Beyond skin and muscle: The unexplored territory of interstitial lung disease in anti‐NXP2‐positive myositis

Anti-nuclear matrix protein 2 (anti-NXP2) -positive myositis is a unique phenotype characterized by severe muscle weakness, subcutaneous calcification, and cancer association.1, 2 Clinical and prognostic heterogeneity in patients with anti-NXP2 antibodies and other forms of myositis are significant (Table 1).3-5 Recently, new aspects regarding the pathogenesis, clinical features, prognostic factors, and treatment strategies of the disease were investigated,2, 6, 7 but there is an urgent need for evidence-based research on the prevalence, risk factors, clinical features, treatment, and prognosis of pulmonary involvement in anti-NXP2 antibody-positive myositis. Interstitial lung disease (ILD) is considered the most common type of lung damage contributing to the poor prognosis of myositis patients.8 In terms of prevalence, ILD in anti-NXP2 antibody-positive patients in different studies varies from 1.27% to 30%.3, 9-11 The incidence of ILD in myositis patients with anti-NXP2 antibodies varied significantly between the study and ethnic groups. In contrast to polymyositis and dermatomyositis, imaging and pathological variants of ILD in anti-NXP2 antibody-positive myositis are rarely reported. This may be related to differences in sample size, race, various methods of patient selection, and diagnostic techniques. Bermudez et al.12 reported the characteristics of lung disease in seven adult patients with confirmed myopathies and positive anti-NXP2 antibodies, most notably that the subclinical lung involvement was not rare in patients with various radiological abnormalities and altered diffusing capacity. Ichimura et al.13 validated the results of Loarce-Martos et al.9 and showed that ILD was less frequently present in juvenile dermatomyositis patients with positive anti-NXP2 antibodies than in adult patients. Additionally, a recent study enrolled 70 adult patients with myopathies with anti-NXP2 antibodies and found that 21 of the 70 patients (30%) had ILD. The main pattern of ILD was nonspecific interstitial pneumonia. Risk factors of ILD and worse prognoses were accompanied by lower levels of lymphocytes and higher levels of serum ferritin.3 Studies indicated that a comprehensive lung assessment should be carried out for anti-NXP2 antibody-positive adult patients with higher age at disease onset, especially when accompanied by lower levels of lymphocytes and higher levels of serum ferritin. Although current research suggests that lung involvement in patients with myositis who have anti-NXP2 antibodies appears common with nonspecific interstitial pneumonia and favorable prognosis, results vary with the type of ILD among studies. Despite lung computed tomography scans being performed in ILD patients, subclinical and early mild ILD are easily missed. The comprehensive lung assessment including respiratory manifestations, imaging features, and exact ILD type requiring imaging or pathological analysis should be performed for anti-NXP2 antibody-positive patients with increased ILD risk factors. Although several other biomarkers, such as interleukin-18,14 Krebs von den Lungen-6,15 and adrenomedullin,16 have been used as predictors of ILD risk in myositis, the exact risk factors of ILD in anti-NXP2 antibody-positive myositis remains unclear. Interstitial lung disease exhibits significant heterogeneity in myositis. The pathological type and lesion range influence the therapy response and prognosis.17 One study reported that 21 ILD patients had a positive anti-NXP2 myositis, whereas no patients had rapidly progressive ILD.3 According to the current findings, ILD patients with myositis who also had anti-NXP2 antibodies frequently had non-serious symptoms and no signs of rapid progression, as well as a potential for a good outcome. Tofacitinib and rituximab are now thought by some researchers to be useful in the treatment of rapidly progressive ILD.18 Refractory anti-NXP2 + dermatomyositis can also be treated with these medications.19 However, only case reports and retrospective studies with limited sample sizes have examined the therapeutic response of patients with ILD caused by myositis that is anti-NXP2-positive. For example, Gossez et al.20 described a case of organizing pneumonia associated with a positive anti-NXP2 dermatomyositis, who presented a complete recovery of lung impairment on glucocorticoids and immunosuppressant therapy. Therefore, potential drugs such as antifibrotics, Janus kinase inhibitors, and biological agents according to ILD severity, progression, and phenotype need to be further explored for treatment. The article highlights the importance to the rheumatologist of the knowledge of ILD prevalence, subtype, risk factors, stratified therapy, and prognoses in anti-NXP2 antibody-positive myositis. Previous studies have focused on high-risk mortality and poor prognoses such as skin and muscle involvement, subcutaneous calcification, and cancer-associated with anti-NXP2-positive myositis. ILD status has not been investigated although the incidence is not rare. Subclinical and mild ILD are easily missed diagnoses in myositis patients, resulting in delaying treatment and poor prognoses. Early and comprehensive assessment of lung damage in anti-NXP2-positive myositis, as well as early diagnosis and treatment, are crucial to improve prognosis. Future research should include the impact of age and ethnicity, the role of overlapping autoantibodies, pathogenesis, predictive factors, cancer association, and novel therapeutic targets on ILD in anti-NXP2-positive myositis. YL: article writing. WH: citation management. YG: technical support. PCS and GBC: paper revision. The authors thank James Cheng-Chung Wei for helping. None. The data that support the findings of this study are openly available in [repository name] at [URL], reference number [reference number].