DISCUSSION
Results of the presented study suggest that azathioprine is remarkably inferior to cyclophosphamide for the induction treatment of CTD-ILD, even in those with favorable baseline parameters, indicated by pulmonary function tests. Moreover, AZA was discontinued in almost 20% of patients due to intolerance. Percent improvement in FVC and HRCT reticulation were also more remarkable in CYC group. Thus, our results suggest that CYC might be the drug of choice as first line treatment in CTD-ILD, especially in those with SSc, RA and pSS. In IMS and IPAF patients, results of both regimens did not differ significantly, therefore AZA could be an alternative for CYC regimen.
There are few studies reported the use of AZA for induction therapy in SSc associated ILD [11, 12, 24], however, none of them compared AZA with intravenous cyclophosphamide and none included radiological assessments. . In these studies, changes in FVC percentages were conflicting, although there was a tendency for improvement in favor of oral CYC treatment. Results of our study are compatible with previous reports oral CYC treatment in SSc patients [25].
Literature on use of immunosuppressives in CTD-ILD is largely limited to SSc and data is scarce about use of them in other CTDs. Therefore treatment strategies are mainly based on extrapolation from the SSc trials. For RA associated ILD, there is only one study which compared AZA with MMF as initial treatment regimen[10]. In a large CTD-ILD cohort AZA showed marginal efficacy in stabilization of lung function, but subgroup analysis were not performed. In another CTD-ILD study, MMF demonstrated improvement of lung function, compared to placebo [26]. Comparative efficacy of CYC and MMF in RA-ILD was studied in a CTD-ILD cohort, and both showed similar improvements in lung functions [9]. Considering our results and available literature, CYC and MMF might be better options for the treatment of RA-ILD, compared to AZA for induction therapy. Efficacy of combined use of biologic agents with AZA, CYC and MMF are conflicting and not clear yet.
The EULAR/ACR recently up dated pSS management recommendations[27]. For pSS associated ILD, they recommended to use AZA for second line and CYC for rescue treatments, due to lack of randomized trials. . There is no prospective head to head study evaluating efficacy of drugs and current evidence for use of AZA in pSS-ILD is limited to case series [13, 28, 29]. None of studies reported radiographic severity or GAP index. In our study, progression was more frequent in AZA group,and FVC levels tend to decrease in AZA whereas tend to improve in CYC group (data not shown). Therefore, we recommend the use of CYC for pSS associated ILD, as in SSC and RA.
The management of inflammatory myositis associated ILD was challenging due to the risk of rapid deterioration of lung disease. AZA and CYC were compared in a recent meta-analysis[30]. In agreement with our results, both treatment modalities had similar efficacy on ILD in patients with IMS.
The interstitial lung disease with autoimmune features is a new concept and since the classification criteria was released in 2015, [31] data are rapidly growing on management of IPAF, although optimal treatment keep its uncertainty. In our cohort, induction therapy with AZA and CYC t had similar progression rates. However, the baseline radiographic extent of lung disease was more prominent in CYC group. Therefore, CYC might be a better choice in extensive disease.
Safety data related to AZA and CYC treatment were consistent with the literature. Treatment discontinuation rate related to AZA was 28.4% in our study, which is similar to previously reported 28% in a CTD-ILD study [10], Safety data of CYC is also compatible with current literature [32]. No fatality occurred during six months observation period in our study.
We have some limitations in our study. Although we have a reliable cohort registry, our study is retrospective and therefore choice of induction was based on the opinion of the physician on duty. However, number of patients were enough to show a clear difference between AZA and CYC in overall group and somewhat in some subgroups. Regarding the scarce data on literature, our study offers a valuable contribution to management of CTD-ILD in daily practice.
In conclusion, our results suggest that induction therapy with azathioprine might be an alternative option in IPAF patients with limited disease extent and inflammatory myositis associated ILD. However, CYC is superior to AZA in SSc, RA and pSS associated ILD and could be preferred over AZA treatment.
Acknowledgments : None
Funding: None.
Conflict of interest: The authors have declared no conflicts of interest