Inclusion body myositis (IBM)

Idiopathic inflammatory myopathies (IIMs), also known as myositis, are disorders with muscle weakness and chronic inflammation in the muscle tissue (Lundberg et al., 2018).

Based on symptoms, such as muscle weakness, skin rash, and histopathology, IIMs include dermatomyositis, polymyositis, antisynthetase syndrome myositis, overlap myositis with systemic autoimmune disease, IBM, and immune-mediated necrotizing myopathy (IMNM). However, this classification system is limited as IBM is clinically and pathologically distinct from the other IIMs. In IBM patients, the onset of muscle weakness is insidious and often thought to have earlier (Badrising et al., 2005) than the mean age of onset of 61 to 68 years (Benveniste et al., 2011; Dobloug et al., 2012; Suzuki et al., 2012; Tan et al., 2013; Suzuki et al., 2016).

Histopathologically, characteristic features are endomysial infiltrates and the invasion of non-necrotic muscle fibers primarily by CD8⁺ T-cells besides the frequent rimmed vacuolated fibers in the muscle biopsies of IBM patients (Greenberg, 2019). Additionally, the selective pattern of atrophy and weakness in quadriceps and forearm distal muscles, i.e., long finger flexors and no response to immune therapies, presents IBM as an enigmatic entity in the IIM group.

The underlying molecular pathomechanisms of IBM are poorly understood, and consequently, no curative therapeutic strategy exists to treat IBM patients yet.

2.3.1 Epidemiology

According to a meta-analysis study, the latest estimates suggest a prevalence of 24-46 per million (Callan et al., 2017).

However, in different relatively isolated populations in Europe, the prevalence of IBM is slightly higher. In Finland, the prevalence of IBM is about 70 per million (Udd, 2007). In Ireland, it is about 112 per million (Lefter et al., 2017). The ratio

of male patients to female patients is highly variable between 0.5 (Wilson et al., 2008) to 6.5 (Amato et al., 1996).

Due to poor understanding of the disease, IBM was initially often misdiagnosed in about 40-53% of patients (Needham et al., 2008; Suzuki et al., 2016; Callan et al., 2017). However, in recent years, the clinical and histopathological awareness of the disease has led to a better diagnosis encouraging a better course of prevalence studies in different populations. On average, it takes 4.6 to 5.8 years from the onset of symptoms to receive a correct diagnosis of IBM (Needham et al., 2008;

Dobloug et al., 2015; Suzuki et al., 2016).

2.3.2 Phenotype

IBM patients show a unique and relatively homogenous pattern of often asymmetric muscle weakness and atrophy in long finger flexors accompanied by atrophy and weakness in quadriceps and, later, the ankle dorsiflexors. Knee extensor weakness and ankle dorsiflexion weakness result in difficulties walking, climbing stairs, and poor rising from the squat, while finger flexor weakness results in a weak grip. These initial symptoms are often presumed as symptoms of aging or arthritis and occasionally lead to a misdiagnosis of polymyositis or a motor neuron disease (Greenberg, 2019).

Interestingly this pattern of weakness in finger flexion, knee extension, and ankle dorsiflexion suggests, apart from the quadriceps weakness, shows a clear overlap with the distal myopathies.

MRI in IBM patients shows characteristic involvement of the corresponding muscles (Tasca et al., 2015) including the distinct atrophy and simultaneous inflammatory edema in the quadriceps. Dysphagia in IBM patients is more evident with the progression of the disease and can often result in poor nutrition, weight loss, and pneumonia, contributing mainly to

IBM-related fatalities (Oh et al., 2008; Cox et al., 2011; Price et al., 2016).

Muscle biopsies of IBM patients show characteristic muscle fiber degeneration, demonstrated by rimmed vacuoles accompanied by cytotoxic CD8⁺ T cell infiltration in non-necrotic fibers and rare congophilic protein accumulations or cytoplasmic inclusions. In addition, mitochondrial pathology and upregulation of MHC-class I antigen are vital components for the diagnosis. However, the precedence of either of these molecular pathological events has remained unclear as patients usually undergo diagnostic evaluations many years after the onset of symptoms. An earlier hypothesis suggests that the aging of muscle fibers and the accumulation of different misfolded or ubiquitinated proteins in muscle fibers may play a primary role in the pathogenesis leading to the degeneration of muscle fibers and consequently inviting immune response (Askanas & Engel, 2001). Alternatively, a widely supported theory of immune-mediated muscle fiber degeneration suggests that IBM is in fact, an autoimmune disease (Koffman et al., 1998; Badrising et al., 2004; Benveniste et al., 2015).

The diagnostic criteria defined by ENMC include two characteristic histopathological diagnostic markers of IBM, endomysial lymphocyte infiltrates with invasion in myofibers and the presence of rimmed vacuoles (Rose & Group, 2013).

However, a revised data-driven diagnostic criterion includes either invasion of non-necrotic muscle fibers or rimmed vacuoles (Lloyd et al., 2014) allowing a more sensitive diagnosis of Polymyositis-Mito or mitochondrial myositis patients as IBM. This division is also referred to as inflammatory myopathy with vacuoles, aggregates, and mitochondrial pathology (IM-VAMP). In IBM, the mitochondrial pathology refers to the presence of COX-negative and SDH-positive myofibers and less frequent ragged red myofibers. Multiple mtDNA deletions are part of the mitochondrial pathology and one of the diagnostic features in IBM (Oldfors et al., 1993; Rygiel et al., 2015). These features

are accompanied by nonspecific myopathic changes: increased fiber size variation and number of internal nuclei. Cytoplasmic inclusions are very rare on light microscopy of muscle biopsy sections of IBM patients. The presence of rimmed vacuoles, mitochondrial pathology, and cytoplasmic inclusions is the degenerative part of IBM pathology. Overexpression of Class I, and to a lesser degree Class II, MHC in all muscle fibers together with the inflammatory cell response make the immune-mediated part of the pathology (Rodriguez Cruz et al., 2014).

Several studies have reported the varying degree of protein aggregation in IBM (Askanas et al., 1991; Mendell et al., 1991;

Askanas & Alvarez, 1992; Askanas et al., 1992a; Askanas et al., 1992b; Askanas et al., 1992c; Askanas et al., 1993a; Askanas et al., 1993b). However, the number of proteins and specificity of protein aggregation in IBM is still challenging to understand (Greenberg, 2009, 2019). Recent studies have shown the presence of more reliable autophagy biomarkers like TARDBP/TDP-43, SQSTM1/p62, and LC3 in IBM muscles (Weihl et al., 2008; Salajegheh et al., 2009; Hiniker et al., 2013). Lately, serum anti-cN1A antibodies have also been reported and are used as a supporting diagnostic marker of IBM. However, the specificity and sensitivity of these antibodies are still under study (Ikenaga et al., 2021; Paul et al., 2021).

The invasion of muscle fibers by highly differentiated CD8⁺ cytotoxic T-cells together with endomysial infiltrates is considered a hallmark feature of IBM (Greenberg et al., 2016;

Greenberg et al., 2019). The highly differentiated CD4⁺ and CD8⁺ cells are seen in both muscles and blood of IBM patients (Salajegheh et al., 2007; Pandya et al., 2010; Allenbach et al., 2014). Additionally, an increase in levels of chemokines and cytokines such as CXCL9 and CCL5 has been reported (Greenberg et al., 2002) suggesting upregulation of IFNg production. Simultaneously, increased expression of genes participating in interferon signaling is seen in IBM muscles

(Raju et al., 2003; Ivanidze et al., 2011; Pinal-Fernandez et al., 2019).

2.3.3 Nomenclature issues

Historically, similar nomenclature and abbreviations largely used in previous literature have contributed to diagnostic issues in IBM. The abbreviation IBM refers to inclusion body myositis and not to inclusion body myopathy or a group of rimmed vacuolar diseases with overlapping clinical features (Greenberg, 2019). The classification of rimmed vacuolar myopathies with predominant distal muscle weakness includes several inherited diseases that have been previously termed inclusion body myopathies. An example of this is the GNE myopathy (Nonaka myopathy), previously known as hereditary inclusion body myopathy (hIBM) or IBM2 due to its hereditary nature and rimmed vacuoles in muscle biopsies of patients. Similarly, distal myopathy phenotypes with rimmed vacuolar pathology caused by pathogenic mutations in DES and MYH2 have been termed IBM1 (OMIM: 601419) and IBM3 (OMIM: 605637), respectively. Multisystemic proteinopathies (table 1) caused by pathogenic mutations in VCP, HNRNPA1, HNRNPA2B1, and SQSTM1 (digenic with TIA1) have also been previously referred to as Inclusion body myopathy with Paget disease with or without frontotemporal dementia (IBMFPD).

The term sporadic IBM or sIBM/s-IBM might separate the myositis phenotype from hIBMs (Askanas & Engel, 1993) referring to the former’s sporadic nature and no family history of weakness. However, the use of sporadic and hereditary terms with the abbreviation IBM gives a wrong impression about the inheritance and phenotype of IBM (Greenberg, 2019). The rare occurrence of familial cases, i.e., multiple/several diagnoses of IBM in different members of the same family, does increase the complexity of the disease nomenclature. However, the use of sporadic IBM and familial IBM (fIBM/f-IBM) is still better than outdated and confusing terms for inherited non-inflammatory myopathies with

rimmed vacuoles. The use of these terms is often confusing and clutter the clinical literature, possibly even hampering the proper diagnosis of patients.