A multicenter study of long-term outcomes of relapsing polychondritis in Iran

Relapsing polychondritis (RP) is a systemic immune mediated disease characterized by recurrent episodes of inflammation in various cartilage-rich areas. RP may cause extensive tissue destruction and is associated with significant morbidity and mortality. In this multicenter study, we considered the remission status and long-term outcomes of RP in patients who were followed-up in six referral rheumatology centers in Iran. Outcomes of disease was assessed by remission status and RP induced damage. A total of 29 patients with RP were examined for enrollment in the study, and 26 patients with a minimum follow-up period of 6 months were included in the RP outcome analysis. Median time to control of symptoms and sustained remission were 5 and 23 weeks, respectively. Prednisolone was discontinued in 8 (30.8%) patients and medication-free remission was achieved in 7 (23.1%) patients. Regarding the disease course, 34.6% of patients had a relapsing–remitting course, 42.3% had a monophasic course, and 23.1% had an always-active course. Despite extensive treatment with immunosuppressive medications, RP induced damage was developed in 21 (80.8%) patients. Ear deformity and osteoporosis were the most common RP induced damage. Long-term remission and medications-free remission in RP is accessible. However, RP related damage occur in majority of patients.


Statistical analysis
Statistical analysis was performed using SPSS software version 16.0 (SPSS, Inc., USA).The normal distribution of data was assessed using the Kolmogorov-Smirnov test.Normally and non-normally distributed continuous variables were reported as mean ± standard deviation (SD) and median (25-75% interquartile range [IQR]), respectively.Categorical variables were reported as frequency and percentage.Kaplan-Meier test was used for survival analysis.P-values less than 0.05 were considered as statistically significant.

Results
A total of 29 patients with RP were examined for enrollment in the study, whose demographic, clinical and laboratory characteristics are shown in Table 1.Finally, 26 patients with a minimum follow-up period of 6 months were included in the RP outcome analysis (Table 2).Mean age of the participants at the time of diagnosis was 42.8 ± 15.3 years and female:male ratio was 1.6.The median (IQR) duration of follow-up was 41 (19, 73) months.Auricular chondritis, nose chondritis, laryngeal chondritis, fever, arthralgia/arthritis, scleritis and uveitis were the most frequent clinical manifestations (Table 1).At least one auto-antibodies including perinuclear antineutrophilic cytoplasmic antibody (P-ANCA), cytoplasmic ANCA (C-ANCA), anti-nuclear antibody (ANA) and rheumatoid factor (RF) was positive in 17 (58.6%)patients (Table 1).
All patients were treated with GCs and/or DMARDs.Prednisolone was the most commonly used medication (Table 2).Other frequently used medications were azathioprine (53.8%), methotrexate (50.0%), and cyclophosphamide (19.2%).As initial therapy, all but 2 patients were treated with DMARDs.Monotherapy with DMARDs was performed in 21 (80.8%)patients and combination therapy was performed in 3 (11.5%)patients.However, during the course of the disease, a second DMARD was added to the treatment regimen in 7 (26.9%)patients, and the first DMARD was changed to another DMARD in 8 (30.8%) patients.Treatment with GCs and DMARDs lead to control of symptoms in 84.6% of patients and sustained remission in 76.9% of patients.Median time to control of symptoms and sustained remission were 5 and 23 weeks, respectively (Table 2 and Fig. 1).In all patients who responded to treatment, the response occurred within 12 months of diagnosis and initiation of treatment (Fig. 1).None of the demographic and clinical characteristics of the participants were predictive of sustained remission (Table 3).Although delay in diagnosis was shorter in patients with sustained remission, the difference did not reach significant levels (Table 3).Prednisolone was discontinued in 8 patients (30.8%) and medication-free remission was achieved in 7 (23.1%)patients.Regarding the disease course, 34.6% of patients had a relapsing-remitting course, 42.3% had a monophasic course, and 23.1% had an always-active course.
Despite extensive treatment with immunosuppressive medications, RP induced damage was developed in 21 (80.8%)patients (Table 4).Sixteen (61.5%) were damaged due to the inflammatory process, 11 (42.3%) were damaged due to treatment complications and 6 (23.1%) suffered from both (Table 4).Median (IQR) RPDAM was 1 (0.8, 2).Ear deformity and osteoporosis were the most common RP induced damage (Table 4).One of the most debilitating RP induced damage is tracheobronchial which occurred in 3 patients (11.5%), and one of them required tracheostomy.We compared the demographic and clinical characteristics of patients with and without damage.Except for the higher frequency of damage in patients with trachea laryngeal involvement, none of the demographic and clinical characteristics of the participants were predictor of damage (Table 5).Surgery was performed in 3 patients (11.5%) for corneal transplant (n = 1), total hip replacement (n = 1) and tracheobronchial stenosis (n = 1).Although delay in diagnosis and time to remission was shorter in patients without damage, the difference did not reach significant levels.Damage severity assessed by RPDAM was lower in patients with sustained remission than in patients with no sustained remission (Table 3) Five years survival rate was 95.5%.One patient died during follow-up due to pneumonia.

Demographic characteristics Sustained remission (N = 20) Active disease (N = 6) P-value
Age at the time of diagnosis, mean ± SD, years 42.

Discussion
Management of RP poses significant challenges due to its rarity and the heterogeneity of symptoms and disease course.This study aimed to evaluate the outcomes and treatment patterns in a cohort of RP patients, shedding light on the current understanding of this complex disease.The results of this study showed that RP was diagnosed 22 weeks after the onset of symptoms and treatment with GCs and DMARDs resulted in symptom control and sustained remission in most patients (85% and 77%).Response to treatment occurred in majority of patients in 5 months and in all patients within 12 months.These results are encouraging, as achieving remission is a primary therapeutic goal in RP to prevent further damage to cartilage structures.Medication-free remission was achieved in 23% of patients.However, relapse occurred in 25% of patients after discontinuation of prednisolone and in 50% of patients after discontinuation of DMARDs, suggesting the need for ongoing monitoring and management to prevent relapse.Although there was no significant difference in the demographic characteristics and clinical manifestations of the studied patients with previous studies 8, [10][11][12][13][14][15][16] , it is difficult to compare treatment results with previous reports   www.nature.com/scientificreports/due to differences in outcome definitions and lack of data on the remission rate in most studies (Table 6).Disease activity in our study as measured by the RPDAI was 31, which is higher than the only study in which disease activity was measured by this instrument, study Yoshida et al. 8 .There was a significant difference in the treatment strategy between the different studies, so that the rate of treatment with biological drugs in the studied patients was lower than the more recent reports 8,15,16 .Despite the availability of many biological drugs in Iran, such as TNFis, rituximab and tocilizumab, the lack of approval of these drugs in the treatment of RP by insurance organizations is a possible reason for the underuse of them in studied patients.Of the 5 patients treated with bDMARDs in this report, sustained remission was achieved in 3 patients, which is comparable to the results of Sangle et al. 16 report.However, there was no significant difference in the rate of sustained remission in patients treated with bDMARDs versus patients not treated with bDMARDs.Nevertheless, the five years survival rate in our study (95.5%) was consistent with recent studies from other countries 8,14,15 .In Shimizu et al. report GCs, csDMARDs and bDMARDs were used in 91, 60 and 14 percent of RP patients 15 .They reported increase in the prescription of csDMARDs and bDMARDs in 2019 compared to 2009 and a decrease in RP mortality from 22 to 3% during this time period 15 .Sangle et al. 16 in a retrospective study reported a diagnosis delay of 55 weeks.Combination therapy with prednisolone and DMARDs was performed in 97% of patients and 63% eventually required biological drugs 16 .However, mortality was 18% 16 .Recent evidences shows that improvements in diagnostic methods and treatment of RP have led to earlier diagnosis and an increase in the 10-year survival rate from 55% in 1986 10 to 91% in 2016 14 .In a single center study from Japan diagnosis delay was 22 weeks 8 .Although 26% of patients experienced sustained remission, relapse occurred in the remaining 74% 8 .Higher CRP level and monotherapy with GCs was associated with relapse 8 .Present study Michet et al. 10 Kong et al. 11 Mathew et al. 12 Sharma et al. 13 Dion et al. 14 Yoshida et al. 8 Shimizu et al. 15 Sangle et al. 16 Number

Figure 1 .
Figure 1.Kaplan Meier survival curve of relapsing polychondritis treatment results in the studied patients.Numbers at the bottom indicate the number of patients at risk and the number of events at each follow-up year.GCs: glucocorticoids; DMARDs: disease modifying anti-rheumatic drugs.

Table 3 .
Comparison of demographic and clinical characteristics of patients according remission status.

Table 5 .
Comparison of demographic and clinical characteristics of patients with and without damage.SD standard deviation, IQR interquartile range, RPDAI relapsing polychondritis disease activity index.Significant values are in bold.

Table 6 .
Comparison of present study findings with previously published data.RPDAI relapsing polychondritis disease activity index, NR not reported, bDMARDs biologic disease-modifying antirheumatic drugs, RPDAM relapsing polychondritis damage index, CKD chronic kidney disease.