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The idiopathic inflammatory myopathies (IIM) are acquired muscle diseases characterized by muscle weakness and inflammation on muscle biopsy. Clinicoserologic classifications do not take muscle histology into account to distinguish the subsets of IIM. Our objective was to determine the pathologic features of each serologic subset of IIM and to correlate muscle biopsy results with the clinicoserologic classification defined by Troyanov et al, and with the final diagnoses. We retrospectively studied a cohort of 178 patients with clinicopathologic features suggestive of IIM with the exclusion of inclusion body myositis. At the end of follow-up, 156 of 178 cases were still categorized as IIM: pure dermatomyositis, n = 44; pure polymyositis, n = 14; overlap myositis, n = 68; necrotizing autoimmune myopathy, n = 8; cancer-associated myositis, n = 18; and unclassified IIM, n = 4. The diagnosis of IIM was ruled out in the 22 remaining cases. Pathologic dermatomyositis was the most frequent histologic picture in all serologic subsets of IIM, with the exception of patients with anti-Ku or anti-SRP autoantibodies, suggesting that it supports the histologic diagnosis of pure dermatomyositis, but also myositis of connective tissue diseases and cancer-associated myositis. Unspecified myositis was the second most frequent histologic pattern. It frequently correlated with overlap myositis, especially with anti-Ku or anti-PM-Scl autoantibodies. Pathologic polymyositis was rare and more frequently correlated with myositis mimickers than true polymyositis. The current study shows that clinicoserologic and pathologic data are complementary and must be taken into account when classifying patients with IIM patients. We propose guidelines for diagnosis according to both clinicoserologic and pathologic classifications, to be used in clinical practice.

Objective: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases characterized by chronic inflammation of muscles. We investigated the role of cellular adhesion molecules implicated in the cohesion of endothelial cells in IIM., Methods: In 22 patients with IIM we investigated plasma concentrations of soluble junctional adhesion molecules [platelet-endothelial cell adhesion molecule (sPECAM-1) and sCD146] and cellular adhesion molecules [sP-selectin, sE-selectin, intercellular adhesion molecule (sICAM-1), and vascular cell adhesion molecule (sVCAM-1)] implicated in leukocyte/endothelial cell interactions. Results were compared to a control group. Muscle biopsy samples from 8 out of 22 IIM patients were studied by immunohistochemistry for tissue expression of these molecules and compared to normal muscle samples. PECAM-1 and CD146 expression was also studied using immunoblots from muscle biopsies from 5 patients and 2 controls., Results: We observed distinct patterns of soluble levels and in situ expression between dermatomyositis (DM), polymyositis (PM), and sporadic inclusion body myositis (s-IBM). PM samples showed significantly increased levels of sCD146, sPECAM-1, and s-ICAM1 and increased expression of CD146, CD31, and ICAM-1 in endothelial cells, whereas CD146 and ICAM-1 were also recorded in some muscle fibers. In DM, sE-selectin, sP-selectin, and sPECAM-1 were significantly increased, with abnormal expression of ICAM-1 in endothelial cells and perifascicular muscle fibers. In the small group of s-IBM samples, results were similar to PM, but the only significant increase was the level of sPECAM-1. Immunoblots confirmed increased expression of PECAM-1 and CD146 in all IIM muscles in comparison to controls, with the highest expression in PM and IBM samples., Conclusion: We observed abnormal increases of soluble levels of adhesion molecules implicated in endothelial cell junctions in PM (sCD146, sPECAM-1) and to a lesser extent in DM and s-IBM (sPECAM-1). We conclude that the distinctly different profiles between PM/s-IBM and DM reflect differences in the pathophysiological background of these diseases.

The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by chronic lymphocytic and macrophagic infiltration in muscle. Because the mechanism for recruitment of these cells probably involves chemokines, we focused on the study of the expression pattern of some beta chemokines and receptors because it may provide a basis for selective immunotherapy. The expression of CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL5 (RANTES) and their main receptors (CCR1 and CCR5) was studied by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry in a series of 16 IIM and five controls (four normal muscles and one tonsil). Except for CCL5, strong expression was observed by RT-PCR with all molecules in all IIM subtypes in comparison to control muscle. Immunohistochemistry revealed diffuse CCL4 expression in all vessels in dermatomyositis. In both polymyositis and sporadic inclusion body myositis (s-IBM) it was restricted to vessels in the vicinity of inflammatory exudates. CCL5 expression was low, restricted to a few inflammatory cells in all IIM; CCR1 expression was mainly restricted to macrophages and s-IBM endothelial cells, whereas CCR5 was localized in inflammatory cells invading non-necrotic muscle fibres. Expressions of both receptors were also recorded in few muscle fibres. In conclusion, the upregulation of beta chemokines and receptors in IIM and their differential expression by various cells may contribute to chronic inflammation and to the peculiar distribution of inflammatory exudates in these diseases.

Two cases are described of pseudotumoral calf hypertrophy after laminectomy for a compressive S-1 radiculopathy. The serum creatine kinase (CK) level was normal or mildly elevated. T2-weighted magnetic resonance imaging (MRI) showed calf enlargement, with an increased signal of the medial head of the gastrocnemius muscle. Electromyography revealed fibrillation potentials and positive sharp waves, but no complex repetitive discharges in the affected gastrocnemius muscle, with motor unit potentials having mixed neurogenic and myopathic features. Muscle biopsy revealed a focal myositis associated with some features of denervation. A brief course of corticosteroids was followed by remission clinically and improvement in the MRI findings.

The inflammatory myopathies include dermatomyositis (DM), polymyositis (PM), and sporadic inclusion-body myositis (s-IBM). In DM, the main immune effector response appears to be humoral and directed against the microvasculature, whereas in both PM and s-IBM, cytotoxic CD8+ T cells and macrophages invade and eventually destroy nonnecrotic muscle fibers expressing major histocompatibility complex class I. The need for more specific and safer therapies in inflammatory myopathies has prompted researchers to better decipher the molecular events associated with inflammation and muscle fiber loss in these diseases. The complex specific migration of leukocyte subsets to target tissues requires a coordinated series of events, namely activation of leukocytes, adhesion to the vascular endothelium, and migration. Cell adhesion molecules (CAM) and chemokines play a major role in this multistep process. In addition, cytokines by stimulating CAM expression and orchestrating T-cell differentiation also influence the immune response. This review focuses on recent advances in defining the molecular events involved in leukocyte trafficking in inflammatory myopathies. Specific topics include a concise summary of clinical features, pathological findings and immunopathology observed in inflammatory myopathies, background information about cytokines, chemokines and cell adhesion molecules, and the expression of these molecules in inflammatory myopathies.

Macrophagic myofasciitis (MMF) is an emerging condition of unknown cause, detected in patients with diffuse arthromyalgias and fatigue, and characterized by muscle infiltration by granular periodic acid-Schiff's reagent-positive macrophages and lymphocytes. Intracytoplasmic inclusions have been observed in macrophages of some patients. To assess their significance, electron microscopy was performed in 40 consecutive cases and chemical analysis was done by microanalysis and atomic absorption spectrometry. Inclusions were constantly detected and corresponded to aluminium hydroxide, an immunostimulatory compound frequently used as a vaccine adjuvant. A lymphocytic component was constantly observed in MMF lesions. Serological tests were compatible with exposure to aluminium hydroxide-containing vaccines. History analysis revealed that 50 out of 50 patients had received vaccines against hepatitis B virus (86%), hepatitis A virus (19%) or tetanus toxoid (58%), 3-96 months (median 36 months) before biopsy. Diffuse myalgias were more frequent in patients with than without an MMF lesion at deltoid muscle biopsy (P < 0.0001). Myalgia onset was subsequent to the vaccination (median 11 months) in 94% of patients. MMF lesion was experimentally reproduced in rats. We conclude that the MMF lesion is secondary to intramuscular injection of aluminium hydroxide-containing vaccines, shows both long-term persistence of aluminium hydroxide and an ongoing local immune reaction, and is detected in patients with systemic symptoms which appeared subsequently to vaccination.

Purpose: A new type of inflammatory myopathy of unknown etiology has recently been described in France. The myopathy, called macrophagic myofasciitis, had never been described in the literature., Methods: In December 1998, 35 cases of macrophagic myofasciitis were reported, showing an increase in its incidence since the description of the first case in 1993. The first 22 cases are described., Results: The 22 patients were each referred with a presumptive diagnosis of either polymyositis (11 patients), polymyalgia rheumatica (5 patients), mitochondrial cytopathy (4 patients), or congenital myopathy or muscle dystrophy (1 patient for each). Clinical symptoms included myalgias (91%), arthralgias (68%), marked asthenia (55%), muscle weakness (45%), and fever (32%). Laboratory findings included elevated CK levels (50%) and a marked increased in the erythrocyte sedimentation rate (37%). Electromyographic recordings showed the existence of myopathy (35%). Muscle biopsy showed a unique pattern characterized by: (i) centripetal infiltration of the epimysium, perimysium and perifascicular endomysium by non epitheloid, cells of the monocyte/macrophage lineage (CD68+, CD1a-, S100-) with both large cytoplasm and PAS-positive content; (ii) absence of necrosis, of both epithelioid and giant cells, and of mitotic figures; (iii) occasional CD8+ T-cells; and, (iiii) minimal myocyte suffering. The disease symptoms were easily distinguishable from those of sarcoid myopathy and fasciitis-panniculitis syndromes. Infectious diseases known to be associated with reactive histiocytosis, including Whipple's disease, Mycobacterium avium intracellulare infection and malakoplakia, could not be documented. Patients' condition improved under corticosteroid therapy, associated or not with non-specific antibiotic therapy., Conclusion: A new inflammatory muscle disorder of unknown etiology, characterized by a distinctive pathological pattern of macrophagic myofasciitis, is emerging in France. Diagnosis is based on muscular biopsy. Numerous clinical, epidemiological and etiopathologic studies initiated by the GERMMAD (Groupe d'études et de recherche sur les maladies musculaires acquises) are in progress.

The idiopathic inflammatory myopathies (IIM), including dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM), are a group of autoimmune diseases characterized by the recruitment of lymphocytes and monocytes to the site of affection. The mechanism for recruitment of these cells likely involves chemokines. The monocyte chemoattractant protein-1 (MCP-1), a chemoattractant to T lymphocytes and monocytes, may play an important role in the pathogenesis of IIM. Frozen muscular tissues were obtained from eight cases of DM, five PM, and four IBM. We investigated the MCP-1 expression by the reverse transcription-PCR technique, immunohistochemistry and in situ hybridization. MCP-1 mRNA was markedly expressed in all the IIM cases. Greater amounts of MCP-1 mRNA were observed in DM, and in situ hybridization showed MCP-1 mRNA accumulation in perivascular mononuclear cells. Immunohistochemistry showed MCP-1 expression in vessels (endothelial cells and walls of veins and arteries) in all IIM cases. Very few mononuclear cells in DM perivascular infiltrates expressed MCP-1, whereas in PM and IBM, it was strongly expressed by mononuclear cells partially invading non-necrotic muscle fibers. These findings suggest that MCP-1 can contribute to the inflammatory response by attracting monocytes and T lymphocytes to sites of cell-mediated immune injury. The morphological characteristics and distribution of positive cells indicate that macrophages, lymphocytes, and endothelial cells previously reported to produce MCP-1, contribute to its production in IIM lesions.

We investigated the immunohistochemical expression of endothelial cell adhesion molecules in 17 cases of idiopathic inflammatory myopathies. The present study revealed: 1) a constitutive expression of ICAM-1, ICAM-2 and PECAM-1, but not VCAM-1, LFA-3 and E-selectin, on endothelial cells in normal muscles; 2) a modification of cell adhesion molecules expression in idiopathic inflammatory myopathies with an increased expression of the expressed molecules constitutively; an expression of LFA-3 and VCAM-1 on capillary endothelial cells in polymyositis/inclusion body myositis, these molecules being only observed on endothelial cells of some arterioles in dermatomyositis; 3) an expression of all these molecules on inflammatory cells in inflammatory myopathies. In dermatomyositis, the expression of ICAM-1 and VCAM-1, predominated on mononuclear cells located near vessels. In polymyositis/inclusion body myositis, a strong expression of ICAM-1, VCAM-1 and LFA-3 was present on inflammatory cells invading non necrotic muscle fibers; 4) absence of E-selectin on endothelial and inflammatory cells in all cases.

Background: An unusual inflammatory myopathy characterised by an infiltration of non-epithelioid histiocytic cells has been recorded with increasing frequency in the past 5 years in France. We reassessed some of these cases., Methods: We did a retrospective analysis of 18 such cases seen in five myopathology centres between May, 1993, and December, 1997. The myopathological changes were reassessed at a clinopathology seminar., Findings: Detailed clinical information was available for 14 patients. The main presumptive diagnoses were polymyositis and polymyalgia rheumatica. Symptoms included myalgias in 12 patients, arthralgias in nine, muscle weakness in six, pronounced asthenia in five, and fever in four. Abnormal laboratory findings were occasionally observed, and included raised creatine kinase concentrations, increased erythrocyte sedimentation rate, and myopathic electromyography. Muscle biopsy showed infiltration of the subcutaneous tissue, epimysium, perimysium, and perifascicular endomysium by sheets of large macrophages, with a finely granular PAS-positive content. Also present were occasional CD8 T cells, and inconspicuous muscle-fibre damage. Epithelioid and giant cells, necrosis, and mitotic figures were not seen. The images were easily distinguishable from sarcoid myopathy and fasciitis-panniculitis syndromes. Whipple's disease, Mycobacterium avium intracellulare infection, and malakoplakia could not be confirmed. Ten patients were treated with various combinations of steroids and antibiotics; symptoms improved in eight patients, and stabilised in two., Interpretation: A new inflammatory muscle disorder of unknown cause, characterised by a distinctive pathological pattern of macrophagic myofasciitis, is emerging in France.

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-1 beta, IL-6, TNF-alpha), Th1 (IFN-gamma IL-2), and Th2 (IL-4) cytokines. Immunohistochemistry was also used to localize morphologically IFN-gamma 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.

Histologic and biochemical anomalies of muscle mitochondria were identified in four patients with predominantly rhizomelic myalgia clinically suggestive of an inflammatory disease but inconsistent biologic evidence of inflammation. This clinical pattern was initially suggestive of atypical polymyalgia rheumatica and could not be ascribed to any other disease. To explain this combination of anomalies, several hypotheses can be put forward, including coincidence, aging, and nonspecific mitochondrial anomalies resulting from immunologic or inflammatory disease. The speculation that these patients have an autonomous syndrome cannot be outruled but should be considered with caution. A therapeutic trial with coenzyme Q is under way.

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.

Several groups of cases of fasciitis and myositis with eosinophilia are reported. The common features are inflammation into fascia and/or perimysium, and/or muscle fibers; eosinophilia in blood and/or in muscle biopsy. The following classification of 24 cases is suggested: at one end of the spectrum are fasciitis with eosinophilia: diffuse fasciitis (Shulman syndrome): 10 cases (3 with hematological complications); 2 cases of diffuse fasciitis with muscle atrophy; 3 cases of restricted fasciitis. Relapsing perimyositis with eosinophilia belong to the same spectrum, either diffuse (5 cases) with myalgias, or localized (2 cases). Other cases are focal myositis or multiple myositis, polymyositis with eosinophilia. The relationship among these cases is discussed. There is a continuum among the different groups. The pathophysiology remains unknown.

Histological and electrophysiological features in cases of inclusion body myositis are often difficult to interpret, suggesting either a "myogenic" or a "neurogenic" disorder. One case of inclusion body myositis is described. Conventional needle electromyography recording was interpreted as "neurogenic": abundant fibrillation potentials and positive sharp waves, reduced interference pattern, polyphasic-high amplitude-long duration motor unit potentials. Macro-EMG was performed in quadriceps muscle. Fibre density was normal and median value of the amplitude of macro motor unit potentials was increased, suggesting a larger size of motor units. Morphologic and electrophysiologic features indicate compensatory and regeneration mechanisms resulting in an increase of motor unit during the course of inclusion body myositis. This can explain atypical electromyographic and morphologic data in this disease.

Inclusion body myositis is now a well-known disease but its incidence is underestimated. We report 12 cases with clinical heterogeneity. Three groups of patients could be described. The first one corresponded to asymmetrical muscle involvement and distribution with a slow clinical course (4 cases). The second was characterized by a polymyositis-like syndrome (3 cas), but steroid therapy was ineffective. The last group mimicked a chronic spinal muscular atrophy (4 cases). One patient showed a scapuloperoneal syndrome. Both myopathic and neurogenic EMG patterns were present in 6 patients; a neurogenic pattern was found in 4 cases and a myopathic pattern in 2 cases. In all patients, muscle biopsies showed rimmed vacuoles with eosinophilic inclusions. In 9 cases ultrastructural studies displayed abnormal filaments of 15-18 nm in diameter in the vacuoles. Intranuclear filaments were rarely observed. The significance of the filaments is unknown and their specificity is doubtful because they are present in other myopathies with rimmed vacuoles (some distal myopathies and oculopharyngeal muscular dystrophies). Finally a rich inflammatory exudate was present in 8 patients only.

Two patients with a syndrome of relapsing myalgia are described. In both cases nonspecific inflammatory features were present and electromyography disclosed a myositic pattern in one. Muscle biopsy in both patients showed a perimysial infiltrate of eosinophils although peripheral eosinophilia was only noted in one patient. In each, relapse occurred after a recovery phase, but eventually recovery was complete, spontaneously in one, and after therapy in the other. The known causes of eosinophilic myositis are reviewed, with emphasis on a companion with the myositis of eosinophilic fascitis (Shulman's syndrome). Because our cases exhibited distinctive features, this new syndrome should be considered in the differential diagnosis of any eosinophilic myositis.

A 49-year old man developed myositis of the left masticatory muscles followed by myositis of the right supinator longus; these two lesions were histologically confirmed. Blood and bone marrow eosinophilia was present. Cure was obtained with systemic corticosteroids. Only one similar case was found in the literature. These cases differ from the various localized or focal forms of myositis as well as from eosinophilic polymyositis. Despite some similarities with masseteric myopathies in animals, no hypothesis can be formulated concerning the cause of the disease.

Childhood polymyositis is generally believed to exhibit specific characteristics including involvement of multiple systems, absence of malignancies, severe outcome, cortico-resistance, perforations of the bowel, and inflammatory vasculitis. On the basis of our experience with 23 cases and a review of the literature, we divide childhood polymyositis into five groups: 1) Severe acute dermatomyositis (11 cases) that fits the description above; 2) subacute or chronic polymyositis (4 cases) that resembles the chronic forms seen in adults; 3) infantile polymyositis (3 cases) whose inflammatory origin has not been proved and whose cause may be dystrophic; 4) inclusion polymyositis (2 cases) that are identical with adulthood inclusion myositis; 5) segmentary polymyositis (3 cases). Thus, in children as in adults, polymyositis remains an obscure disease and is a syndrome rather than an entity.

The inflammatory forms of facioscapulohumeral myopathies are rare. In a series of 52 cases, six patients had these types. Only four cases could be investigated with immunochemical staining (immunoperoxidase). Monoclonal antibodies reactive for B cells, T4 cells, T8 cells, natural killer cells were used for cell typing. Macrophages were identified by the acid phosphatase reaction. Nine muscles have been used as controls: 3 normal muscles, 3 polymyositis and 3 dermatomyositis. In all these inflammatory myopathies T cells were the most abundant cells. NK cells were rare. In inflammatory FSH-D and in polymyositis the infiltrates were principally endomysial, whereas T8 lymphocytes were more abundant than T4 lymphocytes; it was the contrary in the perivascular and perimysial sites of accumulation. In dermatomyositis the infiltrates were especially perivascular. In this site of accumulation T4 was twice abundant than T8, B cells and macrophages were also very abundant. In the endomysium the T8 cells were more numerous than T4 cells. It seems that the inflammatory forms of FSH-D should be considered as an inflammatory myopathy. In these forms a polymyositis should be associated with the dystrophy. These forms could be considered as an association of a polymyositis and a muscular dystrophy, but the circumstances of their appearance and their non-response to corticosteroid administration remain to be determined.

Three cases with eosinophilic infiltration of fascia and muscle are described. In every case at least one relapse occurred. One patient exhibited clinically the definite features of eosinophilic fasciitis. About two cases a tentative diagnosis of Shulman's syndrome is discussed. In these patients, all known causes of eosinophilic myositis had been excluded.

The classification of 135 patients with either dermatomyositis (DM) or polymyositis (PM) showed 34 cases of DM and 56 cases of PM in adults, 6 cases of DM associated with cancer, 9 cases of DM in children, 16 cases of localized PM and 14 cases of an overlapping syndrome. Results of biological tests, erythrocyte sedimentation rate and serum enzyme determinations were inconstantly abnormal. The electromyograms were generally of a myogenic type with spontaneous activity in about half the cases. Muscle biopsy usually showed inflammation necrosis and regeneration, sometimes only of moderate severity only. Results were normal in several cases. In 21 patients only the pathognomonic perifascicular atrophy was reported. Proposed classifications are unsatisfactory. Polymyositis may be considered as a syndrome. Among the primary forms the distinction between acute dermatomyositis and subacute or chronic polymyositis is poorly defined and passage from one disorder to another is frequent. Pseudo-myasthenic forms are not entities and pseudo-myopathic types are actually muscular dystrophies. Associations with polymyositis are common and may consist only in the addition of one sign of no clinical significance (PM "plus"). The polymyositis lesion may be part of a syndrome such as Gougerot-Sjögren's or of another connective tissue disease. A system of diagnostic criteria uses numerical ratings of each criterion as a function of its semiologic importance.