Distal upper limb involvement in myasthenia-myositis association.

INTRODUCTION: Myasthenia gravis-inflammatory myopathy (MG-IM) association has been rarely reported as specific clinical entity characterized by variable myositis manifestations, ranging from subclinical to diffuse muscle involvement with characteristic distal upper limb weakness. Although, in view of this, it has been hypothesized that distal muscle weakness in MG-IM could be due to the muscle inflammation instead of a pure neuromuscular transmission impairment, a biopsy-proven myositis process of distal muscles of upper limbs has not yet been provided. METHODS: We report on clinical, immunological, and myopathological characterization of a novel case affected by MG-IM association showing the typical distal upper limb weakness, including muscle biopsy of a weak forearm muscle. RESULTS: Histological and immunohistochemical studies showed a marked inflammatory process on muscle biopsy of extensor digitorum communis. The patient, a 47-year-old man with 10-year history of anti-acetylcholine receptor (AChR) and anti-titin antibody-positive MG with thymoma, developed a progressive, diffuse, and non-fatigable weakness predominant in distal upper limb muscles, unresponsive to acetylcholinesterase inhibitors associated to myalgia and creatine kinase (CK) elevation. DISCUSSION: We provide the histopathological evidence of a prominent inflammatory process responsible of distal upper limb weakness in MG-IM association. Muscle biopsy does not reveal any typical histopathological feature of other nosologically definite inflammatory myopathy, leading MG-IM association to come close to the group of overlap-myositis (OM) with the myopathological features of non-specific myositis (NSM).

Comparison of quantitative muscle ultrasound and whole-body muscle MRI in facioscapulohumeral muscular dystrophy type 1 patients.

INTRODUCTION: Muscle ultrasound is a fast, non-invasive and cost-effective examination that can identify structural muscular changes by assessing muscle thickness and echointensity (EI) with a quantitative analysis (QMUS). To assess applicability and repeatability of QMUS, we evaluated patients with genetically confirmed facioscapulohumeral muscular dystrophy type 1 (FSHD1), comparing their muscle ultrasound characteristics with healthy controls and with those detected by MRI. We also evaluated relationships between QMUS and demographic and clinical characteristics. MATERIALS AND METHODS: Thirteen patients were included in the study. Clinical assessment included MRC sum score, FSHD score and The Comprehensive Clinical Evaluation Form (CCEF). QMUS was performed with a linear transducer scanning bilaterally pectoralis major, deltoid, rectus femoris, tibialis anterior and semimembranosus muscles in patients and healthy subjects. For each muscle, we acquired three images, which were analysed calculating muscle EI by computer-assisted grey-scale analysis. QMUS analysis was compared with semiquantitative 1.5 T muscle MRI scale. RESULTS: All muscles in FSHD patients showed a significant increased echogenicity compared to the homologous muscles in healthy subjects. Older subjects and patients with higher FSHD score presented increased muscle EI. Tibialis anterior MRC showed a significant inverse correlation with EI. Higher median EI was found in muscles with more severe MRI fat replacement. CONCLUSIONS: QMUS allows quantitative evaluation of muscle echogenicity, displaying a tight correlation with muscular alterations, clinical and MRI data. Although a confirmation on larger sample is needed, our research suggests a possible future application of QMUS in diagnosis and management of muscular disorders.

Prominent mitochondrial pathology in a case of refractory dermatomyositis: coincidence or concause?

INTRODUCTION: Mitochondrial alterations are a common finding in muscle biopsy of sporadic inclusion body myositis (s-IBM) and polymyositis with mitochondrial pathology (PM-Mito). Both disorders generally have poor treatment response. Nevertheless, mitochondrial myopathology has been rarely reported in dermatomyositis (DM) outside areas of perifascicular atrophy and a relationship with therapeutic outcome is not established. METHODS: We report on clinical, immunological, radiological, and myopathological findings of a case of severe, treatment-refractory anti-Mi-2-positive DM. RESULTS: A 77-year-old woman developed anti-Mi-2 DM with severe diffuse muscle weakness associated with abundant mitochondrial abnormalities at muscle biopsy, beside the typical features of inflammatory myopathy. The patient was poorly responsive to multiple-line therapies and finally anti-JAK (anti-Janus activated kinase) was administered, leading to partial clinical improvement. DISCUSSION: Given the usual satisfactory treatment response and favorable outcome of anti-Mi-2 DM, we suppose that mitochondrial dysfunction on muscle biopsy could represent a marker of disease severity in DM, predicting a worse response to treatment and a poor clinical outcome. JAK-inhibitors could represent a good treatment option in refractory anti-Mi-2 DM with mitochondrial abnormalities.

Muscle magnetic resonance imaging in myotonic dystrophy type 1 (DM1): Refining muscle involvement and implications for clinical trials.

BACKGROUND: Only a few studies have reported muscle imaging data on small cohorts of patients with myotonic dystrophy type 1 (DM1). We aimed to investigate the muscle involvement in a large cohort of patients in order to refine the pattern of muscle involvement, to better understand the pathophysiological mechanisms of muscle weakness, and to identify potential imaging biomarkers for disease activity and severity. METHODS: One hundred and thirty-four DM1 patients underwent a cross-sectional muscle magnetic resonance imaging (MRI) study. Short tau inversion recovery (STIR) and T1 sequences in the lower and upper body were analyzed. Fat replacement, muscle atrophy and STIR positivity were evaluated using three different scales. Correlations between MRI scores, clinical features and genetic background were investigated. RESULTS: The most frequent pattern of muscle involvement in T1 consisted of fat replacement of the tongue, sternocleidomastoideus, paraspinalis, gluteus minimus, distal quadriceps and gastrocnemius medialis. Degree of fat replacement at MRI correlated with clinical severity and disease duration, but not with CTG expansion. Fat replacement was also detected in milder/asymptomatic patients. More than 80% of patients had STIR-positive signals in muscles. Most DM1 patients also showed a variable degree of muscle atrophy regardless of MRI signs of fat replacement. A subset of patients (20%) showed a 'marbled' muscle appearance. CONCLUSIONS: Muscle MRI is a sensitive biomarker of disease severity alsofor the milder spectrum of disease. STIR hyperintensity seems to precede fat replacement in T1. Beyond fat replacement, STIR positivity, muscle atrophy and a 'marbled' appearance suggest further mechanisms of muscle wasting and weakness in DM1, representing additional outcome measures and therapeutic targets for forthcoming clinical trials.

Gender effect on cardiac involvement in myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: Cardiac involvement is observed in about 80% of subjects with myotonic dystrophy type 1 (DM1) and is mainly characterized by cardiac conduction and/or rhythm abnormalities (CCRAs), possibly leading to sudden cardiac death (SCD). Our objective was to investigate whether the gender difference may influence the cardiac involvement and SCD in DM1. METHODS: We analyzed prevalence and incidence of cardiological abnormalities in males versus females in 151 consecutive DM1 patients over a 35-year follow-up period. RESULTS: Fifty-five patients, 35 males (62.5%) and 20 females (42.5%), developed some type of CCRA during the follow-up period (mean 7.82 ± 6.21 years). CCRA overall, and specifically cardiac conduction abnormalities (CCAs), were significantly more frequent in males than in females (p = 0.043 and p = 0.031, respectively). CCRAs progressed in 16 males (45.7%) and six females (30%). Twenty-four patients, 14 males (25.0%) and 10 females (21.3%), died during the follow-up. Nine of them, six males (10.7%) and three females (6.4%), had SCD. After correction for Muscular Impairment Rating Scale progression, cytosine thymine-guanine expansion, and follow-up duration, a higher prevalence of CCAs was independently associated with male gender (p = 0.039), but independent association with gender was not detected for CCRAs overall, cardiac rhythm abnormalities, and SCD prevalence, even if prevalence was higher in males than females. CONCLUSIONS: The overall risk of occurrence of CCAs in DM1 is significantly higher in males than females regardless of genetic background and disease severity and progression. Moreover, the data also suggest a similar impact for male gender for CCRAs overall, CCAs, and SCD even if not statistically significant.

Muscle MRI as a biomarker of disease activity and progression in myotonic dystrophy type 1: a longitudinal study.

INTRODUCTION: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease characterized by myotonia and progressive muscular weakness and atrophy. The aim of this study was to investigate the usefulness of longitudinal muscle MRI in detecting disease activity and progression in DM1, and to better characterize muscle edema, fat replacement and atrophy overtime. MATERIALS AND METHODS: This is a prospective, observational, longitudinal study including 25 DM1 patients that performed at least two muscle MRIs. Demographic and genetic characteristics were recorded. Muscular Impairment Rating Scale (MIRS) and MRC score were performed within 3 months from MRIs at baseline (BL) and at follow-up (FU). We analysed 32 muscles of lower body (LB) and 17 muscles of upper body (UB) by T1 and STIR sequences. T1-, STIR- and atrophy scores and their variations were evaluated. Correlations between MRIs' scores and demographic, clinical and genetic characteristics were analysed. RESULTS: Eighty (80%) of patients showed fat replacement progression at FU. The median T1 score progression (ΔT1-score) was 1.3% per year in LB and 0.5% per year in UB. The rate of fat replacement progression was not homogenous, stratifying patients from non-progressors to fast progressors (> 3% ΔT1-score per year). Half of the STIR-positive muscles at BL showed T1-score progression at FU. Two patients with normal MRI at baseline only showed STIR-positive muscle at FU, marking the disease activity onset. STIR positivity at baseline correlated with fat replacement progression (ΔT1-score; p < 0.0001) and clinical worsening at FU (ΔMRC-score; p < 0.0001). Sixty-five (65%) of patients showed STIR- and fat replacement-independent muscle atrophy progression, more evident in UB. CONCLUSIONS: Muscle MRI represents a sensitive biomarker of disease activity, severity, and progression in DM1. STIR alterations precede fat replacement and identify patients with a higher risk of disease progression, while T1-sequences reveal atrophy and fat replacement progression before clinical worsening.

Muscle MRI in immune-mediated necrotizing myopathy (IMNM): implications for clinical management and treatment strategies.

OBJECTIVES: Immune-mediated necrotizing myopathy (IMNM) is the most severe idiopathic inflammatory myopathy (IIM) and early aggressive poly-immunotherapy is often required to reduce long-term disability. The aim of this study is to investigate muscle MRI in IMNM as outcome measure for disease activity, severity, progression, response to treatment, and to better characterize the pattern of muscle involvement. METHODS: This is a retrospective, observational, cross-sectional, and longitudinal study including 22 IMNM patients, divided into three groups based on timing of first MRI and if performed before or under treatment. T1 score and percentage of STIR positive muscles (STIR%) were considered and analyzed also in relation to demographic, clinical and laboratory characteristics. RESULTS: STIR% was higher in untreated patients and in those who performed MRI earlier (p = 0.001). Pelvic girdle and thighs were in general more affected than legs. T1 score was higher in patients with MRI performed later in disease course (p = 0.004) with a prevalent involvement of the lumbar paraspinal muscles, gluteus medius and minimus, adductor magnus and hamstrings. 22% of STIR positive muscles showed fat replacement progression at second MRI. Higher STIR% at baseline correlated with higher risk of fat replacement at follow-up (p = 0.003); higher T1 score correlated with clinical disability at follow-up, with late treatment start and delayed treatment with IVIG (p = 0.03). INTERPRETATION: Muscle MRI is a sensitive biomarker for monitoring disease activity and therapy response, especially when performed early in disease course and before treatment start, and could represent a supportive outcome measure and early prognostic index in IMNM.

Immune-mediated necrotizing myopathy (IMNM): A myopathological challenge.

This review is focused on the myopathological spectrum of immune mediated necrotizing myopathies (IMNMs) and its differentiation with other, potentially mimicking, inflammatory and non-inflammatory myopathies. IMNMs are a subgroup of idiopathic inflammatory myopathies (IIMs) characterized by severe clinical presentation with rapidly progressive muscular weakness and creatine kinase elevation, often requiring early aggressive immunotherapy, associated to the presence of muscle specific autoantibodies (MSA) against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Muscle biopsy usually shows unspecific features consisting in prominent necrosis and regeneration of muscle fibres with mild or absent inflammatory infiltrates, inconstant and faint expression of major histocompatibility complex (MHC) class I and variable deposition of C5b-9 on sarcolemma. Several conditions could present similar histopathological findings leading to possible misdiagnosis of IMNM with other IIMs or non-inflammatory myopathies (nIMs) and viceversa. This review analyses the muscle biopsy data in IMNMs through a systematic revision of the literature from the last five decades. Several histopathological variables have been considered in both SRP- and HMGCR-IMNM, and compared to other IIMs - as dermatomyositis (DM) and anti-synthethase syndrome (ASS) - or other nIMs -as toxic myopathies (TM), critical illness myopathy (CIM) and muscular dystrophy (MD) - to elucidate similarities and differences among these potentially mimicking conditions. The major histopathological findings of IMNMs were: very frequent necrosis and regeneration of muscle fibres (93%), mild inflammatory component mainly constituted by scattered isolated (65%) CD68-prevalent (68%) cells, without CD8 invading/surrounding non-necrotic fibres, variable expression of MHC-I in non-necrotic fibres (56%) and constant expression of sarcoplasmic p62, confirming those that are widely considered the major histological characteristics of IMNMs. Conversely, only 42% of biopsies showed a sarcolemmal deposition of C5b-9 component. Few differences between SRP and HMGCR IMNMs consisted in more severe necrosis and regeneration in SRP than in HMGCR (p = 0.01); more frequent inflammatory infiltrates (p = 0.007) with perivascular localization (p = 0.01) and clustered expression of MHC-I (p = 0.007) in HMGCR; very low expression of sarcolemmal C5b-9 in SRP (18%) compared to HMGCR (56%) (p = 0.0001). Milder necrosis and regeneration, detection of perifascicular pathology, presence of lymphocytic inflammatory infiltrates and myofibre expression of MxA help to distinguish DM or ASS from IMNM. nIMs can present signs of inflammation at muscle biopsy. Low fibre size variability with overexpression of both MHC-I and II, associated with C5b-9 deposition, could could be observed in CIM, while increased connective tissue should lead to consider MD, or TM in absence of C5b-9 deposition. Nevertheless, these features are not constantly detected and muscle biopsy could not be diriment. For this reason, muscle biopsy should always be critically considered in light of the clinical context before concluding for a definite diagnosis of IMNM, only based on histopathological findings. More rigorous collection and analysis of muscle biopsy is warranted to obtain a higher quality and more homogeneous histopathological data in inflammatory myopathies.

A Case of Pathological Complete Response and Resolution of Dermatomyositis Following Neoadjuvant Chemotherapy in HER2-Positive Early Breast Cancer.

INTRODUCTION: Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) mainly characterized by subacute muscle weakness and skin rash sometimes associated with malignancy. CASE PRESENTATION: A 61-year-old female was admitted to our hospital because of progressive proximal muscular weakness, heliotropic rash and left breast rash. Muscle biopsy findings were consistent with dermatomyositis (DM). A full panel of myositis associated (MAA) and specific antibodies (MSA) revealed the presence of anti-nuclear antibodies (1:160, speckled), Anti-Ro52 and anti TIF1-γ antibodies. A whole body Computed Tomography Scan showed three left mammary nodules and homolateral axillary lymphadenopathy. The breast biopsy confirmed the diagnosis of ductal carcinoma. Patient was initiated to neoadjuvant chemotherapy followed by surgery for cancer, and corticosteroid and intravenous immunoglobulins for DM with a complete resolution of muscle weakness and pathological complete response of breast cancer. Discussion and conclusion. Similar cases in literature are commonly referred to a first-line surgery and the role of neoadjuvant chemotherapy is debatable.

Novel ACTA1 mutation causes late-presenting nemaline myopathy with unusual dark cores.

ACTA1 gene encodes the skeletal muscle alpha-actin, the core of thin filaments of the sarcomere. ACTA1 mutations are responsible of several muscle disorders including nemaline, cores, actin aggregate myopathies and fiber-type disproportion. We report clinical, muscle imaging, histopatological and genetic data of an Italian family carrying a novel ACTA1 mutation. All affected members showed a late-presenting, diffuse muscle weakness with sternocleidomastoideus and temporalis atrophy. Mild dysmorphic features were also detected. The most affected muscles by muscle MRI were rectus abdominis, gluteus minimus, vastus intermedius and both gastrocnemii. Muscle biopsy showed the presence of nemaline bodies with several unusual dark areas at Gomori Trichrome, corresponding to unstructured cores with abundant electrodense material by electron microscopy. The molecular analysis revealed missense variant c.148G>A; p.(Gly50Ser) in the exon 3 of ACTA1, segregating with affected members in the family. We performed a functional essay of fibre contractility showing a higher pCa50 (a measure of the calcium sensitivity of force) of type 1 fibers compared to control subjects' type 1 muscle fibers. Our findings expand the clinico-pathological spectrum of ACTA1-related congenital myopathies and the genetic spectrum of core-rod myopathies.

Immune checkpoint inhibitors (ICIs)-related ocular myositis.

We present extensive clinical, serological, morphological and muscle imaging data of a 66-year-old man with isolated bilateral ptosis and external ophthalmoplegia secondary to Immune checkpoint inhibitors (Pembrolizumab). He had elevated CK level (>5000 UI/L). No facial, bulbar, proximal, distal or axial muscular weakness was observed. Electromyography (EMG) showed myopathic pattern, with spontaneous activity. Myositis specific antibodies and anti-striational antibodies were negative. Cardiac and respiratory functions were preserved. Skeletal muscle MRI was unremarkable, whereas extraocular muscles revealed bilateral hyperintensities in inferior rectus, medial rectus and superior oblique muscles in both T1 and STIR sequences, with mild muscle atrophy. Muscle biopsy showed endomysial inflammatory infiltrates, MHC-1 expression was observed in clusters of non-necrotic cells. CD56 positive cells were observed in perifascicular regions. Patient discontinued Pembrolizumab and received corticosteroid treatment with progressive clinical improvement and CK normalization. Our findings support this clinical entity, suggesting that isolated ocular myositis represents a subgroup of generalised myositis with predominant ocular symptoms.

Muscle involvement in myasthenia gravis: Expanding the clinical spectrum of Myasthenia-Myositis association from a large cohort of patients.

Myastenia-Inflammatory Myopathy (MG-IM) association has been described in less than 50 cases, as isolated reports or in few case series. In most cases, MG and IM onset occur simultaneously even if the overlapping clinical manifestations could lead to delay the diagnosis in the early stage of disease. In these cases, thymic pathology is present in more than 50% of cases. Pathological findings can be consistent of polymyositis (63%), dermatomyositis (25%) or granulomatosis (12%). Accurate clinical manifestations and severity of IM in MG, including muscle specific antibodies (MSA) and muscle MRI, have not been systematically investigated and focal or mild subclinical myositis have not been reported. We observed that focal myositis or asymptomatic CK elevation can also occur in MG. In this review we have also retrospectively re-analyzed the clinical, serological, pathological and muscle imaging data from 13 patients with MG- IM from our cohort of 441 MG patients (2,9%). Clinical onset occurred simultaneously in 10/13 patients, whereas in 2 patients the IM appeared later in MG disease course (range 10-14 years) and conversely in 1 patient MG symptoms occurred later in IM disease course (4 years). Median age at disease onset was 51 year (range 24-73 years) regardless of clinical onset (MG or IM). Median clinical follow-up was 88 months (range 31-237 months). IM was suspected by CK elevation in all patients (ranging 800-3000 UI/L at first detection) and non-fatigable muscle weakness unresponsive to acetylcholinesterase inhibitors. All the patients presented mild to moderate MG symptoms. Three main categories of muscle involvement, sometimes overlapping, were recognizable: distal, proximal and subclinical myositits, leading to three main clinical groups (A,B,C) and two overlapping subgroups (A/B and B/C). Thymus pathology was present in 10/13 patients. Anti-AChR was detected in al all patients associated with anti-Titin and -RyR1 in those patients with thymoma. No MSA, nor MAA antibodies were detected. Muscle biopsy confirmed IM in all patients. In conclusion we redefined the clinical spectrum of muscle involvement in MG-IM association, which represent a continuum among 3 main clinical groups: distal, proximal and subclinical muscle involvement. Minimal muscle involvement and focal myositis could be underestimated among myasthenic patients and early aggressive immunotherapy could be required in focal group.