In this study we compared the clinical features and disease behaviors of ASSD-ILD patients with different ARS. ASSD was first defined by Marguerie(9) as a relatively homogeneous syndrome comprising inflammatory myopathy, pulmonary fibrosis, arthritis in 1990 in a retrospective cohort of 29 patients, with 19 anti-JO1 positive, 4 anti-PL7 positive, and 6 anti-PL12 positive. JO1 is the most frequent antibody in all the ASSD studies and represents the most common form(10). Studies showed that specific ARS had different ASSD phenotype, such as skin involvement (heliotrope rash) was more frequent in anti-PL7-positive patients(3, 11), however, few research was performed to understand the correlation between different ARS antibodies and the ILD pattern, which is a common manifestation of ASSD and a main cause of death.
35-45% of patients diagnosed with PM/DM will be afflicted with ILD during the course of myositis(1), some reported the ILD prevalence of 65% in PM/DM(12). ILD occurs after the diagnosis of PM/DM in up to 40% of patients, and precedes the diagnosis of PM/DM in 20–30% of cases(13, 14), causing morbidity and mortality. OP, NSIP, mixed NSIP-organizing pneumonia pattern are more frequent than UIP pattern in PM/DM-ILD(12). The ARS antibodies, one of the myositis specific antibodies (MSA), are positive in 30-45% of patients with a myopathic inflammatory disease (3, 15), PM/DM patients with positive ARS had higher prevalence of ILD than those without such antibodies. ARS can also be positive in ILD patients who don’t meet criteria of inflammatory myositis of any other CTDs, who were considered as idiopathic interstitial pneumonitis (IIP) with positive ARS antibodies, or could be classified as interstitial pneumonia with autoimmune features (IPAF) since 2015(16). ASSD is a term with more preference focusing on the ARS antibody, however, to date, there are no uniform diagnostic criteria of ASSD. In some cohorts the ASSD was defined with a presence of myositis(3), while Connor proposed his ASSD criteria in 2010, which is more pragmatic, defined by a positive ARS antibody plus one or more of myositis, ILD, arthritis, fever, Raynaud, Mechanic’s hands(1). In patients with ASSD, the classic clinical triad (myositis, ILD, arthritis) might have different time onset. In the large cohort of 828 ASSD patients (AENEAS collaborative group)(5), the onset mainly began with a single triad findings, and some cases presented as one/two triad findings in the clinical time course (5), just similar to our study.
ARS is a group of antibodies targeting at the ribonucleoproteins involved in protein synthesis, and eight anti-ARS Abs have been described: anti-histidyl (anti-JO1), anti-threonyl (anti-PL7), anti-alanyl (anti-PL12), antiglycyl (anti-EJ), anti-isoleucyl (anti-OJ), anti-asparaginyl (anti-KS), anti-phenylalanyl (anti-Zo), and anti-tyrosyl (anti-Ha) tRNAs, the former 5 of which are tested routinely in clinical practice.
Studies were applied to explore the significance of distinct ARS antibodies and results were different. JO1 is the most prevalent antibody in either ASSD (60-75%)(17, 18) or inflammatory myositis(found positive in 20-30% PM patients and in 5-10% DM patients)(2, 17). A cross-sectional and longitudinal analysis in 77 patients with inflammatory myositis associated ILD showed that the anti-JO1 positive patients(28) had worse lung function and CT scores over time compared to those without detectable ARS antibodies(19). While another retrospective study of 202 cases of ASSD showed that the 5- and 10-year unadjusted cumulative survival was 90% and 70% for anti-Jo1 positive patients respectively, which were significant better than that of non-JO1 patients (P<0.005)(18). However, in this cohort, the most common cause of death was pulmonary fibrosis (49%), which was similar between Jo-1 and non-JO1 patients (P=0.511)(18). In another cohort of 43 patients with ASSD associated ILD, 6 (14%) patients had died at 5 years, and the anti-JO1 positive ratio was significantly higher in the survivors (86 %) than that of the deceased patients (50 %) ,who had a significantly lower baseline FVC(20).
Anti-PL7/PL12 positive in ASSD patients were found to be associated with more aggressive ILD and decreased survival as compared with those with anti-JO1 antibody. An ASSD cohort included 75 JO1-positive cases, 15 PL7-positive cases, and 5 PL12-positive cases, and the anti-PL7/PL12 positive patients had more ILD compared with those with anti-Jo1 antibody (90% vs. 68%); anti-Jo1 antibody results in more severe myositis, joint impairment and increased risk of cancer(21). In a cohort of 7cases of anti-PL7 positive ASSD-ILD, lung biopsy revealed 50% cases of UIP(22).In another retrospective study of 20 cases of anti-JO1 positive ASSD-ILD, 35% of cases were with UIP pattern on lung biopsy(23). In a cohort of 12 anti-PL7 positive ASSD patients, the mean age at the first sign of clinical symptoms was 56.3 yrs, which was similar with our study, all presented with ILD, in which 9 were NSIP pattern, 2 were with OP pattern and 1 with obliterative bronchiolitis (BO) pattern(24). In another anti-PL7 positive ASSD cohort with 18 patients, all had myositis when first diagnosed, and 10 (55.6%) had ILD(25).
In an anti-PL12 positive ASSD cohort with 17 patients, the mean age when diagnosed was 60.3 yrs, all patients had ILD when diagnosed, 15 out of which were with NSIP pattern and 2 were with OP pattern, and 7 had mild myositis(26).
Another anti-PL12 positive ASSD cohort with 31 patients had a myositis prevalence of 52% (16/31),and ILD prevalence of 90%(28/31, 14 out of which were with a UIP pattern, 5 with NSIP pattern and 5 with OP pattern, confirmed histopathologically in 14 patients received surgical lung biopsy, or either evaluated by HRCT(27).
Studies with larger samples suggest different conclusions that ASSD with various ARS is relatively homogenous, however, the distribution and timing of myositis, ILD alone at onset, and rashes differ among patients. In a retrospective Japanese cohort of ASSD with 166 patients, the ILD alone at onset was 63% in OJ-positive group, 33% in PL12-positive group, 26% in EJ group, 14% in PL7 group, and 5% in JO1-positive group(11), and those with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset. In the AENEAS cohort with 828 ASSD patients, characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence, and the PL7-positive group and EJ-positive group had a higher ILD prevalence compared with JO-positive group(P=0.001, P=0.005, respectively), and EJ-positive group presented more with an acute onset (74%), which was defined as dyspnea progressing rapidly in 4 weeks from respiratory symptoms onset. Moreover, survival was not influenced by the distinct anti-ARS antibodies’ positivity, suggesting that ASSD is a heterogeneous condition and antibody specificity only partially correlates with the clinical course(5).
However, the pulmonary function of ASSD-ILD responding to therapy, one of the disease behaviors, had never been studied before. The change of FVC, one of the most important factors of the ILD clinical course, had been used to classify ILD into reversible or progressive type in classification and clinical trials(28, 29). All patients had an improvement on FVC in our study after therapy, which means even without a presence of myositis, the positive ARS antibody is a treatable trait of steroids or immunosuppressants for ILD. The myositis prevalence showed no differences among the 5 groups, which made the FVC comparable between groups, for the respiratory muscle weakness has impact on the spirometry values, leading to a complicated interpretation(1). No stand treatment has been proposed for ASSD, however, prednisone should be the mainstay, with or without immunosuppressants (30), which was proved again by our study.
Anti-Ro52, a myositis associated antibody, the positive frequency of which was reported as 65% in an anti-Jo1 positive ASSD cohort(31). In our cohort the anti-Ro52 positive rate was 87.9% in Jo-1 group, and 91.3% in EJ group, respectively, which were significantly higher than the other 3 groups. The EJ group and the Jo1 group had the highest frequency of OP pattern, indicating the occurrence of OP might be correlated with the anti-Ro52 positivity.
Our study had some limitations. It was single center and retrospective, the sample was relatively small and the follow up time was not long enough. In another ASSD cohort the RP-ILD was statistically more prevalent in patients with positive anti-PL7 antibody than those without anti-PL7(3). The RP-ILD cases were not included in this study because the spirometry could not be performed when diagnosed due to the patients’ weakness, and in our study the excluded 7 case of RP-ILD included 5 with EJ positive and 2 PL-7 positive. Shi’s cohort, using a Solomon’s criteria of ASSD, showed that a coincidence of anti-Ro52 antibody predicted RP-ILD(3). RP-ILD is more life threatening and needs more study in the future.