1. Baseline characteristics of patients
Table 1 shows that 184 patients were finally included in the analysis, including 81 (44.0%) patients in the pirfenidone group, and 103 (56.0%) patients in the non-pirfenidone group. The mean age of the cohort was 59.4 years old, 54.3% were females, and 53 (28.8%) patients had a history of smoking. There were no differences in gender, smoking history and UIP pattern. However, both FVC% and DLCO% were lower in the pirfenidone group compared with the non-pirfenidone group (FVC%, P < 0.001; DLCO%, P = 0.003). As for the treatment, the baseline data of glucocorticoid and immunosuppressant treatment were not different between the two groups. Generally speaking, 151 (82.1%) patients received oral glucocorticoid, and 13 (7.1%) patients received immunosuppressants. The duration of prednisone treatment was 2.25-40 months, with an average of 28.8 months. The mean duration of pirfenidone treatment was 14.4 months, and the dose of pirfenidone ranged from 600 to 1,800 mg/day, with an average of 1,492 mg/day.
2. Diagnostic characteristics of IPAF patients
Table 2 shows the diagnostic characteristics. Overall, 66 (35.9%) patients met the diagnostic criteria of IPAF using a combination of serological and morphological domains, 53 (28.8%) patients met the diagnostic criteria of IPAF using clinical and morphological domains, 34 (18.5%) patients met the diagnostic criteria of IPAF using clinical and serological domains, and 31 (16.8%) patients met the diagnostic criteria of IPAF using all the three domains.
A breakdown of features into each IPAF domain showed that the most common clinical findings were Raynaud's phenomenon (49, 26.6%) and inflammatory arthritis or polyarticular morning joint stiffness lasting ≥60 min (45, 24.5%). Moreover, 131 patients had positive serum autoantibody (71.2%), and 51 cases had two or more positive antibodies. An ANA ≥ 1:320 (or nucleolar or centromere pattern of any titer) was the most common serological finding (81, 44.0%). Within the morphological domain (150, 81.5%), the NSIP pattern by HRCT was found in 62.0% (114) of patients, while the OP pattern was found in 14.1% (26) patients. There were no differences in the diagnostic characteristics between the pirfenidone group and the non-pirfenidone group.
3. Changes in pulmonary function
The changes in FVC% (Figure 2A) and DLCO% (Figure 2B) between the two groups were compared at the time points of 3, 6, 12, 18, and 24 months. After 12 months of treatment, FVC% in the pirfenidone group was increased by 10.44%, while such value was decreased by 1.18% in the non-pirfenidone group (P=0.013). Besides, a greater increase of FVC% was observed in the pirfenidone group after 6 (P=0.003) and 24 months (P=0.003). A greater improvement of DLCO% was also observed in the pirfenidone group after 6 months (P=0.043).
Considering the potential confounders, we estimated the changes of FVC% (Figure 2C) and DLCO% (Figure 2D) using a mixed-effects model. After adjustment for sex, age, UIP pattern, baseline FVC%, and DLCO%, patients in the pirfenidone group continued to show a greater improvement in FVC% [1.49%, 95% CI (0.14%, 2.84%)] compared with the non-pirfenidone group (χ2 (1) =4.59, P=0.032). However, no difference was observed in the change of DLCO% (χ2 (1) =0.49, P=0.48). In conclusion, pirfenidone was associated with the improvement of FVC% in IPAF patients.
4. Subgroup analysis of the pulmonary function
To further explore the effect of pirfenidone in different subgroups, subgroup analysis was performed. Table 3 shows the average annual change in FVC absolute value. The volume of FVC (liters) was increased by 0.0390 L/year in the pirfenidone group, while such value was decreased by 0.0769 L/year in the non-pirfenidone group (P=0.038). The association between pirfenidone use and greater improvement in FVC showed a qualitatively same trend in patients with FVC < 70% (P=0.021), with pirfenidone > 600 mg/day (P=0.010), and with total medication time > 12 months (P=0.007). Moreover, pirfenidone also showed superior effects in patients diagnosed by morphological and serological domains (P=0.033). Consequently, pirfenidone treatment had superior effects on FVC improvement when dose>600 mg/day and treatment time>12 months.
5. IPAF patients can reduce the dose of prednisone after 12 months
In our cohort, the prednisone dose ranged from 2.5 to 50 mg/day, with an average of 14.4 mg/day. The total dose (Figure 3A) and daily dose (Figure 3B) had no difference between the two groups when assessing the full duration of 40 months. However, when we separated the period into the initial 12 months and the remaining 12-40 months, both the total dose and daily dose of prednisone were significantly lower in the pirfenidone group (total dose, P=0.012; daily dose, P=0.032) during 12-40 months. After adjustment for potential confounders (sex, age, UIP pattern, baseline FVC%, and baseline DLCO%) in the mixed-effects model, patients in the pirfenidone group continued to show a reduced dose of prednisone by 6.27 mg per day (Figure 3C, D, E χ2 (1) =9.8385, P=0.002, pirfenidone n=34, non-pirfenidone n= 27).
6. Side effects of pirfenidone
In the present study, 17 (19.32%) patients had side effects after taking pirfenidone (Figure 4A) with seven (7.95%) cases of severe side effects (one case of anaphylactic shock, one case of arthritis, one case of liver injury, one case of photosensitivity, and three cases of skin rash) who stopped the medication. Skin rash (10.23%) and liver injury (5.68%) were the most common side effects, which were similar to those of IPF patients [12]. Moreover, 14 (14/17, 82.35%) patients experienced side effects at the initial dose (600 mg), and three (17.65%) patients experienced side effects after the dose of pirfenidone was increased (Figure 4B).