Pleuroparenchymal fibroelastosis from a rheumatologic perspective

Abstract

Background:

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease (ILD) associated with systemic autoimmune rheumatic diseases (SARDs). Its clinical characteristics and outcomes in SARDs remain poorly defined.

Objectives:

To describe demographics, imaging patterns, and outcomes in SARD-associated PPFE.

Methods:

Patients diagnosed with PPFE and SARDs at Mayo Clinic (2000-2024) were included. PPFE diagnosis was confirmed by high-resolution computed tomography, and SARD diagnoses were established by rheumatologists.

Results:

Fifteen of 62 patients with PPFE had SARDs with majority having systemic sclerosis (SSc)(n= 7, 46%). Median age at PPFE diagnosis was 57.2 years; 80% were female; 40% were ever-smokers; 40% required supplemental oxygen; 5 had pulmonary hypertension. Coexisting ILD patterns included UIP (26.7%) and NSIP (20%). Coexisting ILD patterns included usual interstitial pneumonia (26.7%) and nonspecific interstitial pneumonia (20%). Three patients died, including two with SSc.

Conclusion:

Systemic sclerosis was the most frequently observed SARD among patients with PPFE, and may coexist with other ILD patterns; recognition may inform risk stratification, multidisciplinary evaluation, and longitudinal follow-up.

Plain language summary

Pleuroparenchymal Fibroelastosis and Rheumatic Disorders: What We Know So Far

Pleuroparenchymal fibroelastosis (PPFE) is an uncommon type of lung scarring that mainly affects the upper parts of the lungs and the thin membrane covering them (the pleura). While PPFE can occur after lung transplants or infections, it is now being recognized in people with autoimmune diseases that also affect the lungs. These conditions are known as systemic autoimmune rheumatic diseases (SARDs) and include illnesses such as scleroderma, rheumatoid arthritis, lupus, and myositis. This study looked at patients diagnosed with PPFE at Mayo Clinic between 2000 and 2023 to better understand how PPFE appears in people with autoimmune diseases. Researchers reviewed medical records and imaging studies (CT scans) and confirmed each case through both lung and rheumatology specialists. Out of 62 people with PPFE, 15 also had an autoimmune disease. The most common condition linked to PPFE was systemic sclerosis, followed by dermatomyositis, rheumatoid arthritis, systemic lupus erythematosus, and mixed connective tissue disease. Most of the affected patients were women in their fifties. Nearly half of them needed oxygen therapy, and some developed pulmonary hypertension. The study found that PPFE can occur across several autoimmune diseases, not just scleroderma. Recognizing this connection can help doctors identify lung scarring earlier and provide more personalized care for people with autoimmune diseases who develop breathing problems.

Keywords

connective tissue diseases ILD pleuroparenchymal fibroelastosis PPFE SARDS

Introduction

Pleuroparenchymal fibroelastosis (PPFE) is part of the rare idiopathic interstitial pneumonia (IIP) that primarily involves the visceral pleura and subpleural lung parenchyma, with a predilection for the upper lobes.^1,2 It was recognized by the American Thoracic Society and European Respiratory Society in 2013.³

PPFE has gained increasing attention in recent years due to its distinct clinical, radiological, and pathological features, as well as its association with various systemic and post-transplant conditions.^1,4 Despite growing recognition, the true incidence and prevalence of PPFE remain unknown, highlighting the need for further investigation into its etiology, pathophysiology, and clinical implications.

PPFE predominantly affects individuals aged 40–70 years, with no apparent gender predilection.⁵ Familial clustering has been reported in some cases, suggesting a potential genetic predisposition, mutations in TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component) have shown some possible association.⁵ PPFE has been associated as well with certain risk factors,^1,6,7 including prior infections and post-transplant conditions such as bone marrow, lung, and hematopoietic stem cell transplantation.^4,5 Another association has been in patients with interstitial lung disease (ILD) and systemic autoimmune rheumatic diseases (SARDs).^4,5,8,9

The clinical presentation of PPFE is often insidious, with patients reporting progressive shortness of breath and a persistent, non-productive cough. Radiological and histopathological findings are central to the diagnosis of PPFE. High-resolution computed tomography (HRCT) typically reveals pleural thickening and subpleural fibrosis in the upper lobes, along with characteristic upper lobe volume loss and traction bronchiectasis.⁵ Histopathological, PPFE is defined by the presence of intraalveolar fibrosis with associated alveolar septal elastosis .^1,4,5 PPFE is also associated with other fibrotic ILD patterns, most notably UIP, which coexists in approximately one-quarter of cases.⁵ NSIP is the second most common coexisting pattern, typically involving the lower lobes.⁵ These overlapping features can complicate diagnosis and management, particularly when the disease presents in a mixed pattern. Upper lobe fibrosis and volume loss, combined with lower lobe involvement, represent a hallmark of PPFE with coexisting ILD.

PPFE has been associated with SARDS-ILD, including systemic sclerosis, rheumatoid arthritis, and inflammatory idiopathic myopathies.¹ While systemic sclerosis represents the most common association, rare cases involving vasculitis have also been documented.¹⁰ These associations suggest that PPFE may represent a manifestation of underlying systemic processes in some patients, emphasizing the need for thorough evaluation for systemic autoimmune rheumatic diseases in individuals diagnosed with PPFE.

This study focused on review cases of patients with SARDS and PFFE, we performed a retrospective review from patients seen at Mayo Clinic, we described the type of SARDS, demographics, CT patterns, and mortality.

Methods

We performed a retrospective review focused on patients diagnosed with PPFE and SARDS from January 1, 2000, to June 30, 2024, seen at Mayo Clinic. A software tool “Advanced Text Explorer” was used to identify patients with PPFE who had in addition documentation from diagnoses of SARDs (Figure 1). We included the following SARDS: “systemic sclerosis, systemic lupus erythematosus, dermatomyositis/polymyositis, mixed connective tissue disease, Sjögren’s syndrome, rheumatoid arthritis, antiphospholipid syndrome, vasculitis, and ankylosing spondylitis.” The diagnosis of PPFE was established based on high-resolution computed tomography (HRCT) findings and confirmed by radiologist reports. Characteristic radiologic features included upper lobes-predominant pleural thickening, subpleural fibrosis, associated upper lobe volume loss, and/or traction bronchiectasis. Initial image interpretation was performed by radiologists. Imaging studies were subsequently reviewed during follow-up by pulmonologists or rheumatologists with expertise in ILD to further support the diagnosis. Patients whose imaging did not demonstrate these characteristic features were excluded from the cohort. Each SARDS diagnosis was performed based on clinical expertise from rheumatologist based on ACR/EULAR criteria to ensure accuracy.

Figure 1.

Inclusion and exclusion criteria of patients with PPFE and SARDS.

This manuscript was prepared in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines (Supplemental Material).¹¹

Descriptive statistics are provided for the overall cohort and by diagnostic group. Continuous variables are summarized using means, standard deviations, medians, interquartile ranges, and ranges. Categorical variables were summarized as counts and percentages.

Results

We identified 110 patients meeting the keyword search criteria. After manual review to exclude patients not meeting the inclusion criteria for diagnosis of SARDS and PPFE, our analysis cohort included 15 patients. Of the 15 patients with SARD, systemic sclerosis was seen in 7 patients, dermatomyositis in 3, rheumatoid arthritis in 2, SLE in 1, and mixed connective tissue disease in 2 (Table 1).

Table 1.

Patient demographics and clinical characteristics.

Patient characteristics	Systemic sclerosis (N = 7)	Rheumatoid arthritis (N = 2)	Dermatomyositis (N = 3)	Lupus (N = 1)	Mixed connective tissue disease (N = 2)	Total (N = 15)
Gender, n (%)
Female	7 (100.0%)	1 (50.0%)	2 (66.7%)	1 (100.0%)	1 (50.0%)	12 (80.0%)
Male	0 (0.0%)	1 (50.0%)	1 (33.3%)	0 (0.0%)	1 (50.0%)	3 (20.0%)
Ethnicity, n (%)
Hispanic or Latino	1 (14.3%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	1 (50.0%)	2 (13.3%)
Caucasian	6 (85.7%)	1 (50.0%)	3 (100.0%)	1 (100.0%)	1 (50.0%)	12 (80.0%)
Asian	0 (0.0%)	1 (50.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	1 (6.7%)
Age at diagnosis of SARD
Mean (SD)	57.8 (20.26)	66.5 (NA)	45.5 (13.67)	55.5 (NA)	50.3 (5.34)	54.3 (15.66)
Median (IQR)	59.1 (39.9, 72.8)	66.5 (66.5, 66.5)	52.2 (29.7, 54.4)	55.5 (55.5, 55.5)	50.3 (46.5, 54.1)	54.1 (46.5, 66.5)
Range	32.2, 84.0	66.5, 66.5	29.7, 54.4	55.5, 55.5	46.5, 54.1	29.7, 84.0
Age at diagnosis of PPFE
Mean (SD)	66.3 (18.01)	76.2 (14.81)	45.4 (13.62)	57.2 ()	48.6 (3.58)	60.5 (17.43)
Median (IQR)	66.2 (44.2, 84.0)	76.2 (65.7, 86.7)	52.0 (29.8, 54.5)	57.2 (57.2, 57.2)	48.6 (46.1, 51.1)	57.2 (46.1, 80.9)
Range	43.2, 85.3	65.7, 86.7	29.8, 54.5	57.2, 57.2	46.1, 51.1	29.8, 86.7
Smoking, n (%)	4 (57.1%)	1 (50.0%)	1 (33.3%)	0 (0.0%)	0 (0.0%)	6 (40.0%)
Use of supplemental oxygen, n (%)	3 (42.9%)	2 (100.0%)	1 (33.3%)	0 (0.0%)	1 (50.0%)	7 (46.7%)
Hospitalization secondary to ILD flare, n (%)	1 (14.3%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	1 (50.0%)	2 (13.3%)
Death, n (%)	2 (28.6%)	1 (50.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	3 (20.0%)

SARDS with PPFE was predominantly observed in females, with 3 of the 15 patients being male. The median age at CTD diagnosis was 54.3 years, while the median age at PPFE diagnosis was 60.5 years. A history of smoking was present in 40% of patients across all CTD subgroups. No pneumothorax was reported in the cohort. Following the diagnosis of PPFE, patients demonstrated variable clinical trajectories. New oxygen requirements were observed in six patients (40%), including patients with systemic sclerosis (n = 3), rheumatoid arthritis (n = 2), and mixed connective tissue disease (n = 1). Among those patients, the median time from PPFE diagnosis to oxygen initiation was 1.6 years (interquartile range, 0.2–4.3 years), ranging from 0 to 7.5 years (see Table 2).

Table 2.

Clinical course and outcomes of patients with SARD and PPFE.

Age	Sex	Ethnicity	SARD	Years from SARD to PPFE diagnosis	Concomitant ILD (type)	O₂ requirements	Death	Time from PPFE to death (years)	Cause of death	New treatment due to PPFE	PAH
61	Female	Caucasian	Systemic sclerosis	5.3	No	No	No	NA	NA	Cellcept	Yes
45	Female	Caucasian	Systemic sclerosis	4.3	No	No	No	NA	NA	Cellcept	No
68	Female	Hispanic	Systemic sclerosis	16.1	NSIP	2 L started 0.7 years after PPFE dx	No	NA	NA	Rituximab	Yes
84	Female	Caucasian	Systemic sclerosis	8.1	UIP	2 L started 0.2 years after PPFE dx	Yes	1.6	ILD	Cellcept (discontinued due to intolerance)	Yes
50	Female	Caucasian	Systemic sclerosis	11.0	NSIP	3 L started 7.5 years after PPFE dx	No	NA	NA	Cellcept	Yes
92	Female	Caucasian	Rheumatoid arthritis	−4.6	No	2 L started 4.3 years after PPFE dx	Yes	6.4	ILD	Rituximab	No
72	Male	Asian	Rheumatoid arthritis	−0.2	UIP	2 L started 2.5 years after PPFE dx	No	NA	NA	Cellcept	No
87	Female	Caucasian	Systemic sclerosis	0.0	UIP	No	No	NA	NA	None	No
89	Female	Caucasian	Systemic sclerosis	17.3	No	No	Yes	1.7	Cardiac	None	Yes
60	Female	Caucasian	SLE	1.8	Organizing Pneumonia	No	No	NA	NA	Cellcept	No
57	Male	Caucasian	Dermatomyositis	0.1	No	No	No	NA	NA	None	No
33	Female	Caucasian	Dermatomyositis	0.0	No	No	No	NA	NA	Prednisone	No
53	Male	Caucasian	Mixed connective tissue disease	−8.0	No	Unknown L; initiated at PPFE diagnosis	No	NA	NA	Cellcept	No
55	Female	Caucasian	Dermatomyositis	−0.2	UIP	No	No	NA	NA	Prednisone	No
52	Male	Hispanic	Mixed connective tissue disease	−3.3	NSIP	No	No	NA	NA	Cellcept	No

Pulmonary hypertension, identified by transthoracic echocardiography, was present in five patients (33%), all of whom had systemic sclerosis.

Mortality occurred in three patients (20%), including two patients with systemic sclerosis and one patient with rheumatoid arthritis. Causes of death included interstitial lung disease–related respiratory failure (n = 2) and cardiac disease (n = 1). The time from PPFE diagnosis to death ranged from approximately 1.6–6.4 years. Two deaths occurred within approximately 2 years of PPFE diagnosis and were attributed to ILD–related respiratory failure, while one death occurred 6.4 years after PPFE diagnosis and was attributed to cardiac disease.

Among the 15 patients with PPFE, 8 patients (53%) had concomitant ILD. Concomitant ILD was most frequently observed in patients with systemic sclerosis (n = 4), followed by rheumatoid arthritis (n = 1), systemic lupus erythematosus (n = 1), dermatomyositis (n = 1), and mixed connective tissue disease (n = 1). The ILD patterns identified included usual interstitial pneumonia (n = 4), nonspecific interstitial pneumonia (n = 3), and organizing pneumonia (n = 1), see Table 2. Patients with concomitant ILD more frequently developed supplemental oxygen requirements compared with those without concomitant ILD 50% (4/8) versus 29% (2/7). Pulmonary hypertension, identified by transthoracic echocardiography, was more common among patients with concomitant ILD (38% vs 29%). Mortality occurred in one patient with concomitant ILD.

The majority of patients received immunosuppressive therapy after PPFE diagnosis, most commonly mycophenolate mofetil (8 of 15 patients, 53%), followed by rituximab (2 patients, 13%) and systemic corticosteroids (2 patients, 13%), 3 patients (20%) did not undergo treatment escalation following PPFE diagnosis (see Table 2).

Hospitalization due to ILD exacerbations occurred in two patients, one with systemic sclerosis and one with mixed connective tissue disease.

Discussion

This study provides additional insight into the association between PPFE and SARDS-ILD, a relationship that remains under active research. In our cohort, systemic sclerosis was the most frequently observed SARD among patients with PPFE. Bonifazi et al. reported a PPFE prevalence of 18% in a cohort of patients with systemic sclerosis; a study conducted by Kang et al. reported that in a cohort of 477 with rheumatoid arthritis-ILD, PPFE was identified in 6.5% of patients.⁷ Among patients in our cohort with both SARDS and PPFE, scleroderma was the most common SARD, identified in 7 of 15 patients. However, because the total number of patients with systemic sclerosis in our cohort was not defined, the true prevalence of PPFE among patients with scleroderma in our population cannot be determined.

Regarding the timing of diagnosis of SARD and PPFE, there was variability in their temporal relationship. The mean time from SARD diagnosis to PPFE diagnosis was 3.18 years (interquartile range: −0.2 to 8.1 years), with a wide range spanning from PPFE diagnosed up to 8 years before SARD diagnosis to PPFE occurring as late as 17.3 years after SARD diagnosis (Table 2). These findings highlight the heterogeneity in temporal presentation and underscore that PPFE may precede, occur concurrently with, or develop long after the diagnosis of SARDs.

The literature reports a high incidence of pneumothorax⁵ in patients with PPFE, in our cohort, no pneumothorax was seen in any of our patients.

The etiology of PPFE remains incompletely understood, and prior studies have suggested associations with chemotherapeutic agents, immunomodulatory medications, and stem cell transplantation. In our cohort, however, none of the patients was exposed to chemotherapeutic agents previously implicated in PPFE, including alkylating agents such as cyclophosphamide, or other reported agents such as daptomycin or dapsone. Additionally, none had undergone stem cell transplantation. While immunosuppressive therapies were commonly used for the management of the underlying systemic autoimmune rheumatic diseases, these reflected standard disease-directed treatments rather than exposures known to be associated with PPFE.

Our study also identified PPFE in patients with a broader range of SARDs, including dermatomyositis, systemic lupus erythematosus, and mixed connective tissue disease. Although the small, retrospective nature of this cohort precludes definitive conclusions regarding disease-specific associations, these observations suggest that PPFE may not be restricted to traditionally reported SARDs. The presence of PPFE across diverse autoimmune conditions raises the possibility of shared pathways of immune-mediated lung injury or fibrosis, a hypothesis that warrants exploration in larger, disease-based cohorts designed to distinguish true associations from incidental findings. Our study as well revealed a higher prevalence in women compared to men, however, SARDS tends to have a higher prevalence in women.

Radiological findings in our cohort were notable in that 26.7% of patients had a pattern of usual interstitial pneumonia (UIP), consistent with prior literature showing UIP coexists in approximately one-quarter of cases.⁵ NSIP was seen in 20% of our cohort.

The clinical course of PPFE in our cohort revealed that nearly half of the patients requiring supplemental oxygen, and two patients experiencing ILD exacerbations that led to hospitalization. As well, it is interesting to note that 4/6 patients who required oxygen, had PPFE and concomitant type of ILD, which could represent a more aggressive course.

Given the significant overlap between fibrotic ILDs, further exploration of PPFE characteristics in other groups, such as idiopathic pulmonary fibrosis (IPF), could help differentiate the phenotype and outcomes between PPFE in IPF versus PPFE in SARDS-ILD.

This study has limitations inherent to its retrospective design, which may impact the generalizability of our results. Case identification relied on a keyword-based electronic search followed by manual chart review, which may have resulted in missed cases due to variability in clinical documentation over the study period. Although diagnoses were confirmed through review by two physicians and supported by documentation from rheumatologists, radiologists, and pulmonologists, ascertainment bias cannot be fully excluded. Consequently, the cohort may not reflect the true prevalence of pleuroparenchymal fibroelastosis among patients with systemic autoimmune rheumatic diseases. However, it provides additional insight into the association between PPFE and SARD-associated ILD and expands the available data on cases demonstrating this relationship. Given the substantial morbidity and mortality associated with PPFE, early recognition and comprehensive multidisciplinary management are essential to improving patient outcomes. Further prospective studies are warranted to refine diagnostic criteria, identify prognostic markers, and explore therapeutic strategies.

Conclusion

In this retrospective cohort, PPFE was most frequently observed in association with systemic sclerosis but was also identified across a broader spectrum of SARDs, including dermatomyositis, systemic lupus erythematosus, and mixed connective tissue disease. Although the small, retrospective nature of this cohort precludes definitive conclusions regarding disease-specific associations, these observations suggest that PPFE may not be restricted to traditionally reported SARDs. The presence of PPFE across diverse autoimmune conditions raises the possibility of shared pathways of immune-mediated lung injury or fibrosis, a hypothesis that warrants exploration in larger, disease-based cohorts designed to distinguish true associations from incidental findings. Larger prospective investigations are needed to better define the epidemiology, clinical course, and optimal management of PPFE in SARD-associated ILD.

Supplemental Material

sj-docx-1-tar-10.1177_17534666261445202 – Supplemental material for Pleuroparenchymal fibroelastosis from a rheumatologic perspective

Supplemental material, sj-docx-1-tar-10.1177_17534666261445202 for Pleuroparenchymal fibroelastosis from a rheumatologic perspective by Maximiliano Diaz Menindez, Alejandro Diaz Arumir Vergara, Vivian Shing, Carolyn Mead Harvey, Ana C. Zamora Martinez and Vivek Nagaraja in Therapeutic Advances in Respiratory Disease

Footnotes

Acknowledgements

Not applicable.

Declarations

ORCID iD

Maximiliano Diaz Menindez

Supplemental material

Supplemental material for this article is available online.

AI use

Not applicable.

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