JDM is a rare idiopathic inflammatory myopathy. Studies showed that more than 2 third of patients developed a chronic course and 4.1% of patients died, 5,6which seriously affected the children's health. MSA is potentially useful biomarker for it is associated with different clinical phenotypes.7, 8 In children with JDM, anti-MDA5, anti-TIF-1γ and anti-NXP2 are the most common MSAs.9–13 The reports from UK and Argentina showed anti-NXP2 antibody were detected in 23% and 25% respectively of patients with JDM.14, 15 In our study, anti-NXP2 seemed to be the most common antibody (30.6%). The ratio of anti-NXP2 antibody in JDM was higher than that in western countries, 4, 15, 16 which may be because the severe patients from all over the country concentrated to our department. The present study reported the characteristics and high risk factors of poor response to the treatment and death of anti-NXP2 antibody-related JDM in Chinese.
Twenty-six patients with anti-NXP2 antibody out of 85 JDM patients were involved. The female to male ratio was 17:9, which was different from reports of adult DM patients that anti-NXP2-antibodies were predominantly found in men. 18,19 The median age at onset is 4.5 years, which was younger than the average age of whole JDM cases.20
As to the onset symptoms, muscle weakness and skin rash were the most common clinical manifestations of the JDM patients in this cohort (92.4%). The skin lesions in this study included rashes (96.2%), skin ulcer (38.5%), edema (19.2%) and calcification (11.5%). Calcification was reported to be highly associated with the anti-NXP2 antibodies (33), 21while only 11.5% of patients showed calcification in our cohort, that might be related to active treatment due to the severe weakness. 22 In the cohort, 96.2% of patients manifested muscle weakness during the course of disease. Serious weakness (strength < = grade 3) was found in 69.2% of patients. In the 15 patients with a CMAS < 10, 9 cases were found CMAS < = 2 and all manifested symptoms of central muscle group including dysphagia/hoarseness/lower voice and bucking. MRI showed muscle involvement in all 26 patients including those without muscle weakness. There was a girl, whose MRI revealed significant abnormalities but she had not muscle weakness at all, suggesting the importance of MRI in evaluating muscle involvement. Electromyography (EMG) showed myogenic damage in 69.2% of cases, suggesting it was not as sensitive as MRI.
The level of serum muscle enzymes plays an important role in the diagnosis of JDM. At the onset of the disease, 9.1% cases were normal, 54.5% of cases varied from 1 to 10 times the normal levels and 36.4% of cases were higher than 10 times the normal levels. It was interesting that the CK level were almost normal in some patients who died of severe JDM; While in some cases who were sensitive to therapy or with mild symptoms, CK was significantly increased (> 10000U/L). The phenomenon suggested that the level of CK was not associated with disease severity. As shown in previous studies, 9 50% of cases in the study were found with mildly elevated level of ALT, but whether it was liver dysfunction or not remains to be validated.
A study of Caucasus reported that none of those cases with anti-NXP2 antibody JDM had any lung involvement.2, 3 However, in the study, HRCT revealed 26.9% of patients had mild ILD, while the corresponding pulmonary manifestations such as dyspnea and cough were not obvious. ILD quickly disappeared after treatment, which was not same as anti-MDA5 antibody-related JDM.
As to treatment of JDM, the first-line treatment is GC combining immunosuppressant. If the response to the treatment is not ideal, another immunosuppressant or biological agents will be added. In the study, all cases were initially treated with GC and immunosuppressive agents except one girl. During the follow up, 6 patients’ CMAS were significantly increased. Nine severe cases including those with gastrointestinal involvement received biological agents treatment, such as rituximab and infliximab. JAKi was used in 7 cases because of no response to conventional therapy. All 7 cases showed good response on JAKi. A severe case, with skin ulcer, edema, muscle weakness and gastrointestinal involvement, received salvage treatment with ASCT. After ASCT, her situation was significantly improved; two years later, she went to kindergarten and no longer needed any medicine. Therefore, ASCT might be an ideal/alternative therapeutic regimen for those refractory and severe cases.
According to response to treatment, we divided the cases into refractory and non-refractory, death group and survival group. Eleven cases were belong to refractory group and 15 cases were belong to no-refractory group. Statistical analysis showed muscle force, edema, skin ulcer, Dysphagia/Hoarseness/Lower voice, CD4/CD8 ratio and SF were significantly different between the two groups. In these factors, the CD4/CD8 ratio (< 1.4) related to refractory cases was firstly reported by the study. Serum SF has been considered to be an indicator for monitoring JDM activity and prognosis prediction. In the study, SF༞200 ng/ml was found in 46.2% of patients with lower CMAS, and was a predictive factor of refractory JDM.
Of the 26 cases, 5 died of gastrointestinal perforation, which accounted for the vast majority of 6 deaths (6/85), suggesting that anti-NXP2 antibody accounted for almost all causes of death in Chinese children with JDM. Among the death group, the ratio of female to male was 4:1 which implied that female cases are more prone to poor prognosis. Statistical analysis showed significant differences of BMI, edema, skin ulcer, Dysphagia/Hoarseness/Lower voice, ANA (+) were found between death group and survival group as well as in groups with and without gastrointestinal involvement.
Among the 5 deaths, very low BMI (< 13) could be seen in 4 children. Univariate logistic regression analysis found BMI < 15 (P = 0.012) was highly correlated with death. The very low BMI was found before they had abdominal pain, so we speculated that the lower BMI might be a result of chronic gastrointestinal vasculitis activity before perforation. Five patients who died of gastrointestinal perforation were found to be with ANA (+) though the dilution was not very high, suggesting positive ANA might be related with gastrointestinal involvement and mortality.