▣ 10.3 Classification of IBM.

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▣ 10.3 Classification of IBM:

⧈ 10.3.1 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.



⧈ 10.3.2 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).



The CN1A [Anti-NT5c1A] antibody is an MAA, as it appears in IBM and in other autoimmune diseases (top right).

Figure is 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.




Figure 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

        □ ^ 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/

        □ Update: Paul, P., Liewluck, T., Ernste, F. C., Mandrekar, J., & Milone, M. (2021). Anti‐cN1A antibodies do not correlate with specific clinical, electromyographic, or pathological findings in sporadic inclusion body myositis. Muscle & Nerve, 63(4), 490–496. https://doi.org/10.1002/mus.27157.
Results: Anti-cN1A antibodies were present in 47/92 (51%) patients with sIBM. Comparison of seropositive and seronegative cohorts yielded no significant difference in clinical features, including facial weakness, oropharyngeal and respiratory involvement, or disease severity. The antibody titer did not correlate with the clinical phenotype, CK value, or presence of myotonic discharges on EMG. Anti-cN1A antibody positive patients appeared to have more frequent auto-aggressive inflammation on muscle biopsy but not as an isolated myopathological feature.
Conclusions: Our study showed that anti-cN1A antibody positive and negative sIBM patients have similar clinical features and disease severity. Anti-cN1A antibodies in our sIBM cohort did not correlate with any studied clinical or laboratory parameter and, therefore, were of limited value in the patient's assessment.

         Update: Ikenaga et al (2020). Myositis associated anti-NT5C1A autoantibody in clinical practice. MedRxiv, 2020.03.25.20043760. https://doi.org/10.1101/2020.03.25.20043760

               Anti-NT5C1A was found in 182/287 patients with IBM (63%)

               Conclusions: This is the largest description of patients tested by a clinical diagnostic lab for anti-NT5C1A. We confirm the sensitivity and specificity of anti-NT5C1A for IBM and identified clinicopathologic features in IBM which correlate with anti-NT5C1A status. Notably, anti-NT5C1A testing increased both the diagnostic sensitivity and specificity of IBM when combined with patient age, gender and creatine kinase (CK) level. We propose that future IBM diagnostic criteria include anti-NT5C1A testing.

        □ Update: Mavroudis, I., Knights, M., Petridis, F., Chatzikonstantinou, S., Karantali, E., & Kazis, D. (2021). Diagnostic accuracy of Anti-CN1A on the diagnosis of inclusion body myositis. A hierarchical bivariate and bayesian meta-analysis. Journal of Clinical Neuromuscular Disease, 23(1), 31–38.https://doi.org/10.1097/CND.0000000000000353
In this study, we investigated the diagnostic accuracy of anti-CN1A antibodies for sporadic IBM in comparison with other inflammatory myopathies, autoimmune disorders, motor neurone disease, using a hierarchical bivariate approach, and a Bayesian model taking into account the variable prevalence. The results of the present analysis show that antiCN1A antibodies have moderate sensitivity, and despite having high specificity, they are not useful biomarkers for the diagnosis of IBM, polymyositis or dermatomyositis, other autoimmune conditions, or neuromuscular disorders. Neither the hierarchical bivariate nor the Bayesian analysis showed any significant usefulness of anti-CN1A antibodies in the diagnosis of IBM.
AntiCN1A antibodies are present in 33%–76% of patients with IBM, and their presence can be related to disease severity, whereas patients positive for them have more pronounced bulbar weakness and higher mortality rate; 19,34 however, these are preliminary observations that require prospective validation. Although, it is worth noting that the same antibodies can be also present in healthy controls, other inflammatory myopathies, and other neurological conditions, but with lower prevalence.

        □ Update: Lucchini, M., Maggi, L., Pegoraro, E., Filosto, M., Rodolico, C., Antonini, G., Garibaldi, M., Valentino, M. L., Siciliano, G., Tasca, G., De Arcangelis, V., De Fino, C., & Mirabella, M. (2021). Anti-cN1A Antibodies Are Associated with More Severe Dysphagia in Sporadic Inclusion Body Myositis. Cells, 10(5), 1146. https://doi.org/10.3390/cells10051146
We did not find significant difference regarding demographic variables, nor quadriceps or finger flexor weakness. Nevertheless, we found that anti-cN1A-positive patients presented significantly lower scores in IBMFRS item 1 (swallowing, p = 0.045) and more frequently reported more severe swallowing problems, expressed as an IBMFRS item 1 score ≤ 2 (p less than 0.001). We confirmed the low sensitivity and high specificity of anti-cN1A Ab in s-IBM patients with a high positive predictive value. The presence of anti-CN1A antibodies identified patients with a greater risk of more severe dysphagia.

        □ Update Polymyositis: There is a viewpoint that polymyositis is often misdiagnosed and is actually a rare subtype. Most PM cases can be reclassified as either IMNM (immune mediated necrotizing myopathy) or CTD-OM (connective tissue disease-overlap myositis). See: Loarce-Martos, J., Lilleker, J. B., Parker, M., McHugh, N., & Chinoy, H. (2021). Polymyositis: Is there anything left? A retrospective diagnostic review from a tertiary myositis centre. Rheumatology, 60(7), 3398–3403. https://doi.org/10.1093/rheumatology/keaa801 Summary: Antibodies are protective proteins produced by the immune system in response to the presence of a foreign substance, called an antigen. Antibodies recognize and latch onto antigens in order to remove them from the body. In the case of an autoimmune disease autoantibodies mistakenly recognize a person’s own tissues and attack them as if they were invaders. Researchers have discovered various autoantibodies directed against various tissues in the body, including skeletal muscle. These discoveries have led to the classification of myositis as an autoimmune disease. Some autoantibodies are only found in specific muscle disorders—myositis-specific [auto] antibodies (MSAs). Other [auto] antibodies may be linked to more than one disorder. When one of these disorders includes a muscle disorder it is called a myositis-associated antibody (MAA). It is a major challenge for researchers to decide if newly discovered autoantibodies belong to either the MSAs or MAAs group. In some cases, the detection of an autoantibody may help with making the diagnosis of a particular condition, in some cases, they are correlated to the way a disease progresses. References:

        □ Allenbach, Y., Benveniste, O., Goebel, H.H., & Stenzel, W. (2017). Integrated classification of inflammatory myopathies. Neuropathology and Applied Neurobiology, 43(1), 62-81. https://doi.org/10.1111/nan.12380

        □ Greenberg, S. A. (2019). Inclusion body myositis: Clinical features and pathogenesis. Nature Reviews Rheumatology 2019, 1. https://doi.org/10.1038/s41584-019-0186-x

        □ Lloyd, T. E., Christopher-Stine, L., Pinal-Fernandez, I., Tiniakou, E., Petri, M., Baer, A., … Mammen, A. L. (2016). Cytosolic 5'-Nucleotidase 1A as a target of circulating autoantibodies in autoimmune diseases. Arthritis Care & Research, 68(1), 66-71. https://doi.org/10.1002/acr.22600

        □ Montagnese, F., Babacic, H., Eichhorn, P., & Schoser, B. (2019). Evaluating the diagnostic utility of new line immunoassays for myositis antibodies in clinical practice: A retrospective study. Journal of Neurology, 266(6), 1358-1366. https://doi.org/10.1007/s00415-019-09266-4

        □ Palterer, B., Vitiello, G., Carraresi, A., Giudizi, M. G., Cammelli, D., & Parronchi, P. (2018). Bench to bedside review of myositis autoantibodies. Clinical and Molecular Allergy, 16(1), 5. https://doi.org/10.1186/s12948-018-0084-9

        □ Santos, L. R., & Isenberg, D. (2019). Myositis. In Neuroimmune Diseases (pp. 787-808). Cham: Springer. https://doi.org/10.1007/978-3-030-19515-1_27

        □ Yeker, R. M., Pinal-Fernandez, I., Kishi, T., Pak, K., Targoff, I. N., Miller, F. W., Rider, L. G., Mammen, A. L., & Childhood Myositis Heterogeneity Collaborative Study Group (2018). Anti-NT5C1A autoantibodies are associated with more severe disease in patients with juvenile myositis. Annals of the rheumatic diseases, 77(5), 714–719. https://doi.org/10.1136/annrheumdis-2017-212436

⧈ 10.3.3 Myositis versus myopathy.


Figure 10.3.3

 Notes on Figure 10.3.3

        □ 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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