Autoimmune diseases are a group of at least 80 illnesses that share a common pathogenesis, which is an immune-mediated attack on the body’s organs
[40]. The immune system is developed to protect hosts from infectious agents; however, it can lead to disease either by an inability of one or more of its components to respond protectively to a pathogen or by the failure to distinguish self from non-self, which is the basis for autoimmune diseases
[41]. The etiology of autoimmune diseases is multifactorial, with genetic, environmental, hormonal, and immunological factors considered essential in their development. However, the onset of at least 50% of autoimmune disorders has been attributed to “unknown trigger factors”
[42]. Some autoimmune diseases that can have pulmonary manifestations include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS). RA and SLE are among the most researched due to their prevalence and the significant impact they can have on multiple organ systems. Both have been shown to have connections to small airways.
Rheumatoid arthritis (RA) is an autoimmune disease that has been recognized as a clinical entity for over two centuries
[42]. It is the most frequent inflammatory arthropathy
[43], characterized by chronic, systemic, and inflammatory manifestations that affect connective tissue
[44][45][46][47]. The autoimmune disorder affects approximately 1% of the population worldwide
[47][48]. Pulmonary involvement is one of the common causes of morbidity in patients with RA.
ILD is the most common and severe manifestation of RA lung diseases associated with parenchymal rheumatoid nodules
[49]. Bronchiectasis is also a common lung characteristic of RA with an estimated prevalence of 10 and 30%, depending on the population analyzed and the imaging methodology used for detection. However, RA directly affects all the compartments of the thorax, including the lung parenchyma, airways, pleura, and less common vessels
[50].
The FEF25, FEF50, FEF75, and FEF25-75 measurements in 99 patients with RA, in the case–control study of Zohal MA et al., revealed that the abnormal results of PFTs in rheumatoid disease were higher than usual
[51]. Respiratory system involvement occurs in 30–40% of RA patients, making it the second leading cause of death in patients with RA
[52]. Older studies have confirmed the existence of a subgroup of non-smoking patients with RA who have isolated small airway obstruction, as indicated by FEV1, FVC, FEV1/FVC, FEF25–75, and diffusing capacity for carbon dioxide (DLCO) measurements
[53], and imaging evidence of airway involvement
[54].
SLE and SS are two chronic autoimmune inflammatory disorders that impact the lungs and can lead to serious morbidity and mortality
[55]. While there is no cure for SLE, it can be managed effectively with medication. However, the mortality rate is still high, with renal disease, cardiovascular disease, and infection being the most common causes of death among patients
[56]. The exact cause or underlying pathophysiological mechanisms that trigger the autoimmune response in these diseases remain largely unknown, although researchers have suggested the role of gene susceptibility. It is believed that a combination of susceptibility genes, the absence of protective genes, and epigenetics may all contribute to the development of these conditions
[55][56][57]. Data from older studies indicate a very high prevalence of pulmonary function abnormalities in SLE patients
[58], obstructive airway disease, and the rapid deterioration of the respiratory function determined by low PFTs, i.e., FVC, DLCO, and FEV1/FVC ratio
[59], or by using, in addition to PFTs, chest X-rays, thoracic CT scans, ventilation–perfusion (VQ) scanning, and plethysmography with TLC measurement, while also identifying other pulmonary features such as pleural disease, pulmonary nodules, pulmonary cysts, and OP
[59][60].
SS is a connective tissue disease that affects the exocrine glands, leading to their dysfunction and eventual destruction. This disease frequently affects the small airways, as indicated by spirometry and chest HRCT imaging, and is associated with mild to severe respiratory symptoms
[61][62]. Lung involvement in SS is well characterized and is observed during the disease, although pleura involvement is more commonly seen in SLE patients. On the other hand, primary SS (pSS) typically involves the airways
[63][64][65]. ILD involvement and the coexistence of small airway lesions in pSS-interstitial lung disease has been revealed through several studies of pSS patients using spirometry and total lung capacity, as well as diffuse lung capacity that were impaired
[66][67]. In a cross-sectional study aimed at estimating the prevalence of chronic respiratory symptoms in pSS, 114 consecutive patients were investigated with PFTs and chest HRCT on inspiratory and expiratory phases. The study found that the most commonly recognized pulmonary disorder among symptomatic pSS patients (one-fifth of the study group) was SAD, followed by xerotrachea and interstitial lung disease
[68].
Sarcoidosis is a systemic inflammatory granulomatous disease of unknown etiology that affects 2 to 160 people per 100,000 worldwide and can involve any organ
[69]. It is considered an autoimmune disease, with growing research suggesting similar patterns of cellular immune dysregulation seen in other autoimmune diseases like RA. Recent large-scale population studies show that sarcoidosis frequently co-presents with other autoimmune diseases
[70]. However, the pathophysiology of the disease remains poorly understood, and known autoantibodies or useful serologic markers for the diagnosis and monitoring of autoimmune disease activity are lacking
[71]. Sarcoidosis is closely linked to environmental factors, especially occupational exposures such as silica, pesticides, and mold or mildew, which are associated with increased odds of pulmonary sarcoidosis
[72]. Its etiology remains undetermined, characterized by variable clinical presentations and disease course
[73].
Sarcoidosis is one of the few ILDs that can affect the entire length of the respiratory tract, from the nose to the terminal bronchioles, and it causes a broad spectrum of airway dysfunction
[73]. Peripheral airway obstruction may be caused by the formation of granulomas in a perilymphatic distribution along the bronchovascular bundles
[73][74]. Older studies suggest that functional abnormalities in small airways may occur early in sarcoidosis
[75]. Patients with pulmonary sarcoidosis who have obstructive airway disease may also have regional air trapping, which indicates SAD and can be visualized on expiratory HRCT and newer imaging modalities
[73][74].
5. Conclusions
In conclusion, SAD significantly contributes to lung function decline in various fibrotic respiratory conditions. Diagnosing SAD can be challenging, as no specific clinical findings exist. However, a combination of methods can be used to assess the quiet zone of the lungs. SAD worsens the prognosis, and several treatments focusing on SAD (such as bronchodilators, inhaled corticosteroids, and immunomodulatory therapies) can help to improve symptoms and slow the disease’s progression. It is important to note that the small airways are a complex and dynamic system with still not fully understood mechanisms. The heterogeneous nature of SAD in fibrotic diseases certainly does not make treating and diagnosing it any easier. Therefore, treatment and diagnosis must be tailored to the individual patient with a personalized and holistic approach, impacting disease progression. Environmental factors such as smoking can contribute to and exacerbate SAD. Patients with SAD can live a long and active life with the necessary changes in their lifestyle, like quitting smoking and exercising regularly. There is a need for more research regarding the impact of SAD in fibrotic respiratory diseases with advancements in imaging instruments and treatment plans, as well as longitudinal studies to observe disease progression and its impact on patients’ lives.