The current study included 66 male and 60 female patients with age of 47.1±13.8 years at disease onset. The age of male patients was comparable to female patients at disease onset (46.1±13.7 vs 48.1±13.8, P=0.408). Median duration of follow-up after diagnosis was 18 months (range 1-153 months), with 34 patients followed up for at least 36 months, 51 patients for at least 24 months and 82 patients for at least 12 months. One patient with airway involvement was lost after 2 months follow-up. Median disease duration since disease onset was 26 months (range 3-162 months). Median diagnostic delay was 5 months (range 0-132 months), and 31 patients were delayed for over a year.
Initial and Cumulative Features
The most frequent initial features included auricular chondritis (n=70,55.6%) and airway involvement (n=54,42.9%) (including 17 patients[13.5%] with laryngeal involvement and 48 patients[38.1%] with tracheobronchial involvement), ocular inflammation (n=25,19.8%), fever (n=20,15.9%), nasal chondritis (n=15,14.3%), arthritis (n=16,12.7%), hearing loss (n=12,9.5%), cardiac involvement (n=8,6.3%), costochondritis (n=3,2.4%), neurological involvement (n=6,4.8%), cutaneous manifestations (n=1,0.8%), and myelodysplastic syndrome (n=1,0.8%). More cumulative features developed during follow-up, which were detailed in Table 1 as well as cumulative features in previous reports [7-9, 11, 13, 14, 16, 27, 31, 32].
At the last follow-up, airway involvement was found in 60 patients (47.7%), among them, 19 patients (15.1%) presented with laryngeal involvement and 51 patients (40.5%) with tracheobronchial involvement, indicating 10 patients with both laryngeal and tracheobronchial involvement (Table 1).
Neurological involvement was seen in 6 patients (4.8%), and no new onset of neurological impairment was observed during follow-up. One patient with rapture of intracranial aneurysm (anterior communicating artery) received surgical procedures. Four patients presented psychiatric symptoms, and 1 patient with headache and diplopia, and the Magnetic Resonance Imaging (MRI) of these 5 patients revealed ischemia and edema of the brain in 4 patients and demyelination in 1 patient, and the lesions were detected in frontal and parietal cerebrum as well as basal ganglia, unilaterally or bilaterally. Cerebrospinal fluid tests of the latter 5 patients were normal in 4 patients and increased white blood cells (mainly neutrophils initially) in 1 patient. The cerebrospinal fluid pressure was increased in 2 patients and normal in 3 patients. Cardiac involvement was found in 13 patients (10.3%), including premature contraction in 8, atrial tachycardia in 2, conduction block in 2, atrial fibrillation in 2, valve insufficiency in 1 and pre-excitation syndrome in 1.
Associated autoimmune conditions were found in 4 patients, including 2 patients with recurrent oral ulceration, 1 patient with Sjögren's syndrome and 1 patient with IgG4 associated periorbital pseudo-tumor.
Clinical pattern and disease evolution
We performed correlation analysis and calculated correlation coefficients between cumulative organ involvement and found a strong negative correlation between airway involvement and auricular chondritis (r=-0.75, P<0.001) and between tracheobronchial involvement and auricular chondritis (r=-0.74, P<0.001). A weak negative correlation was found between laryngeal involvement and auricular chondritis (r=-0.24, P=0.007).
We also found weak negative correlation between ocular inflammation and tracheobronchial involvement (r=-0.32, P<0.001), between arthritis and tracheobronchial involvement (r=-0.26, P=0.003), as well as between auricular involvement and nasal chondritis (r=-0.20, P=0.028). Weak positive correlation was found between hearing loss and nasal chondritis (r=0.36, P<0.001), hearing loss and cardiac involvement (r=0.28, P=0.002), nasal chondritis and tracheobronchial involvement (r=0.20, P=0.021), ocular inflammation and arthritis (r=0.361, P<0.001), nasal involvement and myelodysplasia (r=0.20, P=0.025) as well as cardiac involvement and myelodysplasia (r=0.26, P=0.003). Figure 1 shows the correlationship between different organ involvement.
Based on these findings, 4 clinical patterns were identified: Ear pattern (ear involved but no airway involvement, subgroup A), Airway pattern (airway involved but no ear involvement, subgroup B), Overlap pattern (both ear and airway involved, subgroup C) and Airway-Ear negative pattern (nether auricular nor airway involved, subgroup D), which were detailed in Table 2. Apparently, Ear pattern and Airway pattern constituted the most part of RPC patients (50.8% and 38.9% for Ear pattern and Airway pattern respectively at disease onset and 49.2% and 38.1% for Ear pattern and Airway pattern respectively during follow-up).
A proportion of patients with Ear pattern and Airway pattern presented with auricular chondritis and airway involvement as the sole manifestation at disease onset and during disease course, and were classified as limited RPC and the rest were classified as systemic RPC (Table 2).
After that, we analyzed the evolution of the clinical patterns from disease onset to the last visit, as detailed in Figure 2. The evolution can be summarized as follows. First, one clinical pattern can progress into another clinical pattern. Six patients with Ear pattern (3 limited form and 3 systemic form) developed airway lesions and one patient with Airway pattern developed auricular chondritis and thus they progressed into Overlap pattern. Four patients with Airway-Ear negative pattern developed auricular chondritis and progressed into Ear pattern. Second, limited RPC can progress into systemic RPC. Seven limited RPC patients with Ear pattern and 5 limited RPC patients with Airway pattern progressed into systemic disease. Third, most of the limited RPC patients (25 with Ear pattern and 26 with airway pattern) remained limited form during follow-up, indicating no disease progression in these patients.
Clinical features compared between different patterns
Compared with those with Airway pattern, RPC patients with Ear pattern presented with higher incidence of ocular involvement (38.7% vs 8.3%, P<0.001) and arthritis (27.4% vs 4.2%, P=0.002) but relative lower incidence of nasal chondritis (6.5% vs 25%, P=0.011). Importantly, RPC patients with Airway pattern had higher mortality rate compared with those with Ear pattern (29.2% vs 1.6%, P=0.015). Interestingly, Overlap pattern seems to be a combination of Ear pattern and Airway pattern, since RPC patients with Overlap pattern presented intermediate incidence rate of ocular involvement (23.1%) and arthritis(15.4%) and mortality rate(23.1%) between that of those with Ear pattern and Airway pattern, but relatively higher incidence of hearing loss(23.1%) and nasal chondritis(30.8%) compared to those with Ear pattern and Airway pattern (Table 3). Among 3 Airway-Ear negative pattern patients, all presented with ocular involvement and 2 presented with hearing loss, nasal chondritis, and arthritis respectively. No significant difference of age at disease onset was detected between different patterns but Ear pattern presented lower CRP level compared with Airway pattern and Overlap pattern, indicating lower inflammation of RPC patients with Ear pattern (Table 3).
There were 18 deaths (14.3%) during a median follow-up of 23.5 months (range 5-81 months), and the causes of deaths were refractory disease (n=13), pulmonary infection (n=3), brain tumor (n=1), and unknown cause (n=1), 1 with ear pattern (died of brain tumor), 14 with airway pattern and 3 with overlap pattern.
The probability of survival was significantly different between Ear pattern and the other 2 patterns whereas no difference existed between Airway pattern and Overlap pattern (Figure 3). This indicates that airway involvement may be a predominant factor associated with poor prognosis.