This study included 66 male and 60 female patients with an average 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 follow-up period after diagnosis was 18 months (1-153 months). Among them, 34 patients were followed up for at least 36 months, 51 for at least 24 months and 82 for at least 12 months. One patient with airway involvement was lost after follow-up for 2 months. Median disease duration since the onset was 26 months (3-162 months). Median diagnostic delay between the appearance of the first symptom and the establishment of diagnosis was 5 months (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 lesions (n=1, 0.8%), and myelodysplastic syndrome (n=1, 0.8%). More cumulative features developed during follow-up (Table 1). Cumulative features in previous reports were also detailed in Table 1[7-9, 11, 13, 14, 16, 27, 30, 31].
At the final stages of the follow-ups, airway involvement was found in 60 patients (47.7%). Among them, 19 patients (15.1%) had laryngeal involvement and 51 patients (40.5%) had tracheobronchial involvement, indicating 10 of them had 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 had psychiatric symptoms including persecutory delusion, mania, hallucinations, cognitive disorder, and impaired memory, and 1 patient had headache and diplopia. Magnetic Resonance Imaging (MRI) of these latter 5 patients revealed ischemia and edema of the brain in 4 patients and demyelination in 1 patient. The lesions were detected in frontal, temporal and parietal cerebrum as well as basal ganglia and thalamus, unilaterally or bilaterally. Cerebrospinal fluid tests of these 5 patients were normal in 4 patients , but with increased white blood cells (mainly neutrophils) in 1 patient. The cerebrospinal fluid pressure increased in 2 patients and was normal in 3 patients. Cardiac involvement was found in 13 patients (10.3%), including premature contraction (n=8), atrial tachycardia (n=2), conduction block (n= 2), atrial fibrillation (n=2), pre-excitation syndrome ( n=1) and valve insufficiency (n=1).
Associated autoimmune rheumatic conditions were found in 4 patients, including 2 patients with recurrent oral ulceration resembling Bechet’s syndrome, 1 with Sjögren's syndrome and 1 with IgG4 related disease.
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 also between tracheobronchial involvement and auricular chondritis (r=-0.74, P<0.001). We only found a weak negative correlation between ocular inflammation and airway or tracheobronchial involvement (r=-0.34, P<0.001 and r=-0.32, P<0.001 respcetively). A weak positive correlation was also revealled between hearing loss and nasal chondritis (r=0.36, P<0.001), and between ocular inflammation and arthritis (r=0.36, P<0.001) (Figure 1).
Based on these findings, we consider auricular chondritis and airway involvement to be the most distinguishable variables to define subgroups of RPC, similar to previous reports (28,29). Thus 4 clinical patterns were identified: Ear pattern (ear lesion without airway involvement, subgroup A), Airway pattern (airway lesion without 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) (Table 2). Apparently, a large majority of the patients were classified as Ear pattern and Airway pattern (50.8% and 38.9%, respectively at disease onset, and 49.2% and 38.1%, respectively during follow-up).
A proportion of patients were referred to as the limited RPC when Ear pattern and Airway pattern presented with auricular chondritis and airway involvement as the sole manifestation during the whole disease process, while the rest were referred to as systemic RPC (Table 2).
We then analyzed the evolution of clinical patterns from disease onset to the last visit (Figure 2). A few evolution courses were noticed. First, one clinical pattern may progress to another one. Six patients with Ear pattern (3 limited form and 3 systemic form) developed airway lesions and one patient with Airway pattern developed auricular chondritis, which were collectively classified as Overlap pattern. Four patients with Airway-Ear negative pattern developed auricular chondritis and progressed into Ear pattern. Second, limited RPC may become systemic. Seven limited RPC patients with Ear pattern and 5 limited RPC patients with Airway pattern progressed into systemic disease. Third, a large majority of the limited RPC patients (25 with Ear pattern and 26 with airway pattern) remained unchanged during follow-up, indicating no disease progression in these patients.
Clinical features in different patterns of RPC
Compared with those with Airway pattern, RPC patients with Ear pattern had a higher incidence of ocular involvement (38.7% vs 8.3%, P<0.001) and arthritis (27.4% vs 4.2%, P=0.002), and a relatively lower incidence of nasal chondritis (6.5% vs 25%, P=0.011). Of note, 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 as those patients had an intermediate rate of ocular inflammation (23.1%) , arthritis (15.4%) and mortality(23.1%), between that of those with Ear pattern and Airway pattern, except a relatively higher incidence of hearing loss (23.1%) and nasal chondritis (30.8%) (Table 3). Among 3 patients with Airway-Ear negative pattern, all had ocular inflammation and 2 had hearing loss, nasal chondritis, and arthritis. No significant difference of ages 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). One patient was 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 was detected between Airway pattern and Overlap pattern (Figure 3), suggesting that airway involvement may be a predominant prognostic factor.