Timing impact on the initiation of pirfenidone therapy on idiopathic pulmonary fibrosis disease progression

Abstract

In this editorial, we comment on the article by Lei et al, with a specific focus on the timing of the initiation of the antifibrotic agent pirfenidone (PFD) in the management of idiopathic pulmonary fibrosis (IPF) and its impact on lung function of IPF patients. PFD is an antifibrotic agent that is widely used in the management of IPF in both early and advanced stages. It inhibits various pathways and has antifibrotic, anti-inflammatory, and antioxidant properties. Despite dosage lowering, PFD slowed IPF progression and maintained functional capacity. The 6-min walk distance test indicated that patients tolerated adverse events well, and PFD significantly reduced the incidence of progression episodes and death. Even when a single disease-progression event occurred, continuing PFD treatment had benefits.

Key Words: Idiopathic pulmonary fibrosis; Pirfenidone; Pirfenidone anti-inflammatory mechanism; Pirfenidone antifibrotic activity; Timing impact

Core Tip: Pirfenidone is commonly used to treat idiopathic pulmonary fibrosis (IPF) in its early stages, but it also demonstrated a notable impact on the disease in its advanced stages, having a similar degree of efficacy in individuals with IPF and substantial deterioration of their lung function. It was safe when given to patients with advanced IPF and had a favorable benefit-risk profile, making it an appropriate treatment option for patients with IPF.

INTRODUCTION

Idiopathic pulmonary fibrosis (IPF) is a lung condition that is debilitating, deadly, and persistently fibrosing[1]. For a long time, IPF has had the worst prognosis of all pulmonary disorders. It is still unclear what the etiology is, and our understanding of the pathophysiology is limited. Over the previous 20 years, treatment has been palliative, except for lung transplantation. However, transplantation is seldom possible owing to organ shortages, advanced age, or comorbidities in afflicted patients[2,3]. Pirfenidone (PFD) is a synthetic nonpeptide medication that inhibits the synthesis of collagen 1, platelet-derived growth factor, tumor necrosis factor alpha, interleukin 1 beta, and transforming growth factor beta 1. All of these molecules have been associated with a decrease or removal of excess scar tissue deposited in a number of different organs[4].

PFD is now one of the medications indicated for the treatment of IPF, as the first findings from animal studies using animal models suggest its usage in lung disorders that are characterized by progressive fibrosis[5]. IPF is the most prevalent and aggressive kind of idiopathic interstitial pneumonia. Patients who do not receive antifibrotic medications have a poor prognosis, with a median survival of 2-4 years[5]. PFD has been the subject of recent studies of fibrosing lung disorders other than IPF, such as unclassifiable progressive fibrosing interstitial lung disease. Research on the drug is also being done for other types of interstitial pneumonia[5]. It has also been considered as a potential treatment for cardiac diseases like heart failure with preserved ejection fraction, in which fibrosis plays a significant pathogenetic role[5]. Based on the evidence, PFD is a good option for patients with IPF because of its favorable benefit-risk profile[6].

IPF pathophysiology

Architectural deformation, honeycombing, and patches of fibrosis alternating with some areas being spared are characteristic of this disorder[7]. When there are repeated small injuries of the alveolar epithelium, the wounds do not heal. This results in epigenetic changes, and alveolar endothelial cells become activated in a way that is not normal. These cells generate an abundance of profibrotic growth factors, chemokines, matrix metalloproteinases, and procoagulant factors, including tissue factor, activated factor VII, factor X, and thrombin, all of which promote fibroblast proliferation and differentiation into myofibroblasts. Myofibroblasts play a crucial role in the abnormal wound healing process that leads to increased production of extracellular matrix, tissue scarring, and irreversible lung fibrosis[5,7-9].

Transforming growth factor beta is the most significant factors in IPF because it activates fibroblasts and alveolar endothelial cells via several microRNAs[5]. Almost all eukaryotic cells release extracellular vesicles, tiny vesicles that transport microRNAs in response to various stimuli and actively participate in intercellular communication that stimulates the fibrotic response[10,11]. Lasty, cells that are a part of both the innate and adaptive immune systems, like T and B lymphocytes, monocytes/macrophages, dendritic cells, and their related cytokines, may be involved in the pathophysiology of IPF[5,12].

PFD mechanism of action in the treatment of IPF

PFD is an orally available pyridone analog (5-methyl-1-phenyl-1H-pyridin-2-one)[13]. It is a multifunctional agent with anti-inflammatory, antioxidant, and antifibrotic properties. Solomon Margolin (1920–2008) was an American pharmacologist who discovered PFD[13,14], and it was initially used as an anti-inflammatory agent. It was used as an antifibrotic agent after it was found to reduce fibrosis in a canine lung infection model and to improve lung function in a hamster model of bleomycin-induced lung injury[13]. The antifibrotic effects of PFD have also been documented in several animal models of progressive fibrotic illnesses affecting the kidney, liver, heart, and other organs[15,16]. PFD modulates the expression of profibrotic factors and pro-inflammatory cytokines and potentially suppresses the production of reactive oxygen species[14].

PFD side effects

The most common side effects of PFD are skin disturbances (rash and photosensitivity) and gastrointestinal disturbances (nausea, diarrhea, and vomiting). Patients taking PFD with food may experience less gastrointestinal distress[17-19]. If gastrointestinal issues persist, the antifibrotic dosage may need to be decreased[20]. Acid-secretion inhibitors may decrease the likelihood that PFD will cause anorexia, nausea, or both[21]. Side effects involving the skin can be prevented by avoiding the sun and wearing sunscreen[22,23]. "The main side effect for PFD users was an increase in appetite loss"[17]. All of these side effects were mild and PFD was well tolerated, which encourages its use as a promising new medication for IPF[18,24]. It has been demonstrated that PFD has a favorable safety profile and is generally well tolerated over the long run[25].

The article addressed an important issue about the effects of PFD on lung function in patients in the early treatment of IPF[26]. The study was a retrospective analysis that included 168 individuals with IPF who were admitted to the hospital between November 2017 and January 2023. The study subjects were divided into two groups, an experimental group that received combined methylprednisolone and PFD, and a control group that received methylprednisolone alone. Patients in the PFD therapy group were further divided into subgroups by their admission records, absence of prior medication, chest computed tomography scan, lung function results, and clinical presentation. Patients with worse lung function were assigned to a late-stage therapy group and patients with better lung function, indicating an earlier stage of the disease, were assigned to an observation group. There were thus three groups of patients, with 60 in the observation group, 53 in the control group, and 55 in the late therapy group. The control group consisted of 45 men and 8 women. They were between 45 years to 89 years of age, with an average age of 60.66 ± 10.51 years. The observation group consisted of 45 men and 15 women. They were between 34 years and 91 years of age, with an average of 60.69 ± 10.59 years. The late treatment group comprised 11 women and 44 men whose ages ranged from 40 years to 88 years, with an average of 60.58 ± 10.48 years. There were no statistically significant differences (P > 0.05) of the demographic features in the groups. The control group received methylprednisolone pills in addition to standard medications. The mainstay of routine therapy was symptomatic, including spasmolysis, low-flow oxygen inhalation, and cough suppression. Methylprednisolone tablets (SFDA approval number: H20110064, Pfizer Italia) were given to the patients. For the first 4 weeks, the dosage was 0.4 mg/dose, given once daily. The dosage was then cut in half and continued for an additional 8 weeks. After that, a 0.1 mg was given every day.

The observation group was given PFD in addition to standard care. Symptomatic interventions such as low-flow oxygen, cough suppression, and spasmolysis were part of the traditional treatment protocol. The Beijing Contini Pharmaceutical Co., Ltd. (China) supplied the PFD capsules (SFDA approval number: H20133376). The recommended dosage was three 0.4 g doses per day after meals. Each patient received treatment for a total of 30 weeks.

The two groups were monitored and evaluated by therapeutic clinical effectiveness, occurrence of adverse events like nausea, vomiting, and anorexia including the frequency and severity of the symptoms, pulmonary function tests, levels of inflammatory markers, and pre- and post-treatment 6-min walk distance (6MWD) test results. Following therapy the observation group had significantly higher rates and fewer adverse events than the control group (P < 0.05). The post-treatment symptom severity scores were significantly lower in the observation group than in the control group (P < 0.05). Following therapy, the pulmonary function index values were significantly better in the observation group than in the control group (P < 0.05). Comparison of the levels of the inflammatory indicators interleukin-2, interleukin-8, and C-reactive protein in the two patient groups found significant differences following treatment (P < 0.05). After treatment, the 6MWD results in the two patient groups were significantly different (P < 0.05), with the observation group walking much farther than the control group. The investigators concluded that initiating PFD treatment as soon as possible after an IPF diagnosis improved pulmonary function, increased inflammatory factor levels, and increased the 6MWD.

This conclusion is contrary to the findings of Albera et al[27] which showed that patients with both more preserved [forced vital capacity (FVC) ≥ 80% or GAP model stage I] and less preserved (FVC < 80% or GAP stages II–III) lung function at baseline, had clinically significant disease progression at 12 months evidenced by decreased FVC and 6MWD. The effectiveness of PFD treatment was the same across all subgroups, regardless of how lung function was measured (FVC vs GAP index stage). Also, regardless of baseline pulmonary function, the results demonstrate that PFD was an effective antifibrotic medication in both the early and late stages of IPF. The results support initiating PFD for this patient group regardless of their pre-existing pulmonary function. The results differ from those Lei et al[26] who found that starting PFD treatment immediately after IPF improved pulmonary function, increased the levels of inflammatory factors, and increased the 6MWD, which highlighted the benefit of starting PFD therapy in only early disease-stage patients. However, Albera et al[27] found that PFD therapy was equally effective in in IPF patients at both the early and late stages, Tzouvelekis et al[28] reported that the administration of PFD was safe in patients with advanced IPF, and Hanta et al[29] found that PFD was safe, with acceptable side effects, and was an effective treatment for IPF.

CLINICAL IMPLICATIONS

Patients with IPF may find PFD to be a suitable treatment option owing to its favorable benefit-risk profile. PFD was an effective antifibrotic agent in both the early and late stages of IPF regardless of baseline pulmonary function. The effectiveness of PFD in slowing IPF disease progression continued even at reduced doses. Continued treatment with PFD conferred a benefit even in the presence of a single disease-progression event.

CONCLUSION

PFD is an antifibrotic, anti-inflammatory, and antioxidant agent. Regardless of baseline pulmonary functions, it was an effective antifibrotic agent in both the early and late stages of IPF. PFD had manageable and generally acceptable side effects, and was safe for use in patients with advanced IPF.