Rheumatoid Arthritis-Associated Interstitial Lung Disease: The Relevance of Histopathologic and Radiographic Pattern

doi:10.1378/chest.09-0444

Chest

Volume 136, Issue 5, November 2009, Pages 1397-1405

https://doi.org/10.1378/chest.09-0444 Get rights and content

Interstitial lung disease (ILD) is a frequent extraarticular manifestation of rheumatoid arthritis (RA). While the nonspecific interstitial pneumonia pattern predominates in most forms of connective tissue-associated ILD, studies in patients with RA-associated ILD (RA-ILD) suggest that the usual interstitial pneumonia (UIP) pattern is more common in this patient population. High-resolution CT (HRCT) scans appear accurate in identifying UIP pattern in many patients with RA-ILD. Although the data are limited, UIP pattern appears to predict worse survival in RA-ILD patients. Larger, prospective, multicenter studies are needed to confirm this finding. We propose that the evaluation of patients with RA-ILD should focus on identifying those with UIP pattern on HRCT scans, as these patients are likely to carry a worse prognosis. In patients in whom the underlying pattern cannot be determined by HRCT scanning, surgical lung biopsy should be considered.

Section snippets

RA-ILD: Epidemiology and Clinical Presentation

The reported prevalence of ILD in patients with RA is highly variable and depends on the methods of detection (eg, high-resolution CT [HRCT] scan, chest radiograph, or pulmonary function testing) and the population selected for study (eg, symptomatic or asymptomatic, autopsy series). Studies12, 13, 14, 15, 16, 17, 18, 19 have reported a prevalence as low as 4% and as high as 68%. The majority of cases of RA-ILD occur in patients between the ages of 50 and 60 years. While several studies13, 15,

RA-ILD: Histopathology

Although a broad range of histopathologic patterns has been associated with many of the CTD-ILDs, RA-ILD appears to be one of the most diverse (Fig 2). The predominant histopathologic pattern in patients with scleroderma is NSIP.¹⁰ Limited studies in patients with other forms of CTD-ILD (eg, polymyositis, Sjögren syndrome, and undifferentiated CTD) have also shown a predominance of NSIP pattern on surgical lung biopsy specimens.5, 23, 24, 25 In contrast, the currently available data show that,

RA-ILD: Radiographic-Histopathologic Correlation

The following four major radiographic patterns have been identified in patients with RA-ILD: a UIP-like pattern with bilateral subpleural reticulation with or without honeycombing; NSIP-like pattern with predominant ground-glass opacities; an inflammatory airway disease pattern with centrilobular branching lines with or without bronchial dilatation; and an organizing pneumonia-like pattern with patchy areas of consolidation.²⁷

There are data demonstrating excellent correlation between the

Pathophysiologic Implications

Few studies have assessed whether histopathologic pattern suggests a distinct pathophysiology in RA-ILD patients. Gochuico et al¹⁷ compared patients with RA who had HRCT scan findings consistent with NSIP pattern (n = 21) with those who had findings consistent with UIP pattern (n = 10). They showed that patients with RA and NSIP pattern on HRCT scans had higher concentrations of platelet-derived growth factors AB and BB, interferon-γ, and transforming growth factor β₂ in BAL fluid compared with

Comparing UIP in RA-ILD With IPF

There are limited data directly comparing patients with RA-ILD and UIP pattern with patients with IPF. The lung histopathology of UIP in patients with CTD has been shown⁴⁴ to have fewer fibroblast foci when compared with patients with IPF. In addition, the number of CD4+ lymphocytes appears to be increased in lung specimens from patients with RA-ILD and UIP pattern vs patients with IPF.³⁵ As a group, patients with RA-ILD are thought to have a better prognosis than those with IPF. In a

Diagnostic and Management Approach to RA-ILD

Based on the evidence available to date, UIP pattern in RA-ILD patients appears to be common, identifiable by HRCT scanning, and predictive of poor survival. With this in mind, we propose the following approach to patients with RA-ILD (Fig 4). Given the possibility of subclinical disease, the clinician should have a low threshold for evaluating patients with RA for ILD. Although we do not recommend the routine screening of patients with RA with HRCT scans and PFTs, a future study of the

Gaps in Our Knowledge

Some may continue to question whether the existing data are sufficient to make such recommendations. It can also be argued that if we are going to treat these patients with the same agents regardless of histopathologic and radiographic pattern, does prognostic information alone warrant the risk of surgical biopsy? These are legitimate questions that individual clinicians and patients must answer for themselves. We certainly agree that more information is needed, and this will come only from

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We thank Kirk Jones, MD, for providing the histopathologic images in Figure 1.

References (0)

Cited by (294)

Relationship between idiopathic interstitial pneumonias (IIPs) and connective tissue disease-related interstitial lung disease (CTD-ILD): A narrative review
2024, Respiratory Investigation
While idiopathic interstitial pneumonia (IIP) centering on idiopathic pulmonary fibrosis (IPF) is the most prevalent interstitial lung disease (ILD), especially in the older adult population, connective tissue disease (CTD)-related ILD is the second most prevalent ILD. The pathogenesis of IPF is primarily fibrosis, whereas that of other ILDs, particularly CTD-ILD, is mainly inflammation. Therefore, a precise diagnosis is crucial for selecting appropriate treatments, such as antifibrotic or immunosuppressive agents. In addition, some patients with IIP have CTD-related features, such as arthritis and skin eruption, but do not meet the criteria for any CTD, this is referred to as interstitial pneumonia with autoimmune features (IPAF). IPAF is closely associated with idiopathic nonspecific interstitial pneumonia (iNSIP) and cryptogenic organizing pneumonia (COP). Furthermore, patients with iNSIP or those with NSIP with OP overlap frequently develop polymyositis/dermatomyositis after the diagnosis of IIP. Acute exacerbation of ILD, the most common cause of death, occurs more frequently in patients with IPF than in those with other ILDs. Although acute exacerbation of CTD-ILD occurs at a low rate of incidence, patients with rheumatoid arthritis, microscopic polyangiitis, or systemic sclerosis experience more acute exacerbation of CTD-ILD than those with other CTD. In this review, the features of each IIP, focusing on CTD-related signatures, are summarized, and the pathogenesis and appropriate treatments to improve the prognoses of patients with various ILDs are discussed.
Genetics of autoimmune-associated interstitial lung diseases: A focus on rheumatoid arthritis
2024, Revista Colombiana de Reumatologia
Recent advances in deciphering the genetic architecture of RA-ILD support the hypothesis of RA-ILD as a complex disease with a heterogeneous phenotype encompassing at least the usual interstitial pneumonia (UIP) and non-UIP high-resolution CT patterns. The results of genetic studies support the hypothesis of a common genetic background between idiopathic pulmonary fibrosis (IPF) and RA-ILD, and more specifically RA-UIP, a subset of the disease associated with a poor prognosis. Overall, these findings suggest the existence of shared pathogenic pathways between IPF and RA-ILD providing new opportunities for future intervention in RA-ILD, particularly with drugs that have been shown to be active in IPF.
Los recientes avances en el desciframiento de la arquitectura genética de la artritis reumatoide asociada a enfermedad pulmonar intersticial (EPI-AR) apoyan la hipótesis de que la EPI-AR es una enfermedad compleja, con un fenotipo heterogéneo, que abarca al menos los patrones de neumonía intersticial habitual (NIU) y de TC de alta resolución no NIU. Los resultados de los estudios genéticos apoyan la hipótesis de un trasfondo genético común entre la fibrosis pulmonar idiopática (FPI) y la EPI-AR, y más concretamente la NIU-AR, un subconjunto de la enfermedad asociado a un mal pronóstico. En conjunto, estos hallazgos sugieren la existencia de vías patogénicas compartidas entre la FPI y la EPI-AR que proporcionan nuevas oportunidades para futuras intervenciones en la EPI-AR, particularmente con fármacos que han demostrado ser activos en la FPI.
An overview of screening, treatment, and next steps in research in rheumatoid arthritis interstitial lung disease
2024, Revista Colombiana de Reumatologia
Rheumatoid arthritis associated interstitial lung disease (RA-ILD) has significant clinical impact on patients due to increased morbidity and mortality. Understanding the progression of ILD in patients with RA from when asymptomatic to clinical progression and the clinical, genetic, and novel markers associated with disease progression is an important step in altering the natural history of ILD in patients with RA. We review the natural history and epidemiology of RA-ILD, with a focus on Latin-American epidemiology in RA-ILD. Additionally, we discuss unique features of RA-ILD compared to other forms of ILD, early disease detection, and current concepts in treatment.
La enfermedad pulmonar intersticial asociada a la artritis reumatoide (EPI-AR) representa un impacto clínico significativo para los pacientes debido al aumento de la morbilidad y la mortalidad. Comprender la progresión de la EPI en pacientes con AR de progresión asintomática a clínica y los marcadores clínicos, genéticos y novedosos asociados con la progresión de la enfermedad es un paso importante para alterar la historia natural de la EPI en pacientes con AR. Revisamos la historia natural y la epidemiología de la EPI-AR, con un enfoque en la epidemiología latinoamericana en la EPI-AR. Además, discutimos las características únicas de la EPI-AR en comparación con otras formas de EPI, la detección temprana de la enfermedad y los conceptos actuales en el tratamiento.
Effectiveness and tolerability of antifibrotics in rheumatoid arthritis-associated interstitial lung disease
2024, Seminars in Arthritis and Rheumatism
Our aim was to investigate the effectiveness and tolerability of antifibrotics in a real-world cohort of patients with rheumatoid arthritis-associated interstitial lung diseases (RA-ILD).
In this retrospective cohort study, we identified RA-ILD patients initiating antifibrotics at Mass General Brigham Integrated Health Care System, a large multi-hospital healthcare system in Boston, MA, USA. We used electronic query to identify all patients with at least 2 RA diagnosis codes and a prescription for either nintedanib or pirfenidone (2014–2023). All analyzed patients met 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for RA and had definite RA-ILD according to Bongartz criteria. Data regarding pulmonary function test (PFT) results, adverse events (AEs), tolerability, and clinical data were collected. A linear mixed model with random intercept was used to compare the within-patient trajectory of the percent predicted forced vital capacity (FVCpp) within 18-months before to 18-months after antifibrotic initiation among those with these PFT data. Lung transplant-free survival and drug retention was estimated in a Kaplan-Meier analysis and a Cox regression analysis was performed to identify independent baseline factors associated with lung transplant or mortality.
We analyzed 74 patients with RA-ILD that initiated antifibrotics (mean age 67.8 years, 53 % male); 40 patients initiated nintedanib and 34 initiated pirfenidone. Median follow-up was 89 weeks (min 4, max 387). There was a significant improvement in the estimated slope of FVCpp after antifibrotic initiation (−0.3 % per year after initiation compared to −6.2 % per year before antifibrotic initiation, p = 0.03). Nintedanib and pirfenidone had similar FVCpp trajectory. Twenty-six patients (35 %) died and 4 (5 %) had undergone lung transplantation during follow-up. Male sex and heavy smoking were each associated with the composite outcome of lung transplant or mortality. AEs were reported in 41 (55 %) patients, with gastrointestinal (GI) AEs being most common (n = 30). The initial antifibrotic was discontinued in 34 (46 %) patients mostly due to GI AEs (n = 19). The median drug retention time was 142 weeks (95 %CI 56, 262) with no difference between nintedanib and pirfenidone (p = 0.68).
In this first real-world study of antifibrotic use dedicated to RA-ILD, antifibrotic initiation was associated with a modestly improved trajectory of FVCpp. AEs were frequently reported, particularly GI, and discontinuation was common. However, lung transplant and mortality rates were still high, emphasizing the need for further therapeutic strategies in patients with severe RA-ILD. These real-world data complement previous trial data that investigated efficacy and safety.
Serum antibodies to peptidylarginine deiminase-4 in rheumatoid arthritis associated-interstitial lung disease are associated with decreased lung fibrosis and improved survival
2023, American Journal of the Medical Sciences
Interstitial lung disease (ILD) is a leading cause of mortality in rheumatoid arthritis (RA), particularly in those with the usual interstitial pneumonia subtype (RA-UIP). Serum antibodies to peptidylarginine deiminase type 4 (anti-PAD4), particularly a subset that cross-react with PAD3 (PAD3/4XR), have been associated with imaging evidence of ILD. We aimed to determine the specificity of anti-PAD4 antibodies in RA-ILD and to examine associations with markers of ILD severity.
48 RA-ILD and 31 idiopathic pulmonary fibrosis (IPF) patients were identified from the National Jewish Health Biobank. RA-ILD subtype was defined by imaging pattern on high-resolution chest computed tomography (CT), and serum was tested for anti-PAD4 and anti-PAD3/4XR antibodies. Antibody prevalence, measures of ILD severity (% predicted forced vital capacity, FVC; % predicted diffusion capacity carbon monoxide, DLCO; quantitative CT fibrosis) and mortality were compared between groups.
Anti-PAD4 antibodies were present in 9/48 (19%) subjects with RA-ILD and no subjects with IPF. Within RA-ILD, anti-PAD4 antibodies were found almost exclusively in RA-UIP (89%). Within RA-UIP subjects, % predicted FVC was higher in anti-PAD4+ subjects, and this finding was most strongly associated with anti-PAD3/4XR antibodies. In addition, quantitative CT fibrosis score was lower in anti-PAD4+ RA-UIP subjects, including those with mono-reactive anti-PAD4 antibodies and anti-PAD3/4XR antibodies. Anti-PAD4+ RA-UIP subjects also exhibited decreased mortality.
We demonstrate the presence of serum anti-PAD4 antibodies in a subset of patients with RA-UIP that were notably associated with better lung function, less fibrosis and decreased mortality.
Survival of adults with rheumatoid arthritis associated interstitial lung disease - A systematic review and meta-analysis
2023, Seminars in Arthritis and Rheumatism
Rheumatoid arthritis associated interstitial lung disease (RA-ILD) is associated with high levels of morbidity and mortality. The primary aim of this systematic review was to determine the duration of survival, from time of diagnosis of RA-ILD.
Medline (Ovid), Embase (OVID), CINAHL (EBSCO), PubMed, and the Cochrane Library were searched for studies that reported duration of survival from time of diagnosis of RA-ILD. Risk of bias of included studies was assessed based upon 4 domains of the Quality In Prognosis Studies tool. Results for median survival were presented by tabulation and discussed qualitatively. Meta-analysis of cumulative mortality at 1 year, >1y to ≤3 years, >3 years to ≤5 years, and >5 years to≤ 10 years was undertaken, for total RA-ILD population, and according to ILD pattern.
78 studies were included. Median survival for the total RA-ILD population ranged from 2 to 14 years. Pooled estimates for cumulative percentage mortality up to 1 year were 9.0% (95% CI 6.1, 12.5, I² 88.9%), >1 to ≤3 years 21.4% (17.3, 25.9, I² 85.7%), >3 to ≤ 5 years 30.2% (24.8, 35.9, I² 87.7%), and > 5 to ≤ 10 years 49.1% (40.6, 57.7 I² 85.0%). Heterogeneity was high. Only 15 studies were rated as low risk of bias in all 4 domains assessed.
This review summarises the high mortality of RA-ILD, however the strength of conclusions that can be made is limited by the heterogeneity of the available studies, due to methodological and clinical factors. Further studies are needed to better understand the natural history of this condition.

View all citing articles on Scopus

Funding/Support: This work was supported by National Institutes of Health, National Heart, Lung, and Blood Institute grant HL086516.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

View full text