IMNM is a subclass of IIM characterised by myocyte necrosis, which has been gradually recognised in recent years. Proximal muscle weakness and elevated CK levels are common features of muscular disorders [13]. Based on clinical symptoms alone and without considering muscle biopsy, autoantibody screening, or even genetic testing, it is difficult to distinguish IMNM from other subtypes of IIM as well as some non-IIM [14].
In our muscle biopsy cohort, 61.7% of patients had IIM. In the IIM group, DM was relatively easy to distinguish from IMNM by the presence of typical rashes (heliotrope sign and Gotrron sign) and DM-associated MSAs. In addition, 42.4% of IMNM cases presented with severe muscle weakness, which is higher than that in DM, which can also differentiate IMNM from DM.
According to the 2017 EULAR/ACR diagnostic criteria, 34.3% of IIM patients were diagnosed with PM. However, according to the 2018 ENMC criteria, 32.4% of PM patients could be diagnostically refined as IMNM, and only 3.8% of them met the pathological characteristics of typical PM. Anti-SRP and anti-HMGCR antibodies were the main MSAs of IMNM, although nearly one-third of PM patients were positive for anti-ARS antibodies, which may have contributed to the high prevalence of fever, arthritis, and ILD in PM [15].
LGMD 2B and LSM were the most common non-IIMs that shared similar manifestations with IMNM in our cohort [16, 17], in line with the high prevalence in the Chinese population [18]. However, IMNM has an older age of onset, while the other genetic myopathies have a younger onset age. In addition, the disease course of IMNM is shorter than that of hereditary myopathy. Demographic characteristics seem to vary according to the underlying aetiology. Middle-aged onset and subacute duration suggest IIM; however, young patients present with slowly progressive proximal muscle weakness that can be difficult to differentiate clinically from LGMD. Mohassel et al. [19] reported an anti-HMGCR-positive IMNM case with a more indolent disease course but favourable clinical response to immunotherapy, which is easy to confuse with muscular dystrophy. Tanboon et al. [20] also reported that concurrent anti-HMGCR antibodies and gene mutations indicated the possibility of co-occurrence of IMNM and muscular dystrophy. Thus, testing for these antiantibodies should be an essential part of the evaluation of children with symptoms resembling hereditary muscular disorders. In addition, upper limb weakness and dysphagia are more common in IMNM than in LGMD and LSM, although cervical flexor weakness is more common in LSM. Asymmetric muscle weakness is present only in LGMD 2B patients [21]. The above information reminds muscle specialists, neurologists, or rheumatologists about the necessity of a comprehensive and systemic examination of whole-body muscle strength for muscular diseases.
IMNM, LGMD 2B, and LSM had a significant elevation of CK in this study, although the highest level of peak CK appeared in LGMD 2B. A previous study reported that CK levels in IMNM are always up to 10-15 times the upper normal level, although in LGMD 2B, it can increase more than 20 times. The study also shows that significant CK elevation indicates a higher probability of muscular dystrophy than IMNM [22]. The level of LDH in LSM patients can reach 808 (341, 1248) U/L, with the highest value of up to 2433 U/L, which is higher than that in the other groups. Zhang et al. also observed predominantly higher levels of LDH in LSM [23]. The reason for this is still unclear. LDH has isoforms of liver and muscle. The abnormally high level of LDH in LSM patients may be due to the presence of lipid or glucose metabolic dysfunction and increased liver types. Therefore, identifying the isoforms may help determine its source and distinguish IMNM from metabolic myopathy.
Muscle fibre necrosis is not a specific manifestation of IMNM, which also occurs in patients without IIM. However, the proportion and degree of fibre muscle necrosis were significantly higher than in non-IIM, and diffuse expression of MHC-I and CD4+ T cell perimyosial infiltration were more specific in IMNM. MAC deposition is less common in LSM, indicating that the complement pathway is less involved in the pathogenesis of LSM. Histochemical staining of dysferlin, ORO, and PAS in patients with suspected muscular dystrophy and metabolic myopathy are helpful for clinicians to exclude IMNM from muscular dystrophy and metabolic myopathy [24–26].
One limitation of this study is that a large proportion of patients with CK elevation and/or muscle weakness cannot be definitively diagnosed despite undergoing autoantibodies, muscle biopsy, and even genetic testing. There is also current clinical confusion regarding the diagnosis of muscular diseases.