Clinical and serological characteristics of 125 Dutch myositis patients

The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of systemic diseases that include the familiar disease entities of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). A subset of patients has unique autoantibodies which are specific for IIM (myositis specific autoantibodies; MSAs). We studied the clinical and serological characteristics of IIM in 125 Dutch patients. Sera were analysed by immunoblotting, enzyme-linked immunosorbent assay, and immunoprecipitation. The most frequently encountered MSA was the anti-Jo-1 autoantibody (20%), followed by anti-tRNAHis (6%), anti-Mi-2 (6%), and anti-SRP (4%). The presence of certain MSAs was clearly associated with specific clinical characteristics. Anti-Jo-1 and anti-tRNAHis were associated with the anti-synthetase syndrome, anti-SRP with PM with severe myalgia and arthralgia and a moderate response to immunosuppressive treatment. A novel finding was the presence of anti-Mi-2, not only in DM, but also in PM. MSAs were frequently present in DM/PM sera, but were hardly ever detected in the sera of IBM patients. The few IBM patients with MSAs demonstrated a significant response to immunosuppressive treatment. It can be concluded that MSAs define specific clinical syndromes within the spectrum of IIM and that they can assist in the differential diagnosis and treatment plan of these enigmatic disorders by virtually excluding IBM by their presence, and by potentially identifying a subgroup of steroid-responsive IBM patients.     

Local expression of cytokines in idiopathic inflammatory myopathies

H. Lepidi, V. Frances, D. Figarella-Branger, C. Bartoli, A. Machado-Baeta & J-F. Pellissier (1998) Neuropathology and Applied Biology , 24, 73–79
Local expression of cytokines in idiopathic inflammatory myopathies
The idiopathic inflammatory myopathies (IIM), including dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM), are regarded as autoimmune diseases. They are characterized by chronic lymphocytic and macrophagic infiltration in muscle tissue. Of particular importance in understanding the immune response to IIM is the specific pattern of locally produced cytokines. Frozen muscle tissues from IIM (5 DM, 3 PM, and 1 IBM) were used to investigate the cytokine responses. The RT-PCR technique was instrumental to determine the pattern of expression of pro-inflammatory (IL-1β, IL-6, TNF-α), Th1 (IFN-γ IL-2), and Th2 (IL-4) cytokines. Immunohistochemistry was also used to localize morphologically IFN-γ and IL-4. Our results show that pro-inflammatory cytokines and Th1 cytokines are mainly expressed in IIM. The accumulation of mononuclear inflammatory cells and the inflammatory syndrome in IIM are probably related in part to the production of pro-inflammatory cytokines. Moreover, the pattern of local cytokine expression is consistent with a Th1 immune response related to autoimmune diseases.     

Changes in CSF acetyl- and butyrylcholinesterase activity after long-term treatment with AChE inhibitors in Alzheimer's disease

Jain A, Sharma MC, Sarkar C, Bhatia R, Singh S, Gulati S, Handa R. Detection of the membrane attack complex as a diagnostic tool in dermatomyositis.
Acta Neurol Scand: 2011: 123: 122–129.
© 2010 John Wiley & Sons A/S. Background – Currently there is no reliable diagnostic marker to distinguish between the subgroups of idiopathic inflammatory myopathies (IIMs), i.e. dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). Membrane attack complex (MAC) has been shown to be involved in the pathogenesis of dermatomyositis but its role as a diagnostic marker has not been evaluated. Aim – To assess the diagnostic utility of MAC deposition in distinguishing dermatomyositis from other neuromuscular disorders. Material and methods – Immunohistochemical detection of MAC deposition on endomysial microvessels was carried out on 127 muscle biopsies comprising of 21 cases of dermatomyositis, 42 other IIMs and 64 non‐IIM neuromuscular diseases. Results – MAC deposition showed a high sensitivity (80.9%) and specificity (85%) to differentiate DM from other IIMs. Its specificity was higher (98.4%) in discriminating DM from non‐IIM muscular diseases and IIM from non‐IIMs. Conclusion – MAC deposition can serve as a reliable marker to distinguish DM from other IIMs (i.e. PM and IBM) as well as from non‐IIM diseases. It can also serve as a useful adjunct in diagnosis of IIMs when there is diagnostic dilemma with their morphologic similarities. These results provide further credence to the long‐standing view that MAC‐mediated capillary destruction is involved in the immunopathogenesis of DM.     

Targeted immunotherapy trials for idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies (IIM) are a group of muscle diseases with complex immunopathogenesis that varies between disease subgroups, and possibly between patients within the same subgroup. There exists no universal consensus on optimum management, so that no “standard” therapy has been developed. Treatment-refractive IIM remains a clinical challenge. Progress in the development and application of molecular biology techniques and biological therapeutics are evolving into a new scientific frontier in the management of autoimmune diseases. This review offers an update on those components of the humoral and cellular immunity deemed potential targets for biological therapeutics (monoclonal antibodies and fusion proteins) that have been approved by the US FDA for treatment of immunological disorders. A futuristic approach is envisioned in which each individual will receive targeted therapy tailored to patient-specific immune mechanisms. Risk–benefit and cost analyses should determine whether such targeted therapy is appropriate and feasible for refractive and/or newly diagnosed disease.     

Inclusion body myositis: clinical, morphological, physiological and laboratory findings in 18 cases

Eighteen consecutive patients with inclusion body myositis (IBM) were studied. The mean age of onset of symptoms was 60 years. A typical clinical pattern with insidious onset of muscle weakness in knee extensors and finger flexors combined with dysphagia was observed. Serial measurements of the maximal voluntary muscle strength revealed a mean loss of muscle strength of 1.4% per month. Two of the cases had common variable immunodeficiency, and three cases had reduced levels of the IgG3 subclass. Treatment with prednisone resulted in a temporary improvement of muscle function in three patients. No positive effect of azathioprine or cyclosporine A could be documented. The results show that IBM may be associated with immunodeficiency, and that prednisone treatment may temporarily improve the clinical signs. The results from our studies on the progression of the muscle weakness may provide basis for future studies on treatment of IBM.     

Inflammatory muscle diseases

The three major immune-mediated inflammatory myopathies, dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM), each have their own distinctive clinical features, underlying pathogenetic mechanisms and patterns of muscle gene expression. In DM a complement-dependent humoral process thought to be initiated by antibodies to endothelial cells results in a microangiopathy with secondary ischemic changes in muscles. On the other hand, in PM and IBM there is a T-cell response with invasion of muscle fibers by CD8+ lymphocytes and perforin-mediated cytotoxic necrosis. In IBM degenerative changes are also a feature and comprise autophagia with rimmed vacuole formation and inclusions containing beta-amyloid and other proteins whose accumulation may be linked to impaired proteasomal function. The relationship between the inflammatory and degenerative component remains unclear, as does the basis for the selective vulnerability of certain muscles and the resistance to conventional forms of immunotherapy in most cases of IBM. Patients with DM or PM usually respond to treatment with glucocorticoids and immunosuppressive agents but their use remains largely empirical. Intravenous immunoglobulin therapy can be used to achieve disease control in patients with severe weakness or dysphagia, or in patients with immunodeficiency, but its use is limited by expense. Emerging therapies for resistant cases include TNFalpha inhibitors (etanercept, infliximab) and monoclonal antibodies (rituximab, alemtuzumab). However, experience with these therapies is still limited and there is a need for randomized trials to test their efficacy and establish guidelines for their use in clinical practice.     

Myositis specific autoantibodies as a new diagnostic criterion for idiopathic inflammatory myopathies

Myositis specific autoantibodies (MSA) are the most specific diagnostic criteria for idiopathic inflammatory myopathies (IIM). There is no evidence of MSA presence in patients with other neuromuscular or connective tissue diseases. MSA are associated with homogeneous clinical syndromes: antisynthetases with antisynthetase syndrome, anti-SRP with severe, resistant to treatment myositis, anti-Mi-2 with classic, benign dermatomyositis. Therefore it is important to include the myositis specific antibodies into routine diagnostic scheme of IIM.     

Clinical and histological features of immune-mediated necrotising myopathy: A multi-centre South Australian cohort study

Immune-mediated necrotising myopathy (IMNM) is a recently described entity. We describe a cohort of South Australian IMNM patients in order to define the spectrum of disease, characterise features that distinguish IMNM from other idiopathic inflammatory myopathy (IIM) subtypes and identify factors associated with clinically severe disease. Subjects were identified from the South Australian Myositis Database (SAMD), a histologically defined registry. Consecutive muscle sections from patients with IMNM (n = 62), other forms of IIM (n = 60) and histologically normal muscle (n = 17) were stained using immunohistochemistry and graded. Clinical information was collected from the SAMD and through retrospective chart review. IMNM patients displayed clinical and histological heterogeneity. While most (67%) were profoundly weak at presentation, 24% exhibited mild to moderate weakness and 9% had normal power. Histological myonecrosis ranged from minor to florid. The amount of myofibre complement deposition was closely associated with clinical severity. Patients of Aboriginal and Torres Strait Islander heritage and those with anti-SRP autoantibodies present with a severe phenotype. Despite intense immunotherapy, few IMNM patients recovered full power at one year follow up. The identification of clinical, serological and histological features which are associated with severe forms of the disease may have diagnostic and therapeutic utility.     

Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies

BACKGROUND: Identification of mononuclear cellular infiltrates in skeletal muscle tissue is the histological cornerstone of the diagnosis of idiopathic inflammatory myopathy (IIM). However, these infiltrates are not always present. OBJECTIVE: To determine whether MHC class I antigen expression on the sarcolemma, which is absent in normal muscle tissue, is upregulated in IIM and could serve as an additional diagnostic test. METHODS: Expression of MHC class I antigens was studied in 224 muscle samples of 61 adult patients with IIM (9 dermatomyositis, 23 polymyositis, 29 inclusion body myositis) and 163 controls (normal subjects and patients with various neuromuscular disorders) in a prospective blinded manner. RESULTS: The sensitivity of the test for diagnosing IIM was 78% (95% confidence interval (CI), 66% to 88%), with a specificity of 95% (91% to 98%). The sensitivity before the start of immunosuppressive treatment was 89% (76% to 96%). The sensitivity was not changed by including all patients who had been on immunosuppressive treatment for less than four weeks before muscle biopsy (sensitivity 90% (79% to 97%)). False positive results were found in only seven controls (4%), six of whom had a muscular dystrophy. CONCLUSIONS: Detection of sarcolemmal MHC class I is a valid test for IIM. It is not affected by the short term use of immunosuppressive agents (less than four weeks) and it should be incorporated in the histological evaluation when the diagnosis of IIM is under consideration or needs to be excluded.     

包涵体肌炎的临床与病理特点(附2例报告)

目的 探讨包涵体肌炎的临床与病理特点。方法 对2例包涵体肌炎患者的临床表现、肌肉组织化学、酶组织化学和超微结构等资料进行分析。结果 本组2例患者分别于41岁及54岁发病,均以双下肢无力起病,远端重于近端,并逐渐向上肢发展;血清肌酶轻～中度升高;肌电图示肌源性损害;肌肉活检光镜下主要表现为肌纤维内出现镶边空泡,少数变性坏死纤维,伴炎性细胞浸润。电镜观察证实肌浆内有大量涡轮状髓样小体及管状细丝包涵体。结论 包涵体肌炎临床表现缺乏特异性,肌肉病理学检查是诊断包涵体肌炎的重要手段。     

Clinical, immunopathologic, and therapeutic considerations of inflammatory myopathies.

The inflammatory myopathies encompass a group of heterogenous muscle diseases which have in common an acquired myopathy with histological signs of endomysial inflammation. We present evidence based on recently emerged clinical, histologic, immunopathologic, demographic and therapeutic observations that these myopathies comprise three major and distinct groups: polymyositis (PM), dermatomyositis (DM), and inclusion-body myositis (IBM). Immune-mediated mechanisms characteristic for each group appear to play a primary role in the pathogenesis of these diseases. In DM there is an intramuscular microangiopathy mediated by the C5b-9 membranolytic attack complex, leading sequentially to loss of capillaries, muscle ischemia, muscle fiber necrosis and perifascicular atrophy. In contrast, in PM and IBM the muscle fiber injury is initiated by sensitized CD8+ cytotoxic T cells that recognize MHC-I restricted muscle antigens, leading to phagocytosis and fiber necrosis. Among the viruses implicated in the cause of inflammatory myopathies, only the retroviruses, HIV, HTLV-1 and simian retroviruses, have been convincingly associated with PM. Retroviruses, therefore, appear to be the leading group of viruses capable of triggering these diseases. The treatment of inflammatory myopathies has been largely empirical. A detailed therapeutic plan based on our experience with a large number of patients is presented. Patients with bona fide PM or DM respond to steroids to some degree and for some period of time. In contrast, patients with IBM do not respond to any therapy and the disease should be suspected when a patient with presumed PM has failed treatment. Methotrexate and cyclophosphamide are disappointing. Cyclosporine and Azathioprine are commonly used but they are of uncertain benefit. Plasmapheresis is ineffective. High-dose intravenous immunoglobulin is a promising new therapeutic modality.     

Valosin containing protein associated fronto-temporal lobar degeneration: clinical presentation, pathologic features and pathogenesis

Inclusion body myopathy (IBM) associated with paget's disease of the bone (PDB) and fronto-temporal dementia (FTD) or IBMPFD, is a rare multisystem degenerative disorder due to mutations in valosin containing protein (VCP). VCP is a ubiquitously expressed protein that facilitates the degradation of proteins via the ubiquitin proteasome and autophagy pathways. Affected brain and muscle tissue in IBMPFD have ubiquitinated and TAR DNA binding protein-43 (TDP-43) inclusions. In skeletal muscle, this pathology is consistent with IBM. While in the CNS, IBMPFD is a frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) subtype. Recent studies suggest that IBMPFD mutations in VCP disrupt its function in protein degradation. This review will explore the clinical phenotype and pathology of IBMPFD with an emphasis on central nervous system degeneration. In addition, we will discuss the current understanding regarding VCP's function in terminally differentiated tissue and how disease associated mutations result in both myo- and neurodegeneration.     

Combining MRI and muscle biopsy improves diagnostic accuracy in subacute‐onset idiopathic inflammatory myopathy

Introduction: In 10–20% of patients with subacute‐onset idiopathic inflammatory myopathy (IIM), muscle biopsy is normal or shows nonspecific findings. MRI can be used as a triage test before muscle biopsy and as an add‐on test if the biopsy is nondiagnostic. Methods: MRI scans of skeletal muscles and muscle biopsies were evaluated prospectively in 48 patients suspected to have IIM. The interpretations of MRI and muscle biopsy were compared with the definite diagnosis (based on European Neuromuscular Centre criteria and response to corticosteroids). Results: The false negative rate (FNR) of all muscle biopsies was 0.23. Biopsies of a muscle showing hyperintensity on MRI (as triage test) had an FNR of 0.19. The result of MRI as an add‐on test in patients with a nondiagnostic muscle biopsy decreased the FNR from 0.23 to 0.06. Conclusions: We recommend both MRI and muscle biopsy in patients suspected of having IIM. Muscle Nerve 51 : 253–258, 2015     

Syrian hamster infected with Leishmania infantum: A new experimental model for inflammatory myopathies

Idiopathic inflammatory myopathies (IIMs) are inflammatory disorders of unknown origin. On the basis of clinical, histopathological, and immunological features, they can be differentiated into three major and distinct subsets: dermatomyositis; polymyositis; and inclusion‐body myositis. Although a few animal models for IIM are currently available, they lack several characteristic aspects of IIMs. The aim of our study was to examine skeletal muscle involvement in an experimental animal model of visceral leishmaniasis, a disseminated infection caused by the protozoan parasite Leishmania infantum, and to compare features of associated inflammation with those of human IIM. Syrian hamsters infected intraperitoneally with amastigotes of L. infantum were killed at 3 or 4 months post‐infection, and the skeletal muscles were studied. Focal inflammation was predominantly observed in the endomysium and, to a lesser extent, in perivascular areas. Degenerating muscle fibers were also found, as well as myonecrosis. Immunofluorescence with confocal laser scanning microscopy was used to characterize the phenotype of inflammatory infiltrates and the distribution of MHC class I and II in muscle biopsies. The infiltrating inflammatory cells consisted mainly of T cells, and CD8⁺ T cells were found in non‐necrotic muscle fibers that expressed MHC class I on the sarcolemma. In addition to T cells, several macrophages were present. The model we are proposing closely resembles polymyositis and may be useful in studying certain aspects of this disease such as the role of T cells in muscle inflammation and myocytotoxicity, while also providing novel therapeutic targets. Muscle Nerve, 2009     

Inclusion body myositis and neuromuscular diseases with rimmed vacuoles]

A retrospective study of 40 patients with various neuromuscular disorders and more than 3 muscle fibers with rimmed vacuoles has been performed. Two subgroups of patients were distinguished according to the presence or absence of inflammatory exudates. In the first group (14 patients), inflammatory exudates were observed and numerous fibers showed partial invasion. Abnormal filamentous inclusions (16-18 nm in diameter) were found by electron microscopy in muscle fibers cytoplasm and/or nuclei. The diagnosis of inclusion body myositis (IBM) was made in these cases. They presented with insidious proximal muscle weakness and were not improved by immunosuppressive therapy. Immunohistological studies demonstrated T lymphocytes predominance, only few natural killer and B lymphocytes. The number of T8 lymphocytes was high in endomysial sites while T4 were more numerous in perivascular exudates. Abnormal membranous expression of class I MHC antigens was observed on muscle fibers lying near the inflammatory exudates. In the second group of cases (26 patients), no inflammatory exudate was observed. This group of neuromuscular diseases with rimmed vacuoles was heterogeneous. In 10 cases, abnormal filamentous inclusions (16-18 nm in diameter) were observed in rimmed vacuoles. However, this ultrastructural feature did not help in distinguishing subgroups. Various neuromuscular disorders were observed in this group: oculopharyngeal muscular dystrophy (12 cases with IBM like filaments in 4 cases), chronic spinal atrophy (5 cases with IBM like filaments in 3 cases), post poliomyelitis syndrome (2 cases with IBM-like filaments in one), muscle glycogenosis with IBM like filaments (2 cases), hereditary limb girdle myopathy or distal myopathy (3 cases) and 1 patient clinically presenting with polymyositis and another with cramps and myalgias. No abnormal sarcolemmal expression of class I MHC was found in this group. The pathogenesis of IBM is discussed. Besides T cell mediated cytotoxicity, denervation may be involved. The nature of the abnormal 16-18 nm filamentous inclusions remains unknown. These filaments are not IBM specific.