Effect of pirfenidone on the pulmonary fibrosis of Hermansky–Pudlak syndrome
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.,
References (28)
- et al.
A new variant of Hermansky–Pudlak syndrome due to mutations in a gene responsible for vesicle formation
Am. J. Med.
(2000) - et al.
Altered trafficking of lysosomal proteins in Hermansky–Pudlak syndrome due to mutations in the β3A subunit of the AP-3 adaptor
Mol. Cell.
(1999) - et al.
Hermansky–Pudlak syndrome type 3 in Ashkenazi Jews and other Non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency
Am. J. Hum. Genet.
(2001) - et al.
Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky–Pudlak syndrome, due to mutations in HPS-1
CHEST
(2000) - et al.
Hermansky–Pudlak syndrome: pulmonary manifestations of a ceroid storage disorder
Am. J. Med.
(1979) Pirfenidone in idiopathic pulmonary fibrosis
Lancet
(1999)- et al.
Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice
Toxicol. Lett.
(1997) - et al.
Hermansky–Pudlak syndrome: models for intracellular vesicle formation
Mol. Genet. Metab.
(1998) - et al.
Hermansky–Pudlak syndrome and Chediak–Higashi syndrome: disorders of vesicle formation and trafficking
Throm. Haemost.
(2001) - et al.
Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky–Pudlak syndrome)
N. Engl. J. Med.
(1998)