the ubiquitin-proteosome system (3,46).

Tracheobronchial chondritis in VEXAS syndrome is not always found in case series (6,7,46-49).

Besides overlap organ involvement between RP and VEXAS syndrome, particularly chondritis, arthritis, cochleovestibular, and central nervous system manifestations, some clinical manifestations appear to be more specific for VEXAS syndrome, and should help clinicians in their diagnosis:

• Male patients (X-linked mutation of UBA1) and age >60 years old (6-8,46-48).
• Fever at diagnosis (6-8,46-48), lymphadenopathy, or hepatosplenomegaly (47,48).
• Hematological abnormalities, ranging from macrocytosis, isolated thrombocytopenia, neutropenia, or monocytopenia, to myelodysplastic syndrome or other myeloid pathology. Lymphopenia, monoclonal gammopathy, or multiple myeloma have already been reported. Vacuolization within both erythroid and granulocytic immature forms can be seen in bone marrow aspiration smears can be found (6-8,46-48).
• Skin involvement, with neutrophilic dermatosis such as Sweet’s syndrome, often rich in immature myeloid cells and leukocytoclasis, with flares. Cutaneous vasculitis is not always described (6-8,46-48,50).
• Polymorphic pulmonary manifestations (6-8,46-48), with ground-glass opacities, septal thickening, mediastinal lymphadenopathies and unilateral exudative pleural effusion (49). Broncho-alveolar lavage shows neutrophilic alveolitis (49).
• Orbital or periorbital edema, sometimes associated with scleritis, episcleritis, uveitis, or retinal vasculitis (6-8,46-48).
• Peripheral neurological system manifestations with sensitive neuropathy or multiple mononeuropathy (47,48).
• Gastro-intestinal manifestations with abdominal pain, diarrhea up to intestinal perforation (8,47,48).
• Cardiovascular manifestations with myocarditis or pericarditis. Unprovoked venous thrombosis is common, and arterial thrombosis has also been described (6-8,46-48).
• Rare renal involvement has also been described, but semeiology is still confused between interstitial nephritis or glomerulopathy (7,8,46-48).

Laboratory tests can guide the diagnosis, with hematological abnormalities as previously described, or an increase in CRP levels being more important in VEXAS syndrome than in RP patients (6-8,46-48). Confirmation of the diagnosis is based on UBA1 mutation identification in peripheral blood (3,46).

VEXAS syndrome has a worse prognosis compared to RP, with a mortality rate of up to 40% at 5 years of diagnosis, mainly depending on UBA1 variants, compared to 2–3% at 5 years of diagnosis in RP patients (6,7,18,46,48).

GPA

Tracheal involvement is one of the systemic manifestations of GPA. It represents 1–5% of localized forms (51,52), and may be the initiating event in 20% of cases (53,54). Bronchial involvement may be associated or rarely isolated (53). The age of diagnosis is younger than in RP patients, with a median age of 35 to 40 years (31,53). In cases of localized tracheal disease, the associated manifestations are dominated by ear, nose, throat (ENT) symptoms such as rhinitis and nasal crusts, with a prevalence of around 80%. Pulmonary involvement and arthritis can also be observed in 40% to 60% of cases, and finally skin manifestations and renal involvement in 25% of cases (53). ANCA are positive in 50–60% of cases, with a specificity of 90% for anti-PR3. Rare anti-myeloperoxidase (MPO) specificities have been described, in 10–25% of cases (31,53,54). Chest CT scan shows sub-glottic circumferential stenosis, with cartilaginous erosions and rare calcifications. In addition, lung parenchymal abnormalities such as nodules, ground glass opacities (corresponding to intra-alveolar hemorrhage or non-specific interstitial pneumonia), or the usual interstitial pneumonia pattern may be observed, suggesting another diagnosis than RP, which does not have parenchymal abnormalities (29,31,32,54). Flexible bronchoscopy confirms the presence of a short subglottic stenosis (median distance to the vocal cords about 1 cm, with a length of about 1.5 cm) (29,31,35), sometimes with inflammatory ulcers. The previously described clinical manifestations and ANCA positivity are key in differentiating between GPA and RP.

Sarcoidosis

Sarcoidosis can cause bronchial stenosis, with a prevalence of 1%, mainly proximal, involving multiple bronchus on upper and middle lobes (55). CT scan shows irregular thickening of the bronchial wall with narrowing of the lumen (55). Stenoses are confirmed by flexible bronchoscopy, showing mucosal edema and fine whitish granulations or “cobblestone” nodules close to the narrowing (35,55). Histological examination reveals non-necrotizing epithelioid cell-rich granulomas (56). Stenosis is associated with obstructive ventilatory impairment, without reversibility to bronchodilator challenge (55). Such findings lead to corticosteroids therapy (56). Tracheobronchial obstruction may also be caused by lymph node compression or fibrosing mediastinitis (55-57).

Inflammatory bowel diseases (IBDs)

The prevalence of thoracic manifestations of IBDs, notably Crohn’s disease or ulcerative colitis (UC) is difficult to assess. Case series have reported up to 50% of symptomatic patients, with variable radiological findings. Airway involvement is seen in 39% of cases, with a median age around 50 years, a female predominance and a previous diagnosis of UC (58,59). Patients usually present with other extra-thoracic and digestive manifestations, such as thrombotic microangiopathy, pyoderma gangrenosum, primary sclerosing cholangitis, episcleritis, or arthritis (58). In terms of airway involvement, bronchiectasis, and bronchiolar disease are the most common manifestations. Rare cases of tracheal disease have been reported. Circumferential thickening of the tracheal wall is seen on CT scan, while endoscopic evaluation may reveal mucosal ulceration, with fibrin deposition on an inflammatory mucosa (29,59).

Mucous membrane pemphigoid

The mucocutaneous pemphigoid group, which includes cicatricial pemphigoid, mucocutaneous epidermolysis bullosa acquisita, linear immunoglobulin A (IgA) dermatosis, and lichen planus pemphigoid is an autoimmune bullous dermatosis with mucosal manifestations. It is a rare disease, with two cases per million population, a mean age at diagnosis of 65 years, and a slight female predominance. The mucosal manifestations are localized in order of frequency, to the mouth, eyes, ENT, genitals, anus, esophagus, and then larynx, while the skin is involved in 35% of cases. The pathophysiology is explained by the production of autoantibodies against the basal membrane, leading to dermo-epidermal sloughing and blistering. Tracheobronchial involvement has recently been described. It appears to affect younger patients, with more severe and multifocal disease. Respiratory symptoms (dyspnea, cough, dysphonia, hemoptysis) are rare but should alert clinicians to the appearance of such involvement. Flexible bronchoscopy findings are variable, with inflammatory mucosa, erosions, and ulcerations, sometimes associated with subsequent stenosis. The diagnosis is confirmed by dedicated mucosal or cutaneous histological examination with basal membrane C3 and immunoglobulin G (IgG) deposits on direct immunofluorescence (60-64).

Tracheobronchial amyloidosis

Tracheobronchial amyloidosis is a rare disease, accounting for 1.1% of all amyloidosis involvements (65), but reaching a prevalence of 10% in multi-organ amyloidosis (66). Focusing on localized thoracic amyloidosis (including lung parenchyma), tracheobronchial amyloidosis represents 50% of cases, sometimes combined with parenchyma nodular disease or diffuse interstitial disease (65,67). The majority of tracheobronchial amyloidosis is AL type, but the association with multiple myeloma is rare. Diagnosis occurs at around 50–60 years of age, with a balanced sex-ratio. Respiratory symptoms are non-specific except hemoptysis (65,68). CT scans show irregular circumferential thickening of the tracheal wall, associated with calcifications, and sometimes lung parenchymal lesions including isolated nodules, cysts, or association between micronodules, septal thickening, and reticulations. Lung involvement or mediastino-hilar lymph node findings must lead to investigation for systemic amyloidosis (66,68). Flexible bronchoscopy is a key investigation, with diffuse grey or whitish “cobblestone” submucosal deposits, spontaneous contact bleeding leading to tracheal lumen narrowing (65,68). Biopsy should be performed to increase the diagnostic yield, but with caution, due to easily bleeding lesions (68), consequences of specific vascular involvement or coagulation factor IX and X deficiency mainly seen in systemic amyloidosis.

IgG4-related disease

IgG4-related disease is a systemic chronic fibro-inflammatory disease characterized by a non-clonal lymphoplasmacytic infiltrate, secreting IgG4 associated with storiform fibrosis and obliterating phlebitis. The age at diagnosis is 60 years old, with a balanced sex ratio. Thoracic involvement is pleomorphic, involving all compartments from the airways to the pleura, including the mediastinum, and occurs in 35% of cases overall, but is isolated in 20% of cases (65,69). Chest imaging may reveal lung parenchymal nodules, ground glass opacities, peribronchovascular thickening, associated with interstitial lung disease, mediastino-hilar lymph nodes or pleural thickening. Mediastinal involvement (3–6% of cases) may be fibrosing, leading to compression of vascular structure, lower part of the trachea and main bronchi (57,69). One of the characteristic aspects on CT scan is thoracic paravertebral band-like soft tissue thickening, right-localized, with two-vertebral height (69,70). An elevated plasma or serum IgG4 level >135 mg/dL is present in more than 50% of cases (65,69,70). Other organ involvement such as lachrymal and salivary glands, pancreas, biliary tree or kidney and biological findings like CRP elevation, hypergammaglobulinemia or hypereosinophilia can guide the diagnosis (70). 18-FDG PET scan can be useful to assess organ involvement, with particular sensitivity for arteries, lymph nodes or salivary glands. It also can be used to target an active disease site before biopsy, to monitor therapeutic response or to detect disease relapse (69). Salivary gland biopsy may be useful as a first-line test before moving to more invasive procedures such as endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or CT-guided transthoracic needle biopsy (69,70).

Anthracofibrosis

Anthracofibrosis is an association between endobronchial anthracosis deposits and peribronchial fibrosis resulting in stenosis. Anthracosis deposits are a consequence of inhalation of particles such as tobacco smoke, biomass smoke (from home heating or cooking), or occupational exposures associated with coal mining or other carbon particles (e.g., silica) from rock drilling (71,72). No element can predict the development of fibrosis although coal exposure appears to be one of the key elements (72). The topography of the lesions is mainly in the upper and middle lobes, with multiple involvement in 50% of cases. CT scan may show bronchial wall thickening, stenosis and segmental atelectasis secondary to bronchial obstruction. Flexible bronchoscopy is necessary to visualize and map the lesions to confirm the diagnosis (29,72).

Tracheobronchopathia osteochondroplastica

Tracheobronchopathia osteochondroplastica is a rare disease, of unknown origin with a prevalence between 0.01% and 0.8% based on overall flexible bronchoscopy findings, according to a Chinese cohort study (73). It occurs around 50 years of age, mostly in male patients, with active or former smoking status or occupational exposure to particles. It is characterized by submucosal osteo-cartilaginous nodules in continuity with the tracheobronchial cartilage, which explains a strict localization on the antero-lateral tracheal wall and complete sparing of the posterior wall. CT scan and bronchoscopy findings show a pearly appearance of the tracheal wall, with antero-lateral calcified nodules, including the main bronchus, leading to stenosis (29,73,74).

Idiopathic subglottic stenosis

Idiopathic subglottic stenosis is a predominantly female disease, diagnosed between 30 and 60 years of age, with a prevalence of one case per 400,000 population (75). The pathophysiology remains unclear but the female predominance suggests that an underlying hormonal mechanism may be at the origin of the disease. A recent histologic study on surgical resection specimens (76) showed an overexpression of progesterone and estrogen receptors on fibroblasts of idiopathic subglottic stenosis compared to post-traumatic stenosis. Symptoms are not specific and are indicative of the disease when the stenosis exceeds 50% of tracheal caliber. CT scan and flexible bronchoscopy allow a complete evaluation of stenosis and malacia, before deciding on treatment (75).

The remaining differential diagnoses of tracheobronchial stenosis are detailed in Table 2.

Evolution and prognosis

RP evolves through inflammatory flares and remission phases, with the risk of developing severe manifestations such as respiratory manifestations. Myelodysplastic syndrome was considered a poor prognosis marker prior to the discovery of VEXAS syndrome, explaining the specific phenotype described in previous studies (9,18,26). Besides myelodysplastic syndrome, respiratory and cardiac involvement remain the most severe disease manifestations that affect the prognosis. The study conducted by Dion et al. (18) found an overall survival probability of 94% and 83% at 5 years and 10 years, respectively, from the first symptoms but the respiratory manifestation cluster shows a decrease in survival later, after 20–30 years of follow-up. Recently, Shimizu et al. (83) compared cohorts of RP patients in 2009 and 2019. Mortality decreased significantly over the decade, from 9% in 2009 to 2% in 2019, which could be related to a decrease in the prevalence of airway involvement (49% in 2009, 37% in 2019). The improvement in survival can be explained by the expansion of therapeutic options, with immunosuppressive therapies and biotherapies, that allow rapid and prolonged control of the disease, as soon as the diagnosis is made with less side effects due to steroid treatments. Activity [Relapsing Polychondritis Disease Activity Index (84)] and damages [Relapsing Polychondritis Damage Index (85)] scores have been developed to facilitate the follow-up of RP patients and the assessment of treatment response. However, many items in these scores overlap with the manifestations of VEXAS syndrome, questioning their actual use in routine practice.

Treatment

Medical management

Respiratory involvement in RP is considered as one of the most severe manifestations, which can lead to life-threatening outcomes and functional sequelae if treated late. Most recent guidelines are not based on strong evidence due to the low prevalence of the disease but also to the majority of retrospective studies available.

High-dose corticosteroid therapy should be initiated as first-line treatment with 1 mg/kg prednisone, preceded by methylprednisolone pulses (250–1,000 mg/day for 1 to 3 days) in case of acute respiratory failure (17). Concomitant adjunction of immunosuppressive therapy is usually given with cyclophosphamide (0.5–0.7 g/m²), following the same pattern as in necrotizing vasculitis. Rituximab is not recommended because of the low response rate (86-88). Maintenance treatment after induction phase is also based on immunosuppressive therapy, with methotrexate, azathioprine and, more recently, mycophenolate mofetil (MMF) often used (17,88). The emergence of biotherapies has opened new perspectives in treatment, especially for cortico-resistant/dependent form or refractory to classical immunosuppressive therapies. Their use could be alone or in combination with another immunosuppressive agent such as MMF. A recent review published in 2018 (88) seems to indicate that for respiratory involvement, the use of tumor necrosis factor-α (TNF-α) inhibitors (infliximab, adalimumab, etanercept), tocilizumab or abatacept could allow a significant reduction in activity for 6 months, with an impact on overall survival. These data have been confirmed by Petitdemange et al. (89) with a response rate around 64% for TNF-α inhibitors (and perhaps better for tocilizumab and abatacept, but with less solid results because of their rare use).

Surgical management

Management of the sequelae of tracheobronchial stenosis is the main goal of local treatment. Advances in rigid bronchoscopy have multiplied the therapeutic options. A complete laryngeal and tracheobronchial evaluation must be performed before any treatment decision.

The choice of treatment depends on the focal or diffuse nature of the residual stenosis. In case of focal stenosis, balloon dilatation may be preferred. In case of recurrence of focal stenosis, or the presence of diffuse stenosis, or an association with malacia, tracheal prosthesis, straight or “Y” shaped, could be proposed, depending on the topography (90,91). Nevertheless, specific complications of tracheal prostheses cannot be ignored, such as prosthesis migration, obstruction with granulomatous tissue, or infectious complications due to endotracheal secretion stagnation (20,90-93). In extreme cases, perforation or complete rupture of tracheal wall (due to loss of stiffness) have been reported (93). Veno-venous extracorporeal membrane oxygenation may be required during rigid bronchoscopy in the most severe cases (93,94). Long-term benefit seems encouraging with a prolonged improvement, in subjective and objective assessment of dyspnea, FEV₁ or 6-min walk test (92).

Tracheotomy or Montgomery tube should be considered in case of initial acute respiratory failure with recourse to orotracheal intubation or subglottic stenosis (95). In the study by Catano et al. (31), balloon dilatation was used in 52% of RP patients, prosthesis in 38% and tracheotomy in 14% of patients. In the case of severe isolated TBM, external airway splinting could be proposed, consisting of posterior tracheal wall fixation on non-resorbable synthetic splints (e.g., Gore-Tex^®) (90,95). Although tracheobronchial reconstruction with stented aortic matrices (96,97), has made steady progress in recent years, it has not been evaluated in RP patients.

Supportive care

Finally, non-invasive positive pressure ventilation may be used in addition to systemic and surgical treatment to manage respiratory involvement. No clinical evaluation has been done, but positive pressure ventilation could benefit patients with malacia, even more if chronic hypercapnia has been demonstrated (20,98).

It is important not to neglect general infection prevention measures, such as up-to-date vaccinations [pneumococcal, influenza and severe acute respiratory syndrome coronavirus (SARS-CoV)] and infections related to immunosuppressive therapies (such as Pseudomonas aeruginosa colonization). Respiratory kinesitherapy and maintaining daily physical activity is also strongly encouraged in the context of these chronic diseases characterized by reactive psychological disorders.

A multidisciplinary approach, with appropriate support, can help to Improve the overall quality of life of RP patients.

Conclusions

RP is a rare auto-immune disease. Pathophysiology understanding has progressed but there are still gray areas, which limits improvement in therapeutical management. Differentiating RP from its differential diagnoses can be challenging, because of the absence of specific markers leading to RP diagnosis. Although therapeutic strategies are improving, the evidence base is poor and includes retrospective studies. A multidisciplinary approach including at least pulmonologists, rheumatologists, and surgeons is essential to ascertain an accurate diagnosis before deciding the best management between medical treatment, surgical treatment, and supportive care.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1603/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1603/coif). A.M. received a research grant from Sobi, participated in systemic lupus advisory board for AstraZeneca; received compensation for expert testimony for GSK; received compensation for attending meetings and/or travel from AstraZeneca, GSK, Novartis, and Otsuka; and received consultant and speaker fees from AstraZeneca, GSK, Novartis, and Otsuka. T.G. received compensation from Roche SAS and Oxyvie. Y.U. received compensation for consultancy, lecturing and conference attendance from Boehringer Ingelheim, Sanofi, CSL-Vifor, GSK, and Oxyvie. 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.

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References

1. Jaksch-Wartenhorst R. Polychondropathia. Wien Arch Inn Med 1923;6:93-100.
2. Pearson CM, Kline HM, Newcomer VD. Relapsing polychondritis. N Engl J Med 1960;263:51-8. [Crossref] [PubMed]
3. Beck DB, Ferrada MA, Sikora KA, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 2020;383:2628-38. [Crossref] [PubMed]
4. Belot A, Duquesne A, Job-Deslandre C, et al. Pediatric-onset relapsing polychondritis: case series and systematic review. J Pediatr 2010;156:484-9. [Crossref] [PubMed]
5. Trentham DE, Le CH. Relapsing polychondritis. Ann Intern Med 1998;129:114-22. [Crossref] [PubMed]
6. Ferrada MA, Sikora KA, Luo Y, et al. Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS. Arthritis Rheumatol 2021;73:1886-95. [Crossref] [PubMed]
7. Khitri MY, Guedon AF, Georgin-Lavialle S, et al. Comparison between idiopathic and VEXAS-relapsing polychondritis: analysis of a French case series of 95 patients. RMD Open 2022;8:e002255. [Crossref] [PubMed]
8. Bruno A, Gurnari C, Alexander T, et al. Autoimmune manifestations in VEXAS: Opportunities for integration and pitfalls to interpretation. J Allergy Clin Immunol 2023;151:1204-14. [Crossref] [PubMed]
9. Hazra N, Dregan A, Charlton J, et al. Incidence and mortality of relapsing polychondritis in the UK: a population-based cohort study. Rheumatology (Oxford) 2015;54:2181-7. [Crossref] [PubMed]
10. Zeuner M, Straub RH, Rauh G, et al. Relapsing polychondritis: clinical and immunogenetic analysis of 62 patients. J Rheumatol 1997;24:96-101. [PubMed]
11. Arnaud L, Mathian A, Haroche J, et al. Pathogenesis of relapsing polychondritis: a 2013 update. Autoimmun Rev 2014;13:90-5. [Crossref] [PubMed]
12. Terao C, Yoshifuji H, Yamano Y, et al. Genotyping of relapsing polychondritis identified novel susceptibility HLA alleles and distinct genetic characteristics from other rheumatic diseases. Rheumatology (Oxford) 2016;55:1686-92. [Crossref] [PubMed]
13. Luo Y, Ferrada MA, Sikora KA, et al. Ultra-rare genetic variation in relapsing polychondritis: a whole-exome sequencing study. Ann Rheum Dis 2024;83:253-60. [Crossref] [PubMed]
14. Liu Y, Li X, Cheng L, et al. Progress and challenges in the use of blood biomarkers in relapsing polychondritis. Clin Exp Immunol 2023;212:199-211. [Crossref] [PubMed]
15. Longo L, Greco A, Rea A, et al. Relapsing polychondritis: A clinical update. Autoimmun Rev 2016;15:539-43. [Crossref] [PubMed]
16. Puéchal X, Terrier B, Mouthon L, et al. Relapsing polychondritis. Joint Bone Spine 2014;81:118-24. [Crossref] [PubMed]
17. Mathian A, Miyara M, Cohen-Aubart F, et al. Relapsing polychondritis: A 2016 update on clinical features, diagnostic tools, treatment and biological drug use. Best Pract Res Clin Rheumatol 2016;30:316-33. [Crossref] [PubMed]
18. Dion J, Costedoat-Chalumeau N, Sène D, et al. Relapsing Polychondritis Can Be Characterized by Three Different Clinical Phenotypes: Analysis of a Recent Series of 142 Patients. Arthritis Rheumatol 2016;68:2992-3001. [Crossref] [PubMed]
19. Ernst A, Rafeq S, Boiselle P, et al. Relapsing polychondritis and airway involvement. Chest 2009;135:1024-30. [Crossref] [PubMed]
20. de Montmollin N, Dusser D, Lorut C, et al. Tracheobronchial involvement of relapsing polychondritis. Autoimmun Rev 2019;18:102353. [Crossref] [PubMed]
21. Chen N, Zheng Y. Characteristics and Clinical Outcomes of 295 Patients With Relapsing Polychondritis. J Rheumatol 2021;48:1876-82. [Crossref] [PubMed]
22. Xie C, Shah N, Shah PL, et al. Laryngotracheal reconstruction for relapsing polychondritis: case report and review of the literature. J Laryngol Otol 2013;127:932-5. [Crossref] [PubMed]
23. Le Besnerais M, Arnaud L, Boutémy J, et al. Aortic involvement in relapsing polychondritis. Joint Bone Spine 2018;85:345-51. [Crossref] [PubMed]
24. McAdam LP, O'Hanlan MA, Bluestone R, et al. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore) 1976;55:193-215. [Crossref] [PubMed]
25. Damiani JM, Levine HL. Relapsing polychondritis--report of ten cases. Laryngoscope 1979;89:929-46. [Crossref] [PubMed]
26. Michet CJ Jr, McKenna CH, Luthra HS, et al. Relapsing polychondritis. Survival and predictive role of early disease manifestations. Ann Intern Med 1986;104:74-8. [Crossref] [PubMed]
27. Rednic S, Damian L, Talarico R, et al. Relapsing polychondritis: state of the art on clinical practice guidelines. RMD Open 2018;4:e000788. [Crossref] [PubMed]
28. Lee KS, Ernst A, Trentham DE, et al. Relapsing polychondritis: prevalence of expiratory CT airway abnormalities. Radiology 2006;240:565-73. [Crossref] [PubMed]
29. Grenier PA, Beigelman-Aubry C, Brillet PY. Nonneoplastic tracheal and bronchial stenoses. Thorac Surg Clin 2010;20:47-64. [Crossref] [PubMed]
30. Thaiss WM, Nikolaou K, Spengler W, et al. Imaging diagnosis in relapsing polychondritis and correlation with clinical and serological data. Skeletal Radiol 2016;45:339-46. [Crossref] [PubMed]
31. Catano J, Uzunhan Y, Paule R, et al. Presentation, Diagnosis, and Management of Subglottic and Tracheal Stenosis During Systemic Inflammatory Diseases. Chest 2022;161:257-65. [Crossref] [PubMed]
32. Jalaber C, Puéchal X, Saab I, et al. Differentiating tracheobronchial involvement in granulomatosis with polyangiitis and relapsing polychondritis on chest CT: a cohort study. Arthritis Res Ther 2022;24:241. [Crossref] [PubMed]
33. Lei W, Zeng H, Zeng DX, et al. (18)F-FDG PET-CT: a powerful tool for the diagnosis and treatment of relapsing polychondritis. Br J Radiol 2016;89:20150695. [Crossref] [PubMed]
34. Yamashita H, Takahashi H, Kubota K, et al. Utility of fluorodeoxyglucose positron emission tomography/computed tomography for early diagnosis and evaluation of disease activity of relapsing polychondritis: a case series and literature review. Rheumatology (Oxford) 2014;53:1482-90. [Crossref] [PubMed]
35. Prince JS, Duhamel DR, Levin DL, et al. Nonneoplastic lesions of the tracheobronchial wall: radiologic findings with bronchoscopic correlation. Radiographics 2002;22:S215-30. [Crossref] [PubMed]
36. Ernst A, Feller-Kopman D, Becker HD, et al. Central airway obstruction. Am J Respir Crit Care Med 2004;169:1278-97. [Crossref] [PubMed]
37. Rafeq S, Trentham D, Ernst A. Pulmonary manifestations of relapsing polychondritis. Clin Chest Med 2010;31:513-8. [Crossref] [PubMed]
38. Wang ST, Wang J, Gao X, et al. Risk factors associated with severe adverse events in patients with relapsing polychondritis undergoing flexible bronchoscopy. Orphanet J Rare Dis 2024;19:54. [Crossref] [PubMed]
39. Mohsenifar Z, Tashkin DP, Carson SA, et al. Pulmonary function in patients with relapsing polychondritis. Chest 1982;81:711-7. [Crossref] [PubMed]
40. Tillie-Leblond I, Wallaert B, Leblond D, et al. Respiratory involvement in relapsing polychondritis. Clinical, functional, endoscopic, and radiographic evaluations. Medicine (Baltimore) 1998;77:168-76. [Crossref] [PubMed]
41. Graham BL, Steenbruggen I, Miller MR, et al. Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med 2019;200:e70-88. [Crossref] [PubMed]
42. Stanojevic S, Kaminsky DA, Miller MR, et al. ERS/ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J 2022;60:2101499. [Crossref] [PubMed]
43. King GG, Bates J, Berger KI, et al. Technical standards for respiratory oscillometry. Eur Respir J 2020;55:1900753. [Crossref] [PubMed]
44. Kaminsky DA, Simpson SJ, Berger KI, et al. Clinical significance and applications of oscillometry. Eur Respir Rev 2022;31:210208. [Crossref] [PubMed]
45. Tsuruoka H, Handa H, Yamashiro T, et al. Correlation between Computed Tomographic Analysis and Pulmonary Function Measurements in Patients with Relapsing Polychondritis. Respiration 2021;100:109-15. [Crossref] [PubMed]
46. Koster MJ, Lasho TL, Olteanu H, et al. VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management. Am J Hematol 2024;99:284-99. [Crossref] [PubMed]
47. van der Made CI, Potjewijd J, Hoogstins A, et al. Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS. J Allergy Clin Immunol 2022;149:432-439.e4. [Crossref] [PubMed]
48. Georgin-Lavialle S, Terrier B, Guedon AF, et al. Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients. Br J Dermatol 2022;186:564-74. [Crossref] [PubMed]
49. Borie R, Debray MP, Guedon AF, et al. Pleuropulmonary Manifestations of Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome. Chest 2023;163:575-85. [Crossref] [PubMed]
50. Zakine È, Papageorgiou L, Bourguiba R, et al. Clinical and pathological features of cutaneous manifestations in VEXAS syndrome: A multicenter retrospective study of 59 cases. J Am Acad Dermatol 2023;88:917-20. [Crossref] [PubMed]
51. Iudici M, Pagnoux C, Courvoisier DS, et al. Localized versus systemic granulomatosis with polyangiitis: data from the French Vasculitis Study Group Registry. Rheumatology (Oxford) 2022;61:2464-71. [Crossref] [PubMed]
52. Iudici M, Pagnoux C, Courvoisier DS, et al. Granulomatosis with polyangiitis: Study of 795 patients from the French Vasculitis Study Group registry. Semin Arthritis Rheum 2021;51:339-46. [Crossref] [PubMed]
53. Terrier B, Dechartres A, Girard C, et al. Granulomatosis with polyangiitis: endoscopic management of tracheobronchial stenosis: results from a multicentre experience. Rheumatology (Oxford) 2015;54:1852-7. [Crossref] [PubMed]
54. Marroquín-Fabián E, Ruiz N, Mena-Zúñiga J, et al. Frequency, treatment, evolution, and factors associated with the presence of tracheobronchial stenoses in granulomatosis with polyangiitis. Retrospective analysis of a case series from a single respiratory referral center. Semin Arthritis Rheum 2019;48:714-9. [Crossref] [PubMed]
55. Chambellan A, Turbie P, Nunes H, et al. Endoluminal stenosis of proximal bronchi in sarcoidosis: bronchoscopy, function, and evolution. Chest 2005;127:472-81. [Crossref] [PubMed]
56. Valeyre D, Prasse A, Nunes H, et al. Sarcoidosis. Lancet 2014;383:1155-67. [Crossref] [PubMed]
57. Tabotta F, Ferretti GR, Prosch H, et al. Imaging features and differential diagnoses of non-neoplastic diffuse mediastinal diseases. Insights Imaging 2020;11:111. [Crossref] [PubMed]
58. Black H, Mendoza M, Murin S. Thoracic manifestations of inflammatory bowel disease. Chest 2007;131:524-32. [Crossref] [PubMed]
59. Ji XQ, Wang LX, Lu DG. Pulmonary manifestations of inflammatory bowel disease. World J Gastroenterol 2014;20:13501-11. [Crossref] [PubMed]
60. Jalil BA, Abdou YG, Rosen SA, et al. Mucous Membrane Pemphigoid Causing Central Airway Obstruction. J Bronchology Interv Pulmonol 2017;24:334-8. [Crossref] [PubMed]
61. Ahmed AR, Aksoy M, Kinane TB. Pemphigoid of the pulmonary system (POPS): A review of a less recognized feature. Autoimmun Rev 2022;21:103180. [Crossref] [PubMed]
62. Rousset L, Bohelay G, Gille T, et al. Bronchial involvement in mucous membrane pemphigoid: 2 cases and a literature review. Ann Dermatol Venereol 2023;150:64-70. [Crossref] [PubMed]
63. Rashid H, Lamberts A, Borradori L, et al. European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part I. J Eur Acad Dermatol Venereol 2021;35:1750-64. [Crossref] [PubMed]
64. Schmidt E, Rashid H, Marzano AV, et al. European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II. J Eur Acad Dermatol Venereol 2021;35:1926-48. [Crossref] [PubMed]
65. Uzunhan Y, Jeny F, Kambouchner M, et al. The Lung in Dysregulated States of Humoral Immunity. Respiration 2017;94:389-404. [Crossref] [PubMed]
66. Rech JS, Arnulf B, de Margerie-Mellon C, et al. Lower respiratory tract amyloidosis: Presentation, survival and prognostic factors. A multicenter consecutive case series. Am J Hematol 2019;94:1214-26. [Crossref] [PubMed]
67. Mahmood S, Bridoux F, Venner CP, et al. Natural history and outcomes in localised immunoglobulin light-chain amyloidosis: a long-term observational study. Lancet Haematol 2015;2:e241-50. [Crossref] [PubMed]
68. Milani P, Basset M, Russo F, et al. The lung in amyloidosis. Eur Respir Rev 2017;26:170046. [Crossref] [PubMed]
69. Muller R, Ebbo M, Habert P, et al. Thoracic manifestations of IgG4-related disease. Respirology 2023;28:120-31. [Crossref] [PubMed]
70. Wallace ZS, Naden RP, Chari S, et al. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol 2020;72:7-19. [Crossref] [PubMed]
71. Kim YJ, Jung CY, Shin HW, et al. Biomass smoke induced bronchial anthracofibrosis: presenting features and clinical course. Respir Med 2009;103:757-65. [Crossref] [PubMed]
72. Cho Y, Choi M, Myong JP, et al. The association between bronchial anthracofibrosis and pneumoconiosis: A retrospective cross-sectional study. J Occup Health 2015;57:110-7. [Crossref] [PubMed]
73. Zhu Y, Wu N, Huang HD, et al. A clinical study of tracheobronchopathia osteochondroplastica: findings from a large Chinese cohort. PLoS One 2014;9:e102068. [Crossref] [PubMed]
74. Dumazet A, Launois C, Lebargy F, et al. Tracheobronchopathia osteochondroplastica: clinical, bronchoscopic, and comorbid features in a case series. BMC Pulm Med 2022;22:423. [Crossref] [PubMed]
75. Aravena C, Almeida FA, Mukhopadhyay S, et al. Idiopathic subglottic stenosis: a review. J Thorac Dis 2020;12:1100-11. [Crossref] [PubMed]
76. Schweipert J, Riediger C, Balandat JE, et al. The role of local expression of hormone receptors in the genesis of idiopathic tracheal stenosis. J Thorac Dis 2023;15:2948-57. [Crossref] [PubMed]
77. Pathak V, Shepherd RW, Shojaee S. Tracheobronchial tuberculosis. J Thorac Dis 2016;8:3818-25. [Crossref] [PubMed]
78. Junker K. Pathology of tracheal tumors. Thorac Surg Clin 2014;24:7-11. [Crossref] [PubMed]
79. Gaafar HA, Gaafar AH, Nour YA. Rhinoscleroma: an updated experience through the last 10 years. Acta Otolaryngol 2011;131:440-6. [Crossref] [PubMed]
80. Songu M, Ozkul Y. Risk Factors for Adult Postintubation Tracheal Stenosis. J Craniofac Surg 2019;30:e447-50. [Crossref] [PubMed]
81. Mauhin W, Brassier A, London J, et al. Pulmonary phenotypes of inborn errors of metabolism. Rev Mal Respir 2022;39:758-77. [Crossref] [PubMed]
82. Fortes HR, von Ranke FM, Escuissato DL, et al. Recurrent respiratory papillomatosis: A state-of-the-art review. Respir Med 2017;126:116-21. [Crossref] [PubMed]
83. Shimizu J, Yamano Y, Kawahata K, et al. Nationwide cross-sectional survey of patients with relapsing polychondritis in 2019 demonstrates reduction of airway involvement compared with that in 2009. Sci Rep 2022;12:465. [Crossref] [PubMed]
84. Arnaud L, Devilliers H, Peng SL, et al. The Relapsing Polychondritis Disease Activity Index: development of a disease activity score for relapsing polychondritis. Autoimmun Rev 2012;12:204-9. [Crossref] [PubMed]
85. Mertz P, Belot A, Cervera R, et al. The relapsing polychondritis damage index (RPDAM): Development of a disease-specific damage score for relapsing polychondritis. Joint Bone Spine 2019;86:363-8. [Crossref] [PubMed]
86. Arnaud L, Costedoat-Chalumeau N, Mathian A, et al. French practical guidelines for the diagnosis and management of relapsing polychondritis. Rev Med Interne 2023;44:282-94. [Crossref] [PubMed]
87. Kemta Lekpa F, Kraus VB, Chevalier X. Biologics in relapsing polychondritis: a literature review. Semin Arthritis Rheum 2012;41:712-9. [Crossref] [PubMed]
88. Moulis G, Pugnet G, Costedoat-Chalumeau N, et al. Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study. Ann Rheum Dis 2018;77:1172-8. [Crossref] [PubMed]
89. Petitdemange A, Sztejkowski C, Damian L, et al. Treatment of relapsing polychondritis: a systematic review. Clin Exp Rheumatol 2022;40:81-5. [Crossref] [PubMed]
90. Sarodia BD, Dasgupta A, Mehta AC. Management of airway manifestations of relapsing polychondritis: case reports and review of literature. Chest 1999;116:1669-75. [Crossref] [PubMed]
91. Santos Portela AM, Radu DM, Onorati I, et al. Interventionnal bronchoscopy for the treatment of tracheobronchomalacia. Rev Mal Respir 2023;40:700-15. [Crossref] [PubMed]
92. Wu X, Zhang X, Zhang W, et al. Long-Term Outcome of Metallic Stenting for Central Airway Involvement in Relapsing Polychondritis. Ann Thorac Surg 2019;108:897-904. [Crossref] [PubMed]
93. Mitilian D, Gonin F, Sage E, et al. From relapsing polychondritis to extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg 2013;146:e49-51. [Crossref] [PubMed]
94. Martinod E, Portela AM, Uzunhan Y, et al. Elective extra corporeal membrane oxygenation for high-risk rigid bronchoscopy. Thorax 2020;75:994-7. [Crossref] [PubMed]
95. Spraggs PD, Tostevin PM, Howard DJ. Management of laryngotracheobronchial sequelae and complications of relapsing polychondritis. Laryngoscope 1997;107:936-41. [Crossref] [PubMed]
96. Martinod E, Chouahnia K, Radu DM, et al. Feasibility of Bioengineered Tracheal and Bronchial Reconstruction Using Stented Aortic Matrices. JAMA 2018;319:2212-22. [Crossref] [PubMed]
97. Martinod E, Radu DM, Onorati I, et al. Airway replacement using stented aortic matrices: Long-term follow-up and results of the TRITON-01 study in 35 adult patients. Am J Transplant 2022;22:2961-70. [Crossref] [PubMed]
98. Yamaguchi H, Komase Y, Ono A, et al. Successful treatment with noninvasive positive-pressure ventilation based on the prediction of disease onset using CT and respiratory function tests in an elderly patient with relapsing polychondritis. Intern Med 2013;52:1085-9. [Crossref] [PubMed]