Arch Rheumatol 2020;35(2):180-188 doi: 10.46497/ArchRheumatol.2020.7381 ORIGINAL ARTICLE Efficacy of Combination Therapy With Pirfenidone and Low-Dose Cyclophosphamide for Refractory Interstitial Lung Disease Associated With Connective Tissue Disease: A Case-Series of Seven Patients Lichong SHEN, Qingran YAN, Xiaoxiang CHEN Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai China ABSTRACT Objectives: This study reports a low dose combination therapy of cyclophosphamide (CYC) and pirfenidone (PFD) and the efficiency and safety of the therapy in refractory connective tissue disease associated interstitial lung disease (CTD-ILD) patients. Patients and methods: The study included seven CTD-ILD patients (2 males, 5 females; mean age 48.8 years; range, 32 to 63 years) treated between January 2016 and December 2017 in our clinic. At enrolment, all patients had shown no improvement in their symptoms (dyspnea or cough) after at least one month of high dose steroids treatment. Patients who had received adjusted immunosuppressive agents other than steroids or anti-fibrotic medications within the three months before enrolment were excluded. We changed the treatment to a low dose combination of CYC 0.4 g/m2 monthly and PFD 300 mg twice per day and quickly reduced the steroids. All the patients were followed-up for 12 months. Results: Two patients had anti-synthetase syndrome, two had Sjögren syndrome, two had scleroderma and one had mixed connective tissue disease. The baseline forced vital capacity (FVC) was 39-81% and the six-minute walk distance (6MWD) was 202 m-324 m. Within 12 months follow- up, the median improvement in the FVC was 13.4% (range, 0-35.9%), the median improvement of carbon monoxide diffusing capacity was 6.3% (range, 1.7-16%) and the median improvement of 6MWD was 52.7% (range, 34.4-86.3%). All the patients were self-sufficient, and their dyspnea, chest high-resolution computed tomography scores, and quality of life improved simultaneously. Exceeding our expectations, no adverse events associated with CYC or PFD were observed during the follow-up period. Conclusion: Our study provided preliminary while promising clinical evidence for combination therapy of CYC-PFD for CTD-ILD. A low dose combination of CYC and PFD was unexpectedly well tolerated, with satisfactory effects in refractory CTD-ILD patients. Well-designed controlled studies are needed to further establish the safety and efficacy of this approach. Keywords: Cyclophosphamide, interstitial lung disease, pirfenidone. Interstitial lung disease (ILD) is one of the To treat inflammation in CTD-ILD patients, most serious yet common conditions for patients one immunosuppressant plus steroids is a with connective tissue diseases (CTDs), such as common regimen. In recent clinical trials on systemic sclerosis (SSc),1 dermatomyositis (DM)2 CTD-ILD, cyclophosphamide (CYC) is one of the and Sjögren syndrome (SS).3 CTD-ILD begins as most evidence-supported immunosuppressants, an autoreactive inflammation and can progress to particularly for SSc-ILD. CYC improved the fibrosis. Either of these morbidities can cause lung pulmonary function of 49.2 to 61.5% of the dysfunction, greatly shorten survival and bring subjects during the first one year of follow-up, heavy disease burden to the patients. and improved dyspnea, high-resolution computed Received: December 30, 2018 Accepted: May 16, 2018 Published online: August 26, 2019 Correspondence: Xiaoxiang Chen, MD. Renji Hospital, Shanghai Jiaotong University, School of Medicine, Rheumatology, 200025 Shanghai, China. Tel: 021-53882254 e-mail: [email protected] Citation: Shen L, Yan Q, Chen X. Efficacy of Combination Therapy With Pirfenidone and Low-Dose Cyclophosphamide for Refractory Interstitial Lung Disease Associated With Connective Tissue Disease: A Case-Series of Seven Patients. Arch Rheumatol 2020;35(2):180-188. ©2020 Turkish League Against Rheumatism. All rights reserved. Combination of Cyclophosphamide and Pirfenidone in CTD-ILD Treatment 181 tomography (HRCT) appearance and the health- CYC and PFD might be risky for patients and related quality of life.4,5 hide potential benefits. To stop fibrosis, several small-molecule Therefore, we hypothesized that a low-dose anti-fibrotic agents have been approved in recent combination may improve tolerance. Thus, in decade. Pirfenidone (PFD) was the first of these this study, we reported a low dose combination agents. It is initially approved for idiopathic therapy of CYC and PFD and the efficiency pulmonary fibrosis (IPF), the most treatment- and safety of the therapy in refractory CTD-ILD resistant type of pulmonary fibrosis. In clinical trials patients. on IPF, PFD improved patient forced vital capacity (FVC) and reduced the decline of the six-minute walk distance (6MWD).6,7 The application of PFD PATIENTS AND METHODS to CTD-ILD patients, including patients with Seven CTD-ILD patients (2 males, 5 females; SSc and DM, also showed acceptable efficacy,8,9 mean age 48.8 years; range, 32 to 63 years) who despite most trials still being in progress. had not shown improvement of their symptoms To improve efficacy, a combination of an (dyspnea or cough) after at least one-month of immunosuppressant and anti-fibrotic agent steroid treatment (prednisone ≥1 mg/kg daily could be a reasonable approach. CYC is a or were equivalent) were enrolled sequentially traditional cytotoxic agent that kills activated between January 2016 and December 2017, from lymphocytes to stop inflammation. On the other Renji Hospital, Shanghai Jiao Tong University hand, PFD is an anti-fibrotic agent that inhibits School of Medicine. Patients who had adjusted collagen synthesis and fibroblast proliferation their immunosuppressive agents (including via pro-fibrotic growth factors.10,11 Based on biological agents) other than steroids or had their working mechanisms, PFD and CYC might received anti-fibrotic medications within the three work in synergy. In fact, PFD plus rapamycin months before enrolment were excluded. Patients have shown benefits in an alveolar cell line with with dominant infection or other complications pro-fibrotic stimulation.12 outside of the lungs that required daily prednisone To our knowledge, thus far, the combination over 1 mg/kg were also ruled out. The study of PFD and CYC has never been reported, protocol was approved by the Renji Hospital while other similar combinations have been Ethics Committee. A written informed consent assessed in two clinical trials of SSc-ILD: PFD was obtained from each patient or his/her legal with mycophenolate in Scleroderma Lung Study representative. The study was conducted in (SLS) III study (ClinicalTrials.gov: NCT03221257) accordance with the principles of the Declaration and mycophenolate add on nintedanib in the of Helsinki. Safety and Efficacy of Nintedanib in Systemic We used the 6MWD to assess the patient Sclerosis (SENSCIS) trial.13 The two studies are activity tolerance17 and St. George’s Respiratory still in progress and both make use of full-dose Questionnaire (SGRQ) to evaluate quality of life.18 combination. Pulmonary function tests (PFTs) and HRCT were A concern of full-dose combination is adverse performed at our hospital at three-six-month effects. As monotherapy, pulse CYC at 1.0 g/m2 intervals, according to the changes of symptoms. caused nausea in 36.4% patients, hematuria in The HRCT scores of the patients were calculated 13.6% patients and respiratory tract infections based on the Ichikado criterion by the same two 19 in 13.6% patients14 while daily CYC can cause radiologists. even higher incidence of side effects.4 When We generally changed the patients’ previous taking daily PFD up to 2400 mg, almost all treatments into a standard protocol consisting patients suffered drug-associated adverse events of intravenous CYC 0.4 g/m2 per month and such as rash or gastrointestinal intolerance.15 oral PFD 300 mg twice daily. Additionally, we According to a meta-analysis of IPF trials, cut the oral steroids to prednisone 0.5 mg/kg drug intolerance caused greater withdrawal daily (or equivalent) and tapered it to a stable of patients treated with PFD, compared with dose (prednisone ≤10 mg per day) within six controls.16 Overall, a full-dose combination of months. 182 Arch Rheumatol Statistical analysis steroids were successfully maintained at 10 mg prednisone daily or less. The 6MWD showed a All patients had HRCT scores, PFTs and median increase of 52.7% (range, 34.4 to 86.3%, 6MWD at baseline or follow-up to 12 months p<0.05). For quality of life assessment, after changing their therapy. The differences the SGRQ total score showed a median in the median changes of diffusing capacity improvement of 53.3% (range, 19.5 to 61.7%, of lung for carbon monoxide (DLCO), FVC p<0.05). The HRCT score showed a median percentage, HRCT scores and 6MWD before and decrease of 20.1% (range, 11.7 to 29.6%, after treatment were assessed by Wilcoxon signed p<0.05). Regarding lung functions, the DLCO rank sum test. A p value <0.05 was considered percentage showed a median improvement of statistically significant. 6.3% (range, 1.7 to 16%, p<0.05) and the FVC percentage showed a median improvement of 13.4% (range, 0 to 35.9%, p<0.05) RESULTS (Table 2, Figure 1a-f). Detailed demographic information is shown Although only seven patients were included in in Table 1. Two patients had anti-synthetase this study, it is worth mentioning that all patients syndrome, two had SS, two had SSc and one tolerated the combination therapy unexpectedly had mixed connective tissue disease (MCTD). well. During the 12-month follow-up, none of These patients were diagnosed as ILD by the patients had observable adverse events that chest computed tomography (CT) two to five could be attributed to PFD or CYC, such as years before. At enrolment, the median 6MWD gastrointestinal (nausea, dyspepsia, diarrhea, and was 275 m (range, 202 to 324 m), the anorexia), neurological (dizziness and fatigue), median DLCO was 51% of the prediction dermatological (photosensitivity, rash and (range, 47.7 to 63%) and the median FVC was pruritus), bone marrow suppression, hematuria, 72.3% of the prediction (range, 39 to 81%).