⧈ 1.2.4 Classification of IBM.

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⚀ 1.2.4.1 Introduction:

⚀ 1.2.4.2 Myositis-specific auto-antibodies (MSAs):

⚀ 1.2.4.1 Introduction:

□ 1.2.4.1.1 Muscle diseases have traditionally been put under the umbrella of myopathy: a disease of the muscle that causes weakness of the muscle (not a disease involving the nerves). As discoveries are made, the classification evolves, but there is no currently accepted international classification system for muscle diseases. As a group, these diseases are sometimes referred to as muscular dystrophy diseases. Inclusion body myositis is usually listed under the umbrella of muscular dystrophy diseases. IBM has traditionally been classified along with polymyositis (PM) and dermatomyositis (DM), but the features of IBM are clearly distinct from these other types.

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Figure 1.2.4.1.1a

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Figure 1.2.4.1.1b

□ 1.2.4.1.2 Myositis versus myopathy.

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Figure 1.2.4.1.2

⚀ Notes on Figure 1.2.4.1.2

□ IBM is an abbreviation for 'inclusion body myositis' not 'inclusion body myopathy' (Greenberg, 2019, Milone, 2017). The abbreviation IBM should refer clearly and only to the single disease IBM, not to the hereditary inclusion body myopathies ("hIBMs"). On this page, IBM will only refer to inclusion body myositis and I will not specify sporadic.

□ The hereditary, myopathy type is clearly distinct from the myositis forms: these are actually different diseases.

□  It would be less confusing if, in the future, researchers and doctors only used "IBM" to specify inclusion body myositis, dropped the terms "sporadic" and "hIBM" and used the the names of each specific form of hereditary myopathy discovered, e.g. GNE mutation myopathy, DES mutation myopathy, VCP mutation myopathy, MYHC2A mutation myopathy, and others yet to be discovered (?).

□ Some researchers are now using the term idiopathic as well: "Idiopathic or sporadic inclusion body myositis (IBM)" (Piazzi et al., 2021).

□  * GNE The most common form of hIBM, originally referred to as "hIBM2", was first described in Middle Eastern patients and is tied to mutations of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE, MIM# 603824) gene, hence the name GNE myopathy (MIM# 605820). Was called Nonaka myopathy.

□  # VCP Another "common" form is Hereditary inclusion-body myopathy associated with Paget's disease of bone (PDB) and frontotemporal dementia (IBMPFD1, MIM# 167320). There are also two other forms. This is a rare multisystem degenerative autosomal dominant disorder due to mutations of the valosin-containing protein gene (VCP, also see: MIM# 601023).

□  $ MYHC2A This form of autosomal dominant hIBM was first described in a large multigeneration family from Sweden (MIM# 605637). At one time was called “hIBM3.”

□  See: Broccolini, A., & Mirabella, M. (2015). Hereditary inclusion-body myopathies. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1852(4), 644-650. https://www.sciencedirect.com/science/article/pii/S0925443914002609?via%3Dihub

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⚀ 1.2.4.2  Myositis-specific auto-antibodies (MSAs):

The classification of muscle diseases has been evolving over time as more and more research discoveries are made. Different diseases are being recognized and categories adjusted. Muscle diseases have been classified mainly based on their clinical presentation. Today, the recognition of antibodies associated with different muscle diseases has impacted classification. "A major advancement in the field of myositis was the discovery of auto-antibodies that are specific for myositis, called myositis-specific auto-antibodies (MSAs); present in up to 60% of patients with IIM), which are helpful in establishing a diagnosis of IIM" (Lundberg et al., 2021). Other patients may have auto-antibodies that are also present in other autoimmune disorders, such as systemic lupus erythematosus (SLE), systemic sclerosis, or Sjögren syndrome; these auto-antibodies are named myositis-associated auto-antibodies (MAAs).

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Figure 1.2.4.2.1a

Figure from Ashton, C., Paramalingam, S., Stevenson, B., Brusch, A., & Needham, M. (2021). Idiopathic inflammatory myopathies: A review. Internal Medicine Journal, 51(6), 845-852. Source.

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Figure 1.2.4.2.1b

Figure 1.2.4.2.1b is based on: Mariampillai, K., Granger, B., Amelin, D., Guiguet, M., Hachulla, E., Maurier, F., … Benveniste, O. (2018). Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies. JAMA Neurology, 75(12), 1528. JAMA Neurol. 2018;75(12):1528-1537. doi:10.1001/jamaneurol.2018.2598

Notes on Figure 1.2.4.2.1b

^ trigger: statin use

* trigger: malignancy

** CN1A [Anti-NT5c1A] — [anti-cN1A]: Found in approximately 50 to 60% of IBM patients. Also found in about 25 percent of patients with juvenile myositis and in about 12 percent of healthy children (Yeker et al., 2018). According to Greenberg (2019), "Anti-cN1A antibodies are highly specific to IBM and are seen in 90-95% of patients with IBM compared with 5-10% of patients with polymyositis, dermatomyositis or non-immune neuromuscular diseases." However, these antibodies have only moderate diagnostic sensitivity, ranging from 37% to 76%. Varying sensitivities may be related to the different methods of testing that have been used. In other words, these antibodies are very specific to IBM — if you have them, you probably have IBM but, they are not that sensitive to IBM — only about 50 to 60% of IBM patients will have these antibodies — if you do not have them, you may still have IBM.

□ Anti-NT5C1A autoantibodies were detected in 71 (61%) of 117 patients with IBM, 2 (5%) of 42 patients with PM, 2 (5%) of 42 healthy volunteers, 24 (15%) of 159 patients with DM, 10 (23%) of 44 patients with Sjögren's syndrome, and 13 (14%) of 96 patients with systemic lupus erythematosus" (Lloyd et al., 2016).

□ Anti-cN-1A autoantibodies are demonstrated in one third of the patients with sIBM and in less than 5% with other IIMs or neuromuscular diseases. A recent study demonstrated that positive anti-cN-1A sIBM patients are included in a more severe sIBM subtype and represent a homogeneous group as exhibiting higher mortality risk, less proximal upper limb weakness (not typical of sIBMs) and a cytochrome oxidase deficiency in muscular fibers, when compared to negative patients" (Palterer et al., 2018).

□  For information on myositis-associated autoantibodies see: https://understandingmyositis.org/myositis-antibody-testing/

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