Effect of pirfenidone on the pulmonary fibrosis of Hermansky–Pudlak syndrome

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Abstract

Hermansky–Pudlak syndrome (HPS) consists of oculocutaneous albinism, a platelet storage pool deficiency and, in patients with HPS1 gene mutations, a progressive, fatal pulmonary fibrosis. We investigated the safety and efficacy of an antifibrotic agent, pirfenidone (800 mg, t.i.d.), in treating 21 adult Puerto Rican HPS patients, including 20 homozygous for the same HPS1 mutation. Patients were examined every 4 months for up to 44 months in a randomized, placebo-controlled trial, with rate of change in pulmonary function values as outcome parameters. Using the complete data set of 130 patient admissions, a repeated measures model showed that 11 pirfenidone-treated patients lost FVC at a rate 5% of predicted (∼400 mL) per year slower than 10 placebo-treated patients (p=0.001). A random coefficients model showed no significant difference. However, using data restricted to patients with an initial FVC >50% of predicted, both models showed the pirfenidone group losing FVC (p<0.022), FEV1 (p<0.0007), TLC (p<0.001), and DLCO (p<0.122) at a rate ∼8%/year slower than the placebo group. Clinical and laboratory side effects were similar in the two groups. Pirfenidone appears to slow the progression of pulmonary fibrosis in HPS patients who have significant residual lung function.

Introduction

Hermansky–Pudlak syndrome (HPS) consists of oculocutaneous albinism and a bleeding diathesis due to a platelet storage pool deficiency [1], [2]. Whole mount electron microscopy, demonstrating absence of platelet dense bodies, confirms the diagnosis [3]. Some HPS patients manifest additional complications, including granulomatous colitis, pulmonary fibrosis, and intracellular accumulation of ceroid lipofuscin, a lipid protein complex [4].

At least four different genes cause HPS, an autosomal recessive disease affecting perhaps 1000 patients worldwide. Mutations in HPS1 cause HPS-1 disease, which afflicts ∼400 northwest Puerto Ricans due to a founder mutation [5], [6]. At least 11 other HPS1 mutations have been described in non-Puerto Ricans [1]. Mutations in ADTB3A cause HPS-2 disease, with neutropenia and childhood infections [7]. ADTB3A codes for the β3A subunit of adaptor protein-3, a coat protein complex mediating vesicle formation from the trans-Golgi network or late endosomes [8]. Mutations in HPS3 cause HPS-3 disease, a mild disorder affecting central Puerto Rican patients due to a second founder mutation on the island [9]. Other HPS3 mutations have been identified in non-Puerto Ricans [10]. Mutations in HPS4 cause HPS-4 disease, and the gene product appears to interact with the gene product of HPS1 [11]. Although detailed clinical descriptions of HPS-4 patients are lacking, HPS-1 and HPS-4 apparently have phenotypes which resemble each other.

We know with certainty that HPS-1 disease is associated with pulmonary fibrosis [2], [12], which begins with restrictive lung disease and progresses to death, generally by the fourth or fifth decade [13], [14]. Although no treatment exists, one antifibrotic agent has promise. Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) inhibits TGFβ-mediated fibroblast proliferation and collagen synthesis in cultured cells, and prevents cyclosporine- and bleomycin-induced pulmonary fibrosis in mice [15], [16], [17]. Hence, we initiated a double-blind, randomized, placebo-controlled trial of pirfenidone for the pulmonary fibrosis of HPS.

Section snippets

Patients

Although this was not a natural history study, we did obtain isolated, random pulmonary function test results on as many adult HPS patients as possible. Of 78 individuals providing data, 47 had studies performed prior to or during an NIH Clinical Center admission, as previously described [2], [12]. Of these, 44 were Puerto Ricans homozygous for a 16-bp duplication in exon 15 of HPS1 [5], and 3 were non-Puerto Ricans with other HPS1 mutations. An additional 31 patients from pulmonary clinics in

Natural history of lung disease in HPS-1

Seventy-eight untreated patients with HPS-1 each provided a single data point for cross-sectional analysis of FVC versus age at 5-year intervals (Fig. 1A). The mean FVC fell steadily from 88±3 (SE)% of predicted at age 20–25 years to 63±6% at age 36–40 years. At 41–45 years, the mean FVC was 89±5% of predicted, but again fell decrementally to 67±6% at 56–60 years. In three individual patients selected for analysis because they provided the most data points (7, 10, and 18), FVC fell linearly

Discussion

The hypopigmentation and bleeding diathesis of HPS appear due to defective formation of vesicles of lysosomal lineage, including the melanosome and dense body [1], [8], [20], [21]. In contrast, the cause of pulmonary fibrosis in HPS remains unknown. The finding of increased PDGF [14] and other cytokines [22] in the pulmonary lavage fluid of HPS patients suggests an inflammatory process promoting fibrosis. Hence, we attempted therapy with the anti-inflammatory drug, pirfenidone. This compound

Acknowledgements

The work is dedicated to the courageous patients who participated in this trial. The authors appreciate the recruitment efforts of Carmelo Almodovar and Donna Appell, Presidents of the HPS Networks of Puerto Rico and the United States, respectively, and the nursing assistance of Maria Zayas, Kathy Obunse, and the staff of the 8W ward of the NIH Clinical Center. The pulmonary function laboratory of the NIH Clinical Center performed critical measurements for this trial, and MARNAC, Inc.,

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