The Efficacy And Safety Of Pirfenidone Combined With Immunosuppressant Therapy In Connective Tissue Disease-associated Interstitial Lung Disease:A 24-week Prospective Controlled Cohort Study

Objective:Connective tissue disease(CTD)is a heterogeneous group of systemic disorders that can affect any organ system.Lung involvement is a rather common manifestation of CTD,such as systemic sclerosis(SSc),rheumatoid arthritis(RA),inflammatory myopathy(IIM),systemic lupus erythematosus(SLE),primary Sjogren’s syndrome(pSS),contributing to significant morbidity and mortality.There are different subtypes in pathology and imaging manifestations of interstitial lung disease(ILD)and they may present with subclinical features following a slow or acute progressively course,and the latter turn into clinically significant rapid progression leading to mortality.The purpose of this study was to observe the efficacy and safety of pirfenidone(PFD)combined with IS in the 24-week treatment of CTD-ILD,and to provide real-world data for the treatment of CTD-ILD.Methods:A total of 111 CTD-ILD patients were involved,including SSc-ILD(n=30),IIM-ILD(n=51),RA-ILD(n=17),other CTDs-ILD(including SLE-ILD,pSS-ILD,undifferentiated CTD,n=13).And all the patients were treated with stable dosage of GC and/or IS,according to their clinical characteristics at baseline.After the evaluation of HRCT,pulmonary function(FVC%and DLCo%)and basic disease activity,patients were prescript PFD or not and followed up regularly for 24 weeks,and the changes in pulmonary function were recorded in different subtypes and subgroups.The primary endpoint of the study was the change in pulmonary function(FVC%,DLCo%)after 24 weeks,and the secondary endpoints included the patient’s underlying disease activity and the dose of background GC.Results:1.At baseline,DLCo%in the other CTDs-ILD was lower than SSc-ILD,IIM-ILD,RA-ILD patients(54.58%vs 65.55%,68.71%,66.89%,p=0.036),while there were no significant differences in baseline FVC%among these diseases.The FVC%in the SSc-PFD,IIM-PFD subgroups were lower than that of SSc-no-PFD,IIM-no-PFD respectively,that was 81.06%vs 99.63%(p=0.014),78.23%vs 91.12%,(p=0.010).And IIM-PFD group also present a lower baseline DLCo%than IIM-no-PFD patients(64.25 vs 72.82,p=0.034).In RA-ILD and other CTDs-ILD patients,there was no significant difference in baseline FVC%and DLCo%between PFD group and control group.2.After 24 weeks of treatment,FVC%in SSc-PFD group was improved by 6.60%,while that was 0.55%in SSc-no-PFD patients(p=0.042).The elevation in FVC%was also significant between the IIM-PFD and IIM-no-PFD control(7.50%vs 1.00%,p=0.016).On the other hand,DLCo%of RA-PFD obviously enhanced 7.40%,compared with that of RA-no-PFD decreased 5.50%from baseline(p=0.003).3.When performing a subtype analysis of HRCT images,the change in FVC%among SSc-PFD patients with a tendency towards usual interstitial pueumonia(UIP)(SSc-PFD-UIP)was higher in those given PFD than the no-PFD group(8.05%vs-3.20%,p=0.014).However,in IIM patients with a non-UIP tendency,PFD displayed better therapeutic effects than the control(10.50%vs 1.00%,p=0.005).In addition,DLCo%improved significantly in PFD treated RA-non-UIP subtype,compared with no-PDF patients(10.40%vs-4.45%,p=0.017).4.Dichotomizing the patients around a baseline FVC%or DLCo%value of 70%,the PFD arm had a more improved FVC%than the no-PFD arm within the high-baseline-FVC%subgroups of SSc and IIM patients(6.60%vs 0.10%,p=0.047,6.30%vs 1.10%,p=0.089).In RA-PFD patients,DLCo%showed a significant increase in the subgroup with low baseline DLCo%compared to that in RA-no-PFD patients(7.40%vs-6.60%,p=0.011).5.According to whether the dose of PFD at 24 weeks was less than 800 mg/day,the patients in the high-dose(>800 mg/day)and low-dose(≤800 mg/day)PFD groups had significantly improved FVC%and DLCo%compared with the control group,but no difference of the change in pulmonary function was found between the high and low dose PFD groups(p>0.05).6.Multiple linear regression analysis found that baseline FVC%<70%(HR=5.88,0.40～11.37,HR=6.81,1.28～12.33 respectively)and prescription of PFD(HR=4.56,0.38-8.75,HR=4.37,0.02-8.72 respectively)could positively affect the changes of FVC%and DLCo%from baseline(all p<0.05).7.The safety of PFD combined with immunosuppressant therapy in CTD-ILD was good.The incidence of adverse events in the PFD group and the control group was 32.80%and 20.83%,and most of them were mild to moderate and reversible.Conclusion:The response of PF to PFD was varied in different CTD-ILD subsets.SSc and IIM patients acquired obviously improvement on FVC%,especially in SSc-UIP tendency and IIM-non-UIP.In RA,highlight the subsets of non-UIP and lower DLCo%at baseline was most likely benefited from PFD.