Risk Factors of Interstitial Lung Diseases in Clinically Amyopathic Dermatomyositis
Clinically amyopathic dermatomyositis (CADM) is a distinct subtype of idiopathic inflammatory myopathies characterized by typical cutaneous manifestations of dermatomyositis but with little or no evidence of muscle involvement. CADM accounts for approximately 10% to 20% of all dermatomyositis cases and is associated with a high prevalence of interstitial lung disease (ILD), particularly rapidly progressive ILD (RP-ILD), which significantly contributes to morbidity and mortality. This study aimed to identify risk factors for different types of ILD in CADM, focusing on acute or subacute interstitial pneumonitis (A/SIP) and chronic interstitial pneumonitis (CIP).
Introduction
CADM is a unique form of dermatomyositis that presents with classic skin manifestations, such as Gottron papules and heliotrope rash, but lacks significant muscle weakness. Despite the absence of overt myositis, CADM is strongly associated with ILD, especially RP-ILD, which is a leading cause of poor prognosis in these patients. Early identification of risk factors for ILD in CADM is crucial for improving patient outcomes. This study explored the clinical and laboratory parameters, including myositis-specific and associated antibodies and tumor-associated antigens (TAAs), to identify predictive biomarkers for different types of ILD in CADM.
Methods
This retrospective study analyzed data from 108 inpatients diagnosed with CADM at Peking University People’s Hospital between March 2008 and July 2019. The diagnosis of CADM was based on the Sontheimer or Gerami criteria, which include typical dermatomyositis skin manifestations lasting at least six months, no clinical evidence of proximal muscle weakness, and possible subclinical myositis detected through laboratory, electrophysiologic, or radiologic evaluations. Patients with malignancy at the time of diagnosis were excluded to eliminate the influence of tumors on TAAs.
The presence of ILD was defined according to the 2013 American Thoracic Society and European Respiratory Society guidelines. Patients were considered to have ILD if they exhibited restrictive lung function impairments (total lung capacity and diffusing capacity of the lung for carbon monoxide <80% of predicted) and radiographic signs of ILD on high-resolution computed tomography (HRCT). ILD was further classified into three subgroups: acute interstitial pneumonitis (AIP), subacute interstitial pneumonitis (SIP), and chronic interstitial pneumonitis (CIP). AIP was defined as deterioration within one month, SIP as deterioration within three months but more than one month, and CIP as a slowly progressive presentation with gradual deterioration over more than three months.
Clinical and laboratory data, including TAAs (carcinoembryonic antigen [CEA], alpha-fetoprotein [AFP], cytokeratin-19 fragment [CYFRA21-1], and neuron-specific enolase [NSE]) and myositis autoantibodies (myositis-specific antibodies [MSAs] and myositis-associated antibodies [MAAs]), were analyzed. MSAs included anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, anti-Mi-2a, anti-Mi-2b, anti-signal recognition particle, anti-nuclear matrix protein 2, anti-melanoma differentiation-associated gene 5 (MDA5), anti-transcriptional intermediary factor 1g, and anti-SAE1. MAAs included anti-Ro-52, anti-polymyositis (PM)-Scl100, anti-PM-Scl75, and anti-Ku. Antibody levels were classified as negative (0/3+), weakly (1+/3+), moderately (2+/3+), or strongly (3+/3+) reactive.
Results
Among the 108 CADM patients, 87 (80.5%) had ILD, including 39 (36.1%) with A/SIP and 48 (44.4%) with CIP. Notably, 22 (20.4%) patients had asymptomatic ILD detected only through routine HRCT. The most common respiratory symptom was dyspnea (55.6%), and 15 (13.9%) patients were initially diagnosed with idiopathic ILD before developing typical CADM skin manifestations.
Tumor-Associated Antigens in CADM-ILD
Patients with ILD had significantly higher levels of CYFRA21-1 compared to those without ILD (2.01 [1.78, 2.73] vs. 4.18 [3.28, 7.02] vs. 3.49 [2.31, 5.49] ng/mL; P < 0.001). Additionally, patients with A/SIP had higher levels of CEA and NSE compared to those without ILD and those with CIP (CEA: 5.01 [1.58, 6.40] vs. 2.14 [1.48, 3.52] vs. 2.45 [1.67, 4.87] ng/mL; P = 0.035; NSE: 16.18 [13.82, 20.65] vs. 13.29 [10.85, 17.39] vs. 13.95 [10.97, 16.27] ng/mL; P = 0.011).
Myositis Autoantibodies in CADM-ILD
Anti-MDA5 was the most commonly detected MSA (29.9%), with the highest positive rate in patients with A/SIP (44.1%). Anti-Ro-52 was the most frequently detected MAA (52.4%), with a higher positive rate in patients with CIP (66.7%) compared to those without ILD (28.6%; P = 0.025). Anti-PL-12 was more common in patients with CIP (19.4%) than in those with A/SIP (0%; P = 0.011).
Risk Factors for ILD in CADM
Logistic regression analysis identified CYFRA21-1 as a significant risk factor for ILD in CADM (odds ratio [OR] = 17.838, 95% confidence interval [CI] [2.062–154.297], P = 0.009). Higher titers of anti-MDA5 were associated with an increased likelihood of A/SIP (OR = 5.697, 95% CI [1.242–26.130], P = 0.025), while higher titers of anti-Ro-52 were associated with CIP (OR = 0.308, 95% CI [0.091–0.922], P = 0.036).
Discussion
This study highlights the high prevalence of ILD in CADM patients, with a significant proportion presenting with asymptomatic ILD detected only through HRCT. The findings underscore the importance of routine lung imaging in CADM patients, even in the absence of respiratory symptoms.
Tumor-Associated Antigens as Biomarkers
Elevated levels of CYFRA21-1 were identified as a significant risk factor for ILD in CADM, suggesting its potential as a predictive biomarker. Similarly, higher levels of CEA and NSE were observed in patients with A/SIP, indicating their potential utility in identifying patients at risk for acute or subacute ILD. The exact mechanisms underlying the elevation of these TAAs in ILD remain unclear but may involve pneumocyte proliferation.
Myositis Autoantibodies and ILD Subtypes
Anti-MDA5 was strongly associated with A/SIP, consistent with previous studies linking this antibody to RP-ILD in CADM. However, not all anti-MDA5-positive patients developed ILD, suggesting that additional factors may influence disease progression. Anti-Ro-52 was more common in patients with CIP, highlighting its potential role in predicting chronic ILD. Anti-PL-12 was also associated with CIP, further emphasizing the importance of myositis autoantibodies in distinguishing between ILD subtypes.
Clinical Implications
The identification of risk factors for different types of ILD in CADM has important clinical implications. Routine measurement of TAAs and myositis autoantibodies may aid in the early detection and risk stratification of ILD in CADM patients. This could enable timely intervention and improve patient outcomes, particularly in cases of rapidly progressive ILD.
Limitations
This study has several limitations. Its retrospective, single-center design may introduce selection bias. Additionally, the use of immunoblotting for antibody detection may not reflect exact concentrations, and some MSAs and MAAs were not included in the analysis. Future multi-center studies and prospective cohorts are needed to validate these findings and explore the prognostic value of myositis antibodies in CADM-ILD.
Conclusion
This study provides valuable insights into the risk factors for ILD in CADM, highlighting the clinical significance of TAAs and myositis autoantibodies. CYFRA21-1 was identified as a predictor for ILD, while anti-MDA5 and anti-Ro-52 were associated with A/SIP and CIP, respectively. These findings underscore the importance of comprehensive biomarker profiling in the management of CADM-ILD and suggest potential avenues for future research.
doi.org/10.1097/CM9.0000000000000691
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