In this study we compared the clinical features and disease behaviors of ASSD-ILD patients with different ARS. The JO-1 group had a significant higher rate of mechanic’s hand (57.6%) than the other 4 groups. PM/DM was diagnosed in 25 (23.1%) patients and no difference were observed among the 5 groups. The anti-PL7 positive group had a higher frequency of UIP pattern (13.3%) than the other 4 groups, but the difference was not significant, and the EJ group had the most frequent OP pattern(78.2%), which was significantly higher than the PL-7 (P<0.001) and PL-12 groups (P=0.025). All received prednisone treatment, with or without immunosuppressants, at the 6-month-follow up, the JO-1 and EJ groups had a significantly higher improvement of forced vital capacity than the other 3 groups (P<0.05), and the PL-7 group had the lowest FVC improvement (P<0.05).
ASSD was first defined by Marguerie in 1990(10) as a relatively homogeneous syndrome comprised of inflammatory myopathy, pulmonary fibrosis, and arthritisin a retrospective cohort of 29 patients, including 19 anti-JO1 positive, 4 anti-PL7 positive, and 6 anti-PL12 positive cases. JO1 is the most frequent antibody in all the ASSD studies and represents the most common form(11). In our cohort,PL-7(30/108) had a similar frequency as JO-1(33/108). Studies have shown that specific ARS have different ASSD phenotypes, such as skin involvement (heliotrope rash) being more frequent in anti-PL7-positive patients(3, 12). However, few studies have been 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.
Overall, 35-45% of patients diagnosed with PM/DM will be afflicted with ILD during the course of myositis(1), and some have reported an ILD prevalence of 65% in PM/DM(13). 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(14, 15), causing morbidity and mortality. OP, NSIP, and mixed NSIP-organizing pneumonia patterns are more frequent than UIP patterns in PM/DM-ILD(13). ARS antibodies, one of the myositis specific antibodies (MSA), are positive in 30-45% of patients with a myopathic inflammatory disease (3, 16), and PM/DM patients with positive ARS have higher prevalence of ILD than those without such antibodies. As od 2015, ARS can also be positive in ILD patients who do not meet the criteria of inflammatory myositis of any other CTDs, who are considered as idiopathic interstitial pneumonitis (IIP) with positive ARS antibodies, or can be classified as interstitial pneumonia with autoimmune features (IPAF) (17). ASSD is a term that focuses more on the ARS antibody; however, to date, there are no uniform diagnostic criteria of ASSD. In some cohorts the ASSD was defined by the presence of myositis(3), while Connor’s ASSD criteria proposed in 2010 uses a positive ARS antibody plus one or more of myositis, ILD, arthritis, fever, Raynaud, or Mechanic’s hands, which is more pragmatic(1). In patients with ASSD, the classic clinical triad (myositis, ILD, arthritis) might have different onset times. 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), similar to our study.
ARS is a group of antibodies targeting 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 have been applied to explore the significance of distinct ARS antibodies and the results have been different. JO1 is the most prevalent antibody in either ASSD (60-75%)(18, 19) or inflammatory myositis(found in 20-30% of PM patients and in 5-10% DM patients)(2, 18). 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(20). Meanwhile, another retrospective study of 202 cases of ASSD showed that the 5- and 10-year unadjusted cumulative survivals were 90% and 70% for anti-JO1 positive patients, respectively, which were significantly better than that of non-JO1 patients (P<0.005)(19). 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)(19). In another cohort of 43 patients with ASSD associated ILD, 6 (14%) patients had died at 5 years, and the anti-JO1 positive rate was significantly higher in survivors (86%) than that of the deceased patients (50%) ,who had a significantly lower baseline FVC(21). In our cohort, the baseline FVC and DLCO of the distinct ARS antibody groups had no differences while the improvement with therapy had differences.
Anti-PL7/PL12 positivity in ASSD patients was found associated with more aggressive ILD and decreased survival as compared with those with anti-JO1 antibodies. 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 antibodies (90% vs. 68%). Anti-JO1 antibody results in more severe myositis, joint impairment and increased risk of cancer(22). In a cohort of 7cases of anti-PL7 positive ASSD-ILD, lung biopsy revealed 50% of cases with UIP(23).In another retrospective study of 20 cases of anti-JO1 positive ASSD-ILD, 35% of cases had a UIP pattern on lung biopsy(24). In a cohort of 12 anti-PL7 positive ASSD patients, the mean age at the first sign of clinical symptoms was 56.3 years, which was similar with our study, all presented with ILD, in which 9 had a NSIP pattern, 2 had an OP pattern and 1 had an obliterative bronchiolitis (BO) pattern(25). In another anti-PL7 positive ASSD cohort with 18 patients, all had myositis when first diagnosed, and 10 (55.6%) had ILD(26).
In an anti-PL12 positive ASSD cohort with 17 patients, the mean age at diagnosis was 60.3 years, all patients had ILD when diagnosed, 15 of which had the NSIP pattern and 2 the OP pattern, and 7 had mild myositis(27).
Another anti-PL12 positive ASSD cohort with 31 patients had a myositis prevalence of 52% (16/31)，and an ILD prevalence of 90% (28/31）, 14 out of which had a UIP pattern, 5 a NSIP pattern and 5 an OP pattern; this was confirmed histopathologically in 14 patients who either received surgical lung biopsy, or evaluated by HRCT(28).
In contrast, studies with larger samples suggest 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, ILD alone at onset was 63% in the OJ-positive group, 33% in the PL12-positive group, 26% in the EJ-positive group, 14% in the PL7-positive group, and 5% in the JO1-positive group(12), 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 the triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The PL7-positive group and EJ-positive group had higher ILD prevalence compared with the JO1-positive group(P=0.001, P=0.005, respectively), and the EJ-positive group presented more frequent acute onset (74%), which was defined as dysponea progressing rapidly in 4 weeks from respiratory symptom onset. Moreover, survival was not influenced by the distinct anti-ARS antibody’ 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 behaviours, had never been studied previously. The change of FVC, one of the most important factors of the ILD clinical course, had been used to classify ILD into a reversible or progressive type in classification and clinical trials(29, 30). Most of the patients(96.3%) had a positive response to therapy and an improvement in FVC in our study. The remaining (3.7%) patients were stable after therapy, which means the ARS antibody is a treatable trait of steroids or immunosuppressants for ILD, even without the presence of myositis. The myositis prevalence showed no differences among the 5 groups, which made the FVC comparable between groups, for respiratory muscle weakness impacts the spirometry values, leading to a complicated interpretation(1). No standard treatment has been proposed for ASSD, however, prednisone should be the mainstay, with or without immunosuppressants (31), which was proved again by our study.
Anti-Ro52, a myositis associated antibody, showed a positive frequency of 65% in an anti-JO1 positive ASSD cohort(32). In our cohort, the anti-Ro52 positivity rate was 87.9% in the JO-1 group, and 91.3% in the EJ group, which was significantly higher than the other 3 groups. The EJ and JO1 groups had the highest frequency of OP pattern, indicating that the occurrence of OP might be correlated with anti-Ro52 positivity.
Our study had several limitations. It was single centre and retrospective, the sample was relatively small and the follow up time was not sufficiently long. In another ASSD cohort, the RP-ILD was statistically more prevalent in patients with positive anti-PL7 antibodies than those without anti-PL7(3). The RP-ILD cases were not included in this study because spirometry could not be performed upon diagnosis due to the patients’ weakness; in our study, the excluded 7 cases of RP-ILD included 5 with EJ positivity and 2 with PL-7 positivity. Shi’s cohort, using Solomon’s criteria of ASSD, showed that a coincidence of anti-Ro52 antibody predicted RP-ILD(3). RP-ILD is more life threatening and requires more study in the future.