To our knowledge, this is the first prospective study to explore the efficacy of tacrolimus and GCs in combination with low-dose pirfenidone in IIM-ILD patients. First, we found that tacrolimus was superior in reducing the mortality rate and recurrence rate of IIM-ILD within the first year of treatment initial when compared with other conventional immunosuppressive agents in our retrospective study. In the prospective study, tacrolimus was confirmed as an effective and well-tolerated therapy in terms of improving muscle strength, ameliorating pulmonary dysfunction, and reducing disease activity. Although low -dose pirfenidone on top of tacrolimus has no impact on the survival of IIM-ILD patients, it may reduce the progression of pulmonary fibrosis and decrease respiratory-related flare-ups in those patients. Our prospective study indicated that the treatment of tacrolimus on top of GCs followed by low-dose pirfenidone could improve both muscle and lung involvement of IIM-ILD patients, with a manageable safety profile. This “triple therapy” modality maybe an applicable treatment strategy for IIM patients with ILD.
It is well established that ILD is the gravest manifestation characterized by irreversible decline in lung function which ultimately results in a highly mortality. The prevalence of ILD is as high as 65% in IIM patients and considered as a dominant predictor for poor prognosis. The natural clinical course of ILD patients varies from slow progression to acute exacerbation, even death. Various dosages of GCs are considered as the mainstay of therapy. However, a majority of these patients were resistant to GCs monotherapy, and many of them experienced ILD deterioration or flare-ups during the process of GCs tapering. Higher dosages of GCs and immunosuppressive agents may provide more powerful immunosuppression and modify disease progression in a certain extent, but carry an increased risk of infections, osteoporosis, and other adverse effects. Therefore, more cost-effective treatment modalities that could control progression of primary disease as well as improve pulmonary fibrosis are needed.
Th1-type pulmonary cells are significantly increased in GC-resistant PM/DM-ILD patients, hence, tacrolimus acting as a selectively suppressor of T lymphocytes proliferation may serve as an ideal treatment drugs. Several case reports and small-sample trails demonstrated that tacrolimus could improve disease-free survival and lung physiology in IIM-ILD patients.[6, 28, 29] Similar findings were observed in our study that significant improvements of clinical manifestations and laboratory parameters result from tacrolimus have been seen in both the retrospective and prospective cohorts. In the retrospective cohort, we confirmed a preponderance of tacrolimus in improving survival rate and relapse rates of IIM-ILD patients comparing to other conventional immunosuppressive agents. We also found a remarkable reduction of GCs dosage after one-year treatment with tacrolimus in the prospective cohort, which is another possible advantage of tacrolimus. Ultimately, tacrolimus could not only improve muscle strength and overall disease activity but also permit a substantial spare of GCs.
Of note, our data provided further evidences supporting the efficacy and safety of low-dose pirfenidone in combination with tacrolimus therapy for IIM-ILD patients in the real world. Previous randomized clinical trials of pirfenidone demonstrated a slower decline of the lung function and sufficient drug tolerability in IPF patients. [15, 16, 30] Furthermore, the potential benefits of pirfenidone were also seen in other types of pulmonary fibrosis, such as scleroderma-associated ILD and clinically amyopathic dermatomyositis. More importantly, our study suggested that low-dose pirfenidone on top of tacrolimus had a lower respiratory-related recurrence rate as compared to those receive tacrolimus alone.
Chest HRCT is a reliable predictor of prognosis in IIM-ILD patients. A key finding in our study is that the “triple therapy” containing low-dose pirfenidone significantly improved the lung fibrosis according to the HRCT results from survived patients (26/34) in the prospective study. A significant decrease of total HRCT score was seen in the combination therapy group, which indicates that pirfenidone played a critical role in ameliorating pulmonary fibrosis for IIM-ILD patients. We observed that the airspace consolidation was decreased significantly after pirfenidone add-on treatment, which further confirmed the anti-inflammatory effect of pirfenidone in addition to the anti-fibrosis role. Reticular opacity got significantly worse in tacrolimus group, while no changes were seen in pirfenidone add-on group. In addition, patients in combination therapy groups showed a significant improvement of traction bronchiectasis compared to the control. These results suggested that low-dose of pirfenidone may have both anti-inflammatory and anti-fibrosis effects.
Semi-quantitative visual evaluation of HRCT scans can be challenging because of existence of some subtle lesions. Nevertheless, additional objective and quantitative assessment tools including serum biomarker and pulmonary function tests (PFTs) should be introduced to monitoring disease progression. PFTs are recognized as a useful and non-invasive measurement of lung function. However, the results of PETs were not analyzed in our study because up to 32.3% of the baseline data were unavailable owing to the severity of the respiratory failure of these patients. In addition, due to the rapid COVID-19 pandemic, most of patient in our center were unable to perform PFTs as proposed. Based on the limited data in our study, no additional PFTs improvement was observed in those received pirfenidone compared to the controls.
The common drug-associated adverse effects in our study are infections, disturbances in glucose metabolism, and electrolyte imbalance. Opportunistic infections, such as pneumocystis carinii, CMV and EBV activation, were frequently observed in patients who received combined immunosuppressive treatments, and these infections often trigger original disease flare-ups and exacerbation of ILD. In our study, exacerbation of ILD was the dominant cause of death. Those patients either experienced rapid progression of ILD or opportunistic infections secondary to exacerbation of ILD or excessive immunosuppressive therapies. It is of great significance to prevent potential infections and other complications in addition to control the progression of lung fibrosis in IIM-ILD patients. Thus, trimethoprim/sulfamethoxazole (TMP/SMX) should be administrated to prevent pneumocystis jiroveci pneumonia (PCP). Furthermore, monitoring the serum CMV and EBV levels are needed in order to make timely interventions. It is important to prevent potential infection and other complications in patients, but it is also equally important to give appropriate treatment of progressive lung disease. As reported, the most common adverse events of pirfenidone were gastrointestinal-related nausea and dyspepsia, which are generally responsive to dosage reduction.[15, 16, 30] High-dose pirfenidone may also reduce the compliance of patients due to the financial burden. To some extent, the use of pirfenidone could be limited by side effects as well as treatment costs. Consequently, administration of low-dose pirfenidone may be a rational alternative for IIM-ILD patients. In our study, all patients responded and tolerated well to this “triple therapy”, with manageable side effects.
Because IIM- ILD is a life-threatening condition, it is difficult to conduct randomized clinical trials. There are several limitations in our study. First, this is a single-center, open-label trial, which may have potential bias. Second, information bias and missing data were inevitable in the retrospective study due to the retrospective nature. Third, the limited sample size and relatively short follow-up period was also an issue, especially in prospective study. Forth, not all patients have data on PFTs in the prospective study either due to the severity of the respiratory failure at baseline or COVID-19 epidemic. Last, all patients in the present study were Chinese and it is unclear whether these findings will apply to individuals of different ethnicities. Therefore, further multi-center, randomized control trials with larger population are needed to confirm our results. The long-term outcome and mortality is also warranted to analyze.
In summary, this study demonstrated that IIM-ILD patients treated with tacrolimus showed significant improvements in mortality and flare-ups when compared to other immunosuppressive agents. Tacrolimus results in multidimensional improvements in both myositis and pulmonary involvement, which could serve as a promising therapeutic alternative in the management of IIM-ILD. One year of “triple therapy” not only slowed the pulmonary fibrosis progression but also reduced respiratory-related flare-ups in IIM-ILD patients. This “triple therapy” seems to be well tolerated and should be considered in the future treatment of IIM-ILD patients. Nevertheless, this conclusion should be confirmed by large-sample, randomized controlled studies.