1. Introduction
Idiopathic inflammatory myopathies (IIMs) are a spectrum of systemic autoimmune disorders. Subtypes of IIMs include dermatomyositis (DM), polymyositis (PM), anti-synthetase syndrome (AS), inclusion body myositis, immune-mediated necrotizing myositis, and amyopathic dermatomyositis (ADM) [
1]. The annual prevalence of IIM is estimated to range from 2.4 to 33.8 per 100,000 population and its incidence is reported to be 1.16–19 per million/year [
2]. IIM is characterized by inflammation of the proximal muscles, elevated muscle enzyme levels, and weakness. Skin rash, interstitial lung disease (ILD), joint pains, vasculitis, dysphagia, and conduction abnormalities in the heart are some of the reported extra-muscular manifestations of IIM [
3]. The mortality rate in IIM has been reported in different populations and may be as high as 26% [
4,
5]. Several factors including malignancy and cardiac and pulmonary complications have been key drivers of increased mortality rates in IIM [
6].
ILD is a commonly recognized complication of myositis. It was first described in 1956 [
7]. The estimated prevalence of IIM-associated ILD is variable and ranges between 5 and 78% [
8,
9,
10,
11] depending on the population studied and method of ascertainment. Clinical features range from asymptomatic to severe fulminant respiratory failure, similar to acute respiratory distress syndrome [
12]. ILD in myositis has been reported to be the primary cause of death and hospitalizations due to respiratory failure [
13]. Furthermore, lung disease may be an isolated manifestation of underlying IIM with subtle or late-onset extrapulmonary symptoms, resulting in delayed and/or misdiagnosis and inadequate treatment [
14,
15]. In patients with IIM, those with ILD have worse prognosis and significantly higher mortality in contrast to those without ILD [
13,
16,
17].
Several studies have been conducted in different regions of the world looking at the clinical characteristics of patients with IIM, revealing contrasting results for IIM in general and IIM associated with ILD [
18,
19,
20,
21,
22]. The differences in the prevalence, clinical characteristics, and outcomes in earlier studies underscore the complexity of this entity due to the variability of geographic, socioeconomic, and ethnic factors in these patients. The rural Appalachian region, due to unique environmental and socioeconomic factors and health care disparities, has an increased burden of pulmonary diseases [
23]. Thus, it is foreseeable that the clinical characteristics and outcomes of IIM-ILD in this region may differ. To address the dearth of data in this population, we sought to determine the clinic–radiological characteristics, treatment response, and outcomes of the IIM-ILD rural Appalachian cohort. The identification of these features will add granularity of the distinctive features of patients with IIM-ILD in this cohort. In particular, we sought to determine specific extrapulmonary features that may lead to poor prognostic extrapulmonary features in patients with IIM-ILD. We aim to determine unique patterns of the presentation and course of patients with IIM-ILD.
4. Discussion
This study describes the clinical characteries, outcomes, and risk factors of poor prognosis in IIM-ILD patients in the rural Appalachian region of West Virginia. To our knowledge, this is the first study focusing on the rural population. Key findings of our study include female predominance and the relative infrequency of extrapulmonary symptoms: fatigue (17.24%), joint pain (17.24%), muscle weakness (10.34%), Raynaud’s phenomenon (10.34%), diffuse rash (6.89%) and heliotrope rash (3.44%). DM was the most common phenotype (51.72%), and anti-Jo1 was the most frequent autoantibody (55%) seen in this cohort. A predominant CT pattern was indeterminate for the UIP pattern (41.30%), and the worsening of PFTs was seen in 55.55% of patients in the study. ILD exacerbation and mortality were 60% and 20.69%, respectively, with significantly lower albumin levels observed in patients who died during the study period.
A higher proportion of female patients was seen in this study compared to European studies [
31] but similar to the studies conducted in urban settings of the United States (US) [
32]. Despite having one of the highest smoking rates in the region [
33], smoking rates were relatively lower in our cohort. We found lower rates of extrapulmonary symptoms at the time of presentation in contrast to a study from urban regions of Japan which reported a relatively higher (45.6%) proportion of the patients presenting with arthralgia [
34]. Similarly, another study showed that joint and muscular symptoms were present in 50% and 42% of the patients, respectively [
35]. Patients with the anti-Jo1 antibody have been reported to have a higher proportion of musculoskeletal symptoms in multiple studies, as highlighted by Hallowell et al. [
12]. Our study showed a low prevalence of musculoskeletal symptoms despite having a high proportion of patients with the anti-Jo1 antibody. Similar to our study, Raynaud’s phenomenon has been reported to be a less frequent symptom in patients affected with ILD in IIM [
34,
35]. A lower rate of extrapulmonary symptoms in our cohort may have contributed to a delayed presentation with a higher duration of symptoms at the first encounter. ILD was likely the presenting manifestation of an underlying immune disorder.
Both the IIM phenotype and associated autoantibodies have been reported as prognostic factors in IIM- ILD [
36,
37]. The most common IIM phenotype associated with ILD in our cohort was DM followed by PM. This finding is in keeping with an older study [
38]. However, more recent studies report AS as one of the most common phenotypes in patients with IIM-ILD [
22,
39]. In contrast to our rural population, a study on a urban population in the U.S. reported polymyositis to be the most common phenotype [
32]. Interestingly, the same studies [
22,
32,
39] reported the anti-Jo1 antibody as the most common antibody in IIM-ILD, similar to our cohort. As the anti-Jo-1 antibody has been associated with the presence of ILD in IIM [
40], it is expected to see high prevalence of its positivity in cohorts of patients exclusively with ILD [
31]. A small cohort study of patients with ILD in IIM in Japan showed 71.42% patients to have the anti-Jo1 antibody [
35].
Various radiological findings and patterns have been reported in IIM-ILD. The most common radiologic pattern found in our cohort was the indeterminate UIP. This contrasts the findings from prior studies which reported NSIP to be the most common pattern [
17,
22,
31,
41]. Similar to previous reports [
42,
43], ground glass opacities (GGOs) were the most common, while honeycombing and traction bronchiectasis were the least common CT findings in this cohort. Regardless of the overall CT pattern, isolated findings of GGOs have been associated with poor short-term outcomes in patients with myositis [
44].
A majority of patients were started on the immunosuppression treatment in this study. Oral corticosteroids were the most commonly utilized modality of the treatment in addition to various other steroid-sparing immunosuppressive agents. No prospective trials have compared the efficacy of the various immunosuppressant agents for the treatment of ILD, and there are some data suggesting that most agents are interchangeable [
12]. Despite immunosuppression, a significant proportion (55.55%) of patients in this study had worsening pulmonary function. In addition, only 10.34% noted improvement in their symptoms, 6.90% in their mMRC dyspnea scale, 3.45% in supplemental oxygen requirement and 6.90% in imaging. The low treatment response in our cohort is likely due to the high number of patients with the dermatomyositis phenotype. Previous studies have suggested that patients with dermatomyositis have a less favorable response rate to immunosuppression [
11,
32,
45]. Antifibrotics were used in only two patients who met the criteria for fibrosis and had a progressive disease. While there are no studies available to specifically look at the efficacy of antifibrotics in IIM-associated ILD, they were shown to significantly lower the rate of pulmonary function decline in patients with progressive fibrosing ILD in the INBUILD trial which enrolled 170 patients with auto-immune disease-related ILD [
46].
The ILD exacerbation rate was 66.66% in this cohort which is significantly higher than that which was previously reported in a large case-control study [
47]. It is unclear why there was such a high rate of ILD exacerbation in our study, but the reason may stem from the lack of definitive criteria for ILD exacerbation in IIM, the confounding presentation with other diseases such heart failure, differences in physician practices, and the lack of referral to tertiary care centers with ILD experts. Liang et al. [
47] reported that patients who were admitted with ILD exacerbation tend to have higher CRP levels, lower DLCO% on PFT, and higher prevalence of the ADM phenotype. Similar to their study, peak CRP levels were also higher in patients with ILD exacerbation in our cohort. On the contrary, the rate of ILD exacerbation did not differ by PFT findings. Interestingly, we found lower exacerbation rates in patients with the PM phenotype.
The mortality rate in our cohort of patients with ILD in IIM was 20.69% which was higher than what was observed in a study conducted at a large urban tertiary care center in the U.S. [
13]. Similarly, it was also higher than that from other similar- and larger-sized cohort studies from Europe [
22,
48]. A study on the Chinese population reported hypoalbuminemia and cardiac dysfunction as poor prognostic factors [
37]. In this study, hypoalbuminemia was very prevalent (89.29%). While the prevalence of hypoalbuminemia was not statistically different between patients who survived and those who did not, albumin levels were significantly lower in the patients who died during the study period. Albumin level is a well-established marker of nutritional status [
49]. Poor nutritional status of this cohort may have contributed to the observed increased mortality. Cardiac disease was not prevalent in our cohort; therefore, it is difficult to conclude the significance of cardiac involvement with regard to poor outcomes.
Multiple poor prognostic factors such as older age, amyopathic phenotype, anti-MDA5 antibody, and lower CK levels have been reported previously [
11,
31,
38,
50]. This study did not find any significant association of mortality with the myositis phenotype, which is similar to the study by Johnson et al. [
13]. Only one patient in the study had the amyopathic subtype; therefore, an association with mortality could not be established. This study also did not show any association of mortality with age, the duration and severity of symptoms at presentation, and the antibody type. Overall, this study is limited by its small sample size which may explain the lack of statistical significance.
The characteristics and outcomes of patients with IIM-associated ILD in the rural Appalachian region are dissimilar from previously published cohort studies of general and urban populations, posing significant diagnostic, management, and treatment challenges. Given the low prevalence of extrapulmonary symptoms, it is important to note that ILD can be the first manifestation of the disease. A good understanding of clinical, immunological, and radiologic features of IIM-ILD are crucial to improve outcomes. Given the complexity involved in the diagnosis of IIM-associated ILD and its exacerbation, early referral to tertiary care ILD centers with multidisciplinary team support can provide an early diagnosis and appropriate treatment for these patients. A suboptimal response to immunosuppression was observed in this cohort similar to other studies which signifies the need for larger studies to evaluate the role of immunosuppression and antifibrotics in IIM-ILD. Lastly, poor nutritional status in our cohort, as denoted by albumin levels, was associated with increased mortality in our cohort. Early referral to a dietary specialist for nutritional care for these patients may be key to improving outcomes.
Limitations: this study is limited in its generalizability and ability to generate statistically significant results due to the small sample size. However, the rarity of IIM-ILD and the shifting diagnostic criteria for IIM likely limited recruitment. The retrospective nature of the study may potentially lead to selection bias. Larger prospective studies are needed to determine prognostic markers that may alter the course and outcomes of patients with IIM-ILD.