Baseline demographic characteristics of patients with stage I IPF according to the JRS severity system
The study population consisted of 179 patients (148 males [83%] and 31 females [17%]) with a mean age of 71.5 years (range, 43–86 years). One hundred fifty seven patients had a smoking history. Mean PaO2 was 90.3 Torr in room air. The percentage of patients with oxygen desaturation on the 6MWT was 37.4%. The mean %FVC and predicted DLco (%DLco) were 81.5% (range, 37.4–129.1%) and 68.8% (range, 23.7–143.2%), respectively (Table 1).
Table 1
Baseline demographic characteristics of patients with IPF with a disease severity of stage I according to the JRS severity system
Variable
|
Mean ± SD or number
|
Range
|
Age, yrs
|
71.5 ± 7.0
|
43–86
|
Sex, male/female
|
148/31
|
|
BMI, kg/m2
|
21.6 ± 4.3
|
14.0–32.6
|
Smoking history, N/F/C
|
22/121/36
|
|
GAP staging (I/II/III)
|
111/58/10
|
|
mMRC (0/1/2/3/4)
|
28/72/62/13/3
|
|
PaO2, Torr
|
90.3 ± 9.1
|
62.7–127
|
%FVC, %
|
81.5 ± 19.2
|
37.4–129.1
|
%DLco, %
|
68.8 ± 21.3
|
23.7–143.2
|
Desaturation on 6MWT, +/–
|
73/106
|
|
KL-6, U/ml
|
938 ± 586
|
193–3374
|
SP-D, ng/ml
|
271 ± 216
|
36.7–1390
|
Histological UIP diagnosis (%)
|
40 (22.3%)
|
|
Data is presented as mean ± standard deviation. IPF, idiopathic pulmonary fibrosis; JRS, Japanese Respiratory Society; BMI, body mass index; N/F/C, Never/Former/Current; GAP, gender–age–physiology; mMRC, modified Medical Research Council; PaO2, partial pressure of oxygen in arterial blood; FVC, forced vital capacity; DLco, diffusion capacity of the lungs for carbon monoxide; 6MWT, 6-minute walk test; KL-6, Krebs von den Lungen-6; SP-D, surfactant protein–D; UIP, usual interstitial pneumonia
|
Correlation between the numbers of patients with different JRS disease severities according to the JRS severity system and the GAP staging model
JRS stage I (n = 179) consisted of the following GAP staging model breakdown: stage I, 111 cases; stage II, 58 cases; stage III, 10 cases. The percentage of patients with GAP stage II/III with JRS stage I was 37.9% (Table 2).
Table 2
Correlation between the numbers of patients with different disease severities according to the JRS severity system and GAP staging model
|
|
JRS severity system
|
|
|
Stage I
|
Stage II
|
Stage III
|
Stage IV
|
GAP staging model
|
Stage I
|
111
|
14
|
34
|
7
|
|
Stage II
|
58
|
4
|
24
|
22
|
|
Stage III
|
10
|
0
|
13
|
18
|
JRS, Japanese Respiratory Society; GAP, gender–age–physiology
|
Comparison of clinical and demographic characteristics between JRS stage I with and without oxygen desaturation on the 6MWT
Baseline GAP staging, modified Medical Research Council (mMRC) value, serum Krebs von den Lungen (KL)-6, and serum surfactant protein (SP)-D in patients with JRS stage I with oxygen desaturation were significantly higher compared with patients with JRS stage I without oxygen desaturation on the 6MWT, and PaO2, %FVC, %DLco, 6-minute walking distance (6MWD), and lowest percutaneous oxygen saturation (SpO2) on the 6MWT were significantly lower for patients with JRS stage I with oxygen desaturation on the 6MWT compared with patients with JRS stage I without oxygen desaturation on the 6MWT (Table S1).
The duration from the initial visit to disease progression was shorter in patients with JRS stage I with oxygen desaturation on the 6MWT compared with patients with JRS stage I without oxygen desaturation on the 6MWT (median survival time [MST], 13.9 months vs. 37.4 months, P = 0.002; Fig. 2A). The Kaplan–Meier survival curve showed a significantly poorer outcome in patients with JRS stage I with oxygen desaturation on the 6MWT compared with patients with JRS stage I without oxygen desaturation on the 6MWT (MST = 40.8 months vs. 64.9 months, P = 0.002; Fig. 2B).
Comparison of clinical and demographic characteristics between patients with JRS stage I with GAP stage I and GAP stage II/III
The mean age, ratio of male, GAP staging, mMRC, and serum SP-D were significantly higher in patients with JRS stage I with GAP stage II/III compared with patients with JRS stage I with GAP stage I. In contrast, body mass index, %FVC, %DLco, 6MWD, and lowest SpO2 on the 6MWT were significantly lower in patients with JRS stage I with GAP stage II/III compared with patients with JRS stage I with GAP stage I (Table S2).
The duration from the initial visit to disease progression was shorter in patients with JRS stage I with GAP stage II/III compared with patients with JRS stage I with GAP stage I (MST = 17.3 months vs. 34.4 months, P = 0.006; Fig. 3A). The survival time for patients with JRS stage I with GAP stage II/III was significantly shorter compared with patients with JRS stage I with GAP stage I (MST = 39.1 months vs. 64.1 months, P = 0.004; Fig. 3B).
Antifibrotic treatment for patients with JRS stage I with oxygen desaturation on the 6MWT and JRS stage I with GAP stage II/III
Forty eight patients with JRS stage I with oxygen desaturation on the 6MWT and 39 patients with JRS stage I with GAP stage II/III were treated with antifibrotic drugs during 6 months. Fifteen of 48 patients with JRS stage I with oxygen desaturation on the 6MWT and 11 of 39 patients with JRS stage I with GAP stage II/III were treated with nintedanib, and each remaining patient received pirfenidone. There was no difference in comparative clinical and demographic characteristics between antifibrotic drug-treated patients and non-treated patients in JRS stage I with oxygen desaturation on the 6MWT and JRS stage I with GAP stage II/III (Table S3, S4).
As a result, in patients with JRS stage I with oxygen desaturation on the 6MWT, the rate of decline in FVC over 6 months was − 61 mL ± 178 mL in the antifibrotic drug-treated group and − 147 mL ± 172 mL in the non-treated group (P = 0.02). In patients with JRS stage I with GAP stage II/III, the rate of decline in FVC over 6 months was − 32 mL ± 176 mL in the antifibrotic drug-treated group and − 121 mL ± 185 mL in the non-treated group (P = 0.04) (Fig. 4). Moreover, the relative decline in %FVC over 6 months was significantly lower in antifibrotic drug-treated patients compared with non-treated patients (JRS stage I with oxygen desaturation on the 6MWT: − 7.0% ± 8.4% vs − 2.4% ± 9.8%, P = 0.02; JRS stage I with GAP stage II/III: − 6.8% ± 9.2% vs − 0.6% ± 10.1%, P = 0.009) (Fig. 5).
Although there was no difference in comparative efficacy between antifibrotic drug-treated patients and non-treated patients (rate of disease progression in JRS stage I with oxygen desaturation on the 6MWT: antifibrotic drug-treated group vs. non-treated group, 41.6% vs. 62.1%, respectively, P = 0.08; JRS stage I with GAP stage II/III: antifibrotic drug-treated group vs. non-treated group, 38.4% vs. 53.1%, respectively, P = 0.23), the efficacy of antifibrotic treatments tended to be better.