A Randomized, Double-Blind, Placebo-Controlled Trial of Fufei Huazhuo Tongluo Formula Combined With Standardized Medicine in Patients With Anti-Synthetase Syndrome-Associated Interstitial Lung Disease

Overview

The goal of this clinical trial is to learn if the traditional Chinese medicine formula "FuFei HuaZhuo TongLuo Granule" combined with standardized western medicine works to treat anti-synthetase syndrome-associated interstitial lung disease (ASS-ILD). It will also learn about the safety of this combined therapy. The main questions it aims to answer are: Does the Chinese herbal formula plus standardized western medicine increase the proportion of patients who successfully reduce their glucocorticoid dose to a low maintenance level (prednisone ≤ 7.5 mg/day) at 24 weeks, compared with placebo plus standardized western medicine? Does this herbal formula provide additional clinical benefits in terms of glucocorticoid sparing, delaying lung function decline, reducing infection risk, and improving traditional Chinese medicine syndrome scores? What medical problems do participants have when taking this herbal formula? Researchers will compare the Chinese herbal granule to a placebo granule (a look-alike substance that contains no active ingredients) to see if the herbal formula works to treat ASS-ILD. Both groups will receive standardized western medicine treatment based on disease severity. Participants will: Take the Chinese herbal granule or a placebo every day for 12 weeks Visit the clinic at 8 time points: baseline, weeks 2, 4, 8, 12, 16, 20, and 24 for checkups and tests Undergo pulmonary function tests (at baseline, week 12, and week 24) and high-resolution CT scans (at baseline, week 12, and week 24) Receive disease activity assessments (MITAX score), traditional Chinese medicine syndrome evaluations, and safety monitoring (blood routine, liver and kidney function, adverse event recording) at each follow-up visit Provide peripheral blood samples at weeks 0, 4, 12, and 24 for exploratory immunology and metabolomics research Record their daily glucocorticoid dosage and concomitant medications throughout the study

Background Anti-synthetase syndrome (ASS) is an autoimmune disease characterized by anti-aminoacyl-tRNA synthetase (ARS) antibodies and represents a major subtype of idiopathic inflammatory myopathy (IIM). Its clinical manifestations are heterogeneous, frequently involving the lungs, muscles, joints, and skin. Interstitial lung disease (ILD) is the most common and characteristic organ involvement, occurring in over 80% of patients and often presenting as the initial manifestation. In some patients, ASS-ILD follows a rapidly progressive course (RP-ILD), leading to acute respiratory failure within weeks or even days, with a 1-year survival rate of approximately 75%, making it a leading cause of critical illness and early death in rheumatology. Current Western medical treatment for ASS-ILD relies on potent immunosuppression, primarily high-dose glucocorticoids combined with conventional immunosuppressants (e.g., cyclosporine, tacrolimus, cyclophosphamide). Biologics targeting B cells (rituximab) and JAK inhibitors have also been recommended for severe or refractory cases. However, long-term high-dose glucocorticoid and immunosuppressant use presents two major challenges: difficulty in tapering without disease relapse-rapid reduction often triggers pulmonary flares, while slow tapering increases cumulative toxicity, resulting in low successful tapering rates to safe doses within 24-40 weeks in real-world practice-and significant treatment-related toxicity, with exponentially increased risk of opportunistic infections (e.g., Pneumocystis jirovecii pneumonia, invasive fungal infections, cytomegalovirus infection). In traditional Chinese medicine (TCM), ASS-ILD is classified as "lung impediment"or "lung atrophy". Based on long-term clinical experience, our group proposes that the core pathogenesis is "deficiency of lung collaterals as the root, with damp-heat, phlegm, and blood stasis as the manifestations." In the early stage, pathogenic heat and dampness obstruct the lung collaterals; as the disease progresses, chronic involvement leads to phlegm-stasis obstruction and eventually "collateral stasis with accumulation," which corresponds to reticular opacities, fibrotic nodules, and linear shadows on imaging. Guided by the principle of "unblocking collaterals to restore function," we developed the original Chinese herbal formula FuFei HuaZhuo TongLuo Granule (composed of Danggui, Qianghuo, Yinchen, Fangfeng, Cangzhu, Baizhu, Zhimu, Shengma, Gegen, Huangqin, Yiyiren, Ezhu, Dilong, Jiangcan, Gancao, etc.). Preliminary pilot and retrospective studies suggest that this formula may improve dyspnea, control TCM syndrome scores, facilitate glucocorticoid tapering, and reduce opportunistic infections. Objectives The primary objective is to evaluate the rate of successful safe glucocorticoid (prednisolone or equivalent) tapering to a low maintenance dose (≤7.5 mg/day) at 24 weeks with the herbal formula plus standardized Western medicine, compared with placebo plus standardized Western medicine. Secondary objectives include exploring the clinical benefits on TCM syndrome scores, disease activity, reduction of Western drug side effects, and preservation of lung function; and investigating potential molecular targets and mechanisms through immunomics and multi-omics analyses of peripheral blood and other biospecimens. Study Design Overview This is a single-center, randomized, double-blind, placebo-controlled pragmatic clinical trial (PCT). A total of 54 eligible patients will be enrolled and randomized in a 2:1 ratio using block randomization (stratified by baseline disease severity) to either the integrative medicine group (herbal plus standardized Western medicine) or the Western medicine alone group (placebo plus standardized Western medicine). The intervention consists of daily granule administration for 12 weeks, with a total follow-up of 24 weeks. There are 8 clinical visits: baseline (week 0) and weeks 2, 4, 8, 12, 16, 20, and 24. At each follow-up visit, all patients undergo disease activity assessment (MITAX score), traditional Chinese medicine (TCM) syndrome differentiation analysis, and safety monitoring, including complete blood count, liver and renal function tests, and adverse event recording. Peripheral blood samples are collected at weeks 0, 4, 12, and 24 for immunology and metabolomics research. Pulmonary function tests and high-resolution computed tomography (HRCT) scans are performed at baseline, week 12, and week 24. Throughout the study, daily glucocorticoid dosage and concomitant medications are recorded.