Demographic and clinical features
A total of 46 DM patients (anti-MDA5 11, anti-Mi-2 10, anti-NXP2 13, anti-TIF1γ 8, anti-SAE 4) were included (Table 2). The median age at onset was 48 years and the median time from onset to biopsy was 4 months. Most of the patients showed preferential involvement of proximal muscle. Total MMT scores varied from 30 (severe) to 80 (normal) with the median of 63. The most frequent biopsy site was quadriceps, followed by biceps brachii, gastroenemius, tibialis anterior and deltoid muscles. More than half of the DM patients (52.2%) were on steroids use at the time of biopsy while the median duration from steroids use to biopsy was 2 months (0.875-5.5 months).
The clinical features of different subgroups were compared (Fig. 1). Anti-SAE patients had a later onset compared with the anti-MDA5 group. Interestingly, patients with anti-Mi-2 autoantibodies were more likely to have severe muscle weakness than patients with anti-MDA5, anti-NXP2 and anti-TIF1γ patients (p < 0.05). No significant difference was found between other groups. Patients with anti-Mi-2 autoantibody had significantly higher levels of creatine kinase (CK) compared with the anti-MDA5, anti-TIF1γ and anti-SAE groups. The anti-TIF1γ group had intermediate CK levels, while anti-MDA5 and anti-SAE groups had normal or slightly elevated serum CK levels. Patients with anti-NXP2 had a wide range of CK levels. Similar trends were observed for the level of lactate dehydrogenase (LDH) and CK/LDH ratio.
MRI of the thigh muscles was performed in 32 patients (anti-MDA5 5, anti-Mi-2 6, anti-NXP2 11, anti-TIF1γ 7, and anti-SAE 3) using a 1.5-T machine (GE; Signal). Representative MRI imaging for DM with anti-Mi-2, anti-MDA5 and anti-SAE are shown in Fig. 2. Patients with anti-Mi-2 exhibited diffuse edema on STIR images, especially the anterior compartments of the thigh. In contrast, fascial edema or patchy distribution were detected in patients with anti-MDA5 and anti-SAE autoantibodies. In the anti-NXP2 and anti-TIF1γ groups, a wide range from foggy distribution to diffuse involvement were observed (Supplementary Fig. 1).
Muscle pathological features among DM subgroups
The pathological score in each domain were compared (Fig. 3, Table 3). In the muscle fiber domain, more severe muscle fiber pathology was demonstrated in anti-Mi-2 group compared with anti-MDA5 group (p < 0.001). The anti-Mi-2 group showed obvious PFA (9 of 10, or 90%), perifascicular (90%) or non-perifascicular (80%) necrosis and regeneration of muscle fiber (70%). In anti-Mi-2 group, all samples showed perifascicular sarcoplasmic MxA expression (100%). In contrast, most patients with anti-MDA5 autoantibody had very mild, minimal myofiber abnormalities with little degeneration or regeneration (18.2%). Only 36.4% (4/11) of anti-MDA5 patients demonstrated PFA, meanwhile, sarcoplasmic MxA expression was found only in 45.5% (5/11) of anti-MDA5 autoantibody positive groups. The MxA expression often highlighted the perifascicular areas, but a scattered distribution pattern was observed exclusively in anti-MDA5 groups (Fig. 4).
In the inflammatory domain, high level of inflammation was demonstrated in anti-Mi-2 and anti-SAE group compared with anti-MDA5 group (p < 0.01). The anti-Mi-2 group showed obvious infiltration of CD8 positive T cells (9/10), CD20 positive B cells (4/10) and CD68 positive macrophages (7/10). In anti-SAE group, 3/4 of the samples displayed CD8 positive T cells and CD20 positive B cells in the endomysial tissue (Supplementary Fig. 2). In contrast, anti-MDA5 group had little or no inflammatory infiltrates. A few CD4 + T cells (3/11) and CD68 + macrophages (1/11) were seen, while CD8 + T cells and CD20 + B cells were not present in these samples. Almost 90% (39/46) samples showed MHC-I upregulation in cytosol or sarcolemmal membrane. Even in anti-MDA5 group, 10 of 11 cases showed increased MHC-I expression. There were also significant differences in the MAC deposition among groups. All anti-Mi-2 samples showed MAC deposition on capillaries, and 2 samples even showed sarcolemmal deposition, while only 3 of 11 cases showed capillary MAC deposition in the anti-MDA5 group (Fig. 4). In the connective tissue domain, no significant difference between groups were seen.
Overall, patients with anti-Mi-2 demonstrated higher pathological severity scores, both in the myofiber domain and inflammation domain. In contrast, MDA5 associated myopathies generally had minimal myofiber abnormalities with little or no inflammatory infiltration, scattered MxA upregulation and few complement deposition on capillaries. Patients with SAE had more inflammatory cell infiltration and MAC deposition compared to MDA5 group. NXP2 and TIF1 γ group showed a wide range in muscle pathological scores.