Rheumatoid Arthritis and the Lungs	13

Joshua J. Solomon, Kevin Brown,

and Mary Kristen Demoruelle

Introduction

Rheumatoid arthritis (RA) is the most common of the connective tissue diseases, with a global prevalence of 0.24– 0.5% (more than 18 million people) [1, 2]. It is among the top 50 contributors to global disability [1] and leads to high healthcare related costs [3]. It has long been known that RA is not a disease isolated to the joints. Extra-thoracic manifestations (ExRA) are well described, reported in nearly every organ system, and lead to signi cant morbidity and mortality [4]. All compartments of the respiratory system can be involved (Table 13.1), with the interstitium, pleura, and airway most commonly affected. In addition to the direct pulmonary involvement, the lungs are at risk for secondary pulmonary complications such as drug-induced lung disease and opportunistic infections. Lung involvement of any kind is seen in 60–80% [5–7], though a signi cant number of these cases are either subclinical (no associated symptoms) or not clinically signi cant (not contributing to death or disability). Though the lung disease often follows the development of the articular disease, lung involvement may be rst manifestation of RA in a subset of patients. In this chapter we will discuss the major lung manifestations of RA, namely interstitial lung disease, airways disease, and pleural disease.

J. J. Solomon

Autoimmune Lung Center and Interstitial Lung Disease Program, National Jewish Health, Denver, CO, USA

e-mail: [e-mail]

K. Brown (*)

National Jewish Health, Denver, CO, USA e-mail: [e-mail]

M. K. Demoruelle

Rheumatology, University of Colorado, Denver, CO, USA e-mail: [e-mail]

Table 13.1  Pulmonary involvement in RA

Pleura

Pleural effusions

Pleural brosis

Airway

Cricoarytenoid arthritis

Bronchiectasis

Follicular bronchiolitis

Bronchiolitis obliterans

Diffuse panbronchiolitis

  Chronic obstructive pulmonary disease

Mild airway infammation

Interstitium

Usual interstitial pneumonia

Nonspeci c interstitial pneumonia

Organizing pneumonia

Lymphocytic interstitial pneumonia

Diffuse alveolar damage

Acute eosinophilic pneumonia

Apical brobullous disease

Amyloid

Rheumatoid nodules

Vasculature

Pulmonary hypertension

Vasculitis

  Diffuse alveolar hemorrhage with capillaritis

Secondary pulmonary complications

Opportunistic infections

Pulmonary tuberculosis

Atypical mycobacterial infections

Nocardiosis

Aspergillosis

Pneumocystis jiroveci pneumonia

Cytomegalovirus pneumonitis

Drug toxicity

Methotrexate

Gold

d-penicillamine

Sulfasalazine

Lefunomide

Biologic therapy

© Springer Nature Switzerland AG 2023	207
V. Cottin et al. (eds.), Orphan Lung Diseases, https://doi.org/10.1007/978-3-031-12950-6_13

208	J. J. Solomon et al.

Rheumatoid Arthritis-Associated Interstitial

Lung Disease

Epidemiology

Interstitial lung disease (ILD), de ned as varying degrees of infammation or brosis in the interstitial compartment of the lung, is common in RA with a prevalence that varies with the population studied and the mode of detection (Table 13.2). Accurate prevalence estimates are further hindered by a lack of established diagnostic criteria, the absence of standard approaches to screening, and variations in the populations studied (i.e. age, presence of symptoms, modality of diagnosis). Studies that rely on health care databases are additionally subject to diagnostic coding and classi cation bias. When studying unselected RA patients, the prevalence ranges from 19% to 67% [6, 8–13]. Prevalence estimates for the general population range from 3.2 to 6.0 RA-ILD cases per 100,000 persons (with incidence rates from 2.7 to 3.8 per 100,000 persons) [14]. Studies of the US RA population have yielded cumulative incidence estimates of clinically signi cant RA-ILD in 5% of patients at 10 years [15], 6.3% at 15 years [16], and 6.8% over 30 years [17] of follow-up with an estimated lifetime risk of developing clinically signi cant ILD of 7.7% [18]. A large study of over 40 million US death certi cates identi ed 160,000 records of decedents

Table 13.2  Prevalence and cumulative incidence of interstitial lung disease in rheumatoid arthritis

Cumulative incidence of RA-ILD	5% at 10 years
	[15]
	6.3% at
	15 years [16]
	6.8% at
	30 years [17]
Lifetime risk of RA-ILD	7.7% [18]
Clinically signi cant RA-ILD (de ned as	6.8% in women
contributing to death)	[19]
	9.8% in men
	[19]
Prevalence of RA-ILD in ethnic subgroups	3% in Koreans
	[21]
	4.2% in Italians
	[22]
	3.7% in
	Spaniards [23]
	4.8% in Turks
	[24]
Prevalence of RA-ILD in “high risk” patients	91% [26]
(symptoms or abnormalities on PFTs or CXR)
Prevalence of RA-ILD in unselected patients	19–67% [6,
	8–13]
Prevalence of RA-ILD using a multi-modality	58% [9]
approach

RA-ILD rheumatoid arthritis-associated interstitial lung disease, PFTs pulmonary function testing, CXR chest X-ray

with RA; investigators found clinically signi cant ILD (de ned as a contributor to death) in 6.8% of women and 9.8% of men [19]. Prevalence rates of RA-ILD have been reported for certain ethnic groups: 3.7% in a cohort of Hispanic and Asians [20], 3% in Koreans [21], 4.2% in Italians [22], 3.7% in Spaniards [23], and 4.8% in Turks [24]. Though the incidence of disease appears stable [14, 15], both the prevalence and the death from ILD among decedents with RA are on the rise [14, 15, 19, 25].

Healthcare costs among this patient population are signi cant. The total excess societal costs attributable to RA are estimated to be US $39.2 billion [3]. RA-ILD patients have an incurred annual healthcare cost of $30,000–$50,000 and a mean total 5-year healthcare cost of US $173,405 per patient [14].

Risk Factors for ILD (Table 13.3)

The presence of RA is a strong risk factor for the development of clinically signi cant ILD with an odds ratio of 8.96 [18]. In established RA, a number of risk factors for the development of ILD have been identi ed, though few have strong supporting data. Smoking, a documented risk factor for the development of RA in general [27], increases the risk of RA-ILD [28–30] and has been reported to do so in a ­dose-­dependent manner [10]. Although RA is more common in women [31], male sex seems to be a risk factor for RA-ILD [9, 10, 12, 18, 32]. Age increases the risk [6, 16, 18], with a hazard ratio of 1.41 for every 10-year increase in age [16]. Higher RA disease activity, as measured by the Health Assessment Questionnaire [16], Disease Activity Score 28 [33], erythrocyte sedimentation rate [6, 16, 18], rheumatoid factor (RF) [6], erosions/ destructive joint changes and rheumatoid nodules [18] have also been associated with the development of RA-ILD. Higher scores on the HAQ have also been associated with disease progression as measured by longitudinal declines in the forced vital capacity (FVC) and diffusing

Table 13.3  Possible risk factors for rheumatoid arthritis-associated interstitial lung disease

Stronger Evidence

Smoking

Male sex

Advanced age

  Rheumatoid arthritis disease activity

Weaker Evidence

Methotrexate

Anti-TNF agents

Anti-cyclic citrullinated antibodies

Genetics

TNF tumor necrosis factor

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