Neuromuscular Disorders

Updated 04.16.2023
Released 03.11.1994
Expires For CME 04.16.2026

Polymyositis, necrotizing autoimmune myositis, myofasciitis, and overlap-myositis

Author: Marinos C Dalakas MD

Editor: Michael K Hehir MD

Introduction

Historical note and terminology

Although first recorded by Wagner in 1863 (150), polymyositis became a recognized clinical entity 75 years later when Walton and Adams published a remarkable monograph titled Polymyositis (151). These authors defined the term “polymyositis” as an all-inclusive designation of a group of myopathies characterized by a single basic disease process related to "other collagen" diseases or arising as the result of "hypersensitivity response to allergic inflammation." Today, described by neurologists as a neuromuscular disorder, polymyositis is cared for not only by neurologists but also by rheumatologists, who approach the illness as in a setting of other rheumatic diseases. Polymyositis is a rare disorder that, by all accounts, is the most overdiagnosed acquired myopathy and, although now unclear whether it exists as a distinct entity, it is discussed not only for historical reasons but also because it is still diagnosed by various practitioners. Although this author believes that it does not exist as a single entity, the evolution and now almost extinction of what was considered as polymyositis 3 to 4 decades ago, has taught us a lot about muscle immunopathology. It is discussed here in the context of two similar but now distinct and more frequent entities, which have evolved in the last two decades, namely necrotizing autoimmune myositis and overlap myositis, while emphasizing its distinction from inclusion body myositis.

The study of polymyositis requires a scholarly review of the neurologic examination, muscle histopathology, immunopathology, and biochemistry to ensure that toxic, metabolic, or mitochondrial muscle diseases are not missed and that the two more common entities, the inclusion body myositis and the necrotizing autoimmune myositis, are not overlooked (12; 73; 29; 30; 36; 37; 39; 46; 47; 49; 132; 40; 114; 46; 46).

Clinical manifestations

Presentation and course

Polymyositis, as traditionally had been viewed and with the reservations discussed above, has no unique clinical features, and its diagnosis is one of exclusion (29; 30; 36; 37; 39; 49; 132; 40; 46). Polymyositis is best defined as an inflammatory myopathy of subacute onset (weeks to months) and steady progression occurring in adults not presenting the following symptoms: (1) rash; (2) involvement of eye and facial muscles; (3) family history of a neuromuscular disease; (4) endocrinopathy; (5) history of exposure to myotoxic drugs or toxins; and (6) neurogenic or dystrophic disorder, metabolic myopathy, or inclusion body myositis, or necrotizing autoimmune myositis, as determined by muscle enzyme histochemistry and biochemistry. Unlike dermatomyositis, in which the rash secures early recognition, the actual onset of polymyositis cannot be easily determined, and the disease may exist for several months before the patient seeks medical advice.

Patients with polymyositis commonly present with a myopathy characterized by proximal and often symmetric muscle weakness manifested as difficulty performing tasks requiring the use of proximal muscles. Symptoms develop relatively slowly (weeks to months), occasionally insidiously, but rarely acutely (30; 36; 37; 39; 49; 46). Symptoms include difficulty getting up from a chair, climbing steps, stepping onto a curb, lifting objects, and combing hair. In contrast, fine-motor movements that depend on the strength of distal muscles, such as buttoning a shirt, sewing, knitting, or writing, are affected late in the disease. If these muscles are affected early and the patient complains of frequent falling, then the diagnosis of inclusion body myositis is more likely (30; 36; 37; 39; 43; 46; 47; 49; 40; 46). Ocular muscles remain normal even in advanced untreated cases, and if these muscles are affected, then the diagnosis of inflammatory myopathy should be in doubt. Facial muscles also remain normal except for rare advanced cases; in contrast, facial muscles are often affected in patients with inclusion body myositis. The pharyngeal and neck-extensor muscles can be involved, causing dysphagia or premature fatigue and difficulty in holding up the head. In advanced cases and rarely in acute cases, as in necrotizing autoimmune myositis, respiratory muscles may also be affected. Severe weakness is almost always associated with muscular wasting. Sensation remains normal. The tendon reflexes are preserved, but may be absent in severely weakened or atrophied muscles. Myalgia and muscle tenderness may occur in some patients, usually early in the disease and especially when polymyositis occurs in the setting of a connective tissue disorder. When the fascia is affected, as in fasciitis, there is diffuse muscle induration and tenderness but minimal muscle weakness.

Primary cardiac abnormalities due to myocarditis may be present in a small number of patients, mainly manifested as atrioventricular conduction defects, tachyarrhythmias, low-ejection fraction, dilated cardiomyopathy, or congestive heart failure. Cardiac abnormalities, however, appear overall to be secondary to hypertension associated with long-term steroid use or to pulmonary hypertension related to interstitial lung disease (30; 38; 49; 40). Interstitial lung disease may occur in up to 10% to 40% of these patients, who do not have polymyositis but the antisynthetase syndrome with anti-Jo-1 antibodies or antibodies to various ribonucleoproteins (29; 30; 38; 49; 55; 40; 01; 144). The prevalence of interstitial lung disease, best detected with high-resolution CT, is up to 70% among patients with anti-Jo-1 antibodies. Interstitial lung disease, however, may rarely be iatrogenic due to methotrexate use, a known but very rare cause of pneumonitis (“methotrexate-pneumonitis”). General systemic disturbances, such as fever, malaise, weight loss, arthralgia, and Raynaud phenomenon denote antisynthetase syndrome or overlap myositis but may occur when polymyositis is associated with a connective tissue disorder.

Polymyositis is a rare disease seen exclusively in adults. The disease is extremely rare in childhood, and if a diagnosis is made in patients below the age of 16 years, then a careful review is needed to exclude another disease, especially certain dystrophies that may be associated with endomysial inflammation (40; 49). Most patients still diagnosed as having polymyositis actually have another disease—either inclusions body myositis (described in a separate article), necrotizing autoimmune myositis (described below), or antisynthetase syndrome (most often anti-Jo-1 syndrome; also described below). The rarity of polymyositis has now become a reality; it is not included, and correctly so, in the newest classifications of inflammatory myopathies. A previously reported cohort of 255 patients from the United Kingdom, 37 of whom were classified some years ago as having polymyositis based on Eular/ACR criteria, highlights the rarity of the disease (109). A re-review of those patients did not show any convincing cases of true polymyositis, with the authors concluding “is there anything left?” Accordingly, as polymyositis is now correctly being questioned as a distinct clinicopathologic entity, a view we have been advocating for years, the inflammatory myopathies can be safely classified into four major subgroups: necrotizing autoimmune myositis, antisynthetase syndrome overlap myositis, dermatomyositis, and inclusion body myositis (144).

Prognosis and complications

The natural history of what had been considered as polymyositis is unknown because of the almost universal administration of early steroid treatment and the disease rarity. The mortality rates reported 30 to 40 years ago are outdated (30; 132). Several cases of probable polymyositis, referred to our institution as definite polymyositis, have been diagnosed as necrotizing autoimmune myositis, inclusion body myositis, toxic myopathy, antisynthetase syndrome, or inflammatory dystrophy on careful clinical examination and repeated muscle biopsy. In general, older age, interstitial lung disease, and frequent pneumonias due to esophageal dysfunction are factors associated with poor prognosis. Some patients still do not adequately respond to therapies and remain disabled; whether in these circumstances the disease was a bona fide polymyositis or another disorder erroneously diagnosed as polymyositis is unclear.

For years we have been advocating that when treatment of polymyositis is unsuccessful, the patient should be reevaluated and the muscle-biopsy specimen reexamined. A second biopsy might be considered to affirm the correct diagnosis. As mentioned, disorders most commonly mistaken for polymyositis include: inclusion body myositis; sporadic limb-girdle muscular dystrophy, which is suspected when the disease has a slow onset and progression, and the muscle biopsy specimen does not show primary inflammatory features; metabolic myopathy (eg, phosphorylase deficiency); endocrinopathy; and neurogenic muscular atrophies.

In cases of eosinophilic myositis associated with eosinophilic infiltration of an organ (heart, lung), the prognosis usually depends on the severity of cardiac or pulmonary involvement. Such cases may not respond to immunosuppression and usually carry an unfavorable prognosis (105). These patients are also predisposed to develop hematological malignancies (75; 76). Otherwise, uncomplicated cases of eosinophilic myositis usually respond to nonsteroidal anti-inflammatory or steroid medications, either with resolution or marked improvement. About one third of these patients, however, develop recurrences when these medications are discontinued (99) and need prolonged immunosuppression. Macrophagic myofasciitis also responds to steroids.

Biological basis

Etiology and pathogenesis

Polymyositis appears to be a syndrome of diverse causes that often occurs in association with systemic autoimmune diseases, viral infections, or connective tissue disorders. As a stand-alone clinical entity, polymyositis is a very uncommon disorder, if it exists. Other than D-penicillamine, tacrolimus (149), and immune checkpoint inhibitors, the other potential myotoxic drugs such as zidovudine, emetine, chloroquine, or ipecac do not cause polymyositis. Instead, myotoxic drugs elicit a toxic noninflammatory myopathy that is histologically different (or histologically distinct) from polymyositis and do not require immunosuppressive therapy (45). Certain cholesterol-lowering drugs may rarely exert an immune-modulating effect and have been thought to possibly trigger histologic features of autoimmune myositis responding to immunotherapies (45). As discussed below, however, statins can rarely cause acute rhabdomyolysis or myalgia within the first six weeks of therapy initiation and, although they have been implicated in the cause of necrotizing autoimmune myopathies, their causative role in patients who develop such myositis after a chronic statin use remains still uncertain. Several animal parasites, such as protozoa (Toxoplasma, Trypanosoma), cestodes (cysticerci), and nematodes (Trichinae), may produce a focal or diffuse inflammatory myopathy known as “parasitic polymyositis” (12). In the tropics, a suppurative myositis known as “tropical polymyositis” or “pyomyositis” may be produced by Staphylococcus aureus, Yersinia, Streptococcus, or other anaerobes. Pyomyositis, previously rare in the West, had been seen in patients with AIDS early in the epidemic when no treatment was available (78; 50). Certain bacteria, such as Borrelia burgdorferi of Lyme disease and Legionella pneumophila of Legionnaire disease (11; 152), may infrequently be the cause of polymyositis.

Polymyositis can be seen in patients with common connective tissue disorders such as systemic lupus erythematosus, Sjögren syndrome, or rheumatoid arthritis. In contrast, systemic sclerosis and mixed connective tissue diseases are more often associated with dermatomyositis than with polymyositis (30; 38; 39; 41; 49; 132). Patients with systemic sclerosis and mixed connective tissue disease may develop a rare but distinct myositis subtype identified as brachio-cervical inflammatory myopathy, characterized by weakness of proximal muscles of the upper limbs and cervical flexor and extensor muscles (128; 77).

Polymyositis can also be rarely manifested during the course of another systemic autoimmune disease, such as Crohn disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult celiac disease, chronic graft-versus-host disease, discoid lupus, ankylosing spondylitis, Behcet disease, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimoto disease, granulomatous diseases, agammaglobulinemia, hypereosinophilic syndrome, Lyme disease, Kawasaki disease, autoimmune thrombocytopenia, hypergammaglobulinemic purpura, hereditary complement deficiency, IgA deficiency, and AIDS (12; 29; 30; 50).

Among viruses, HIV and HTLV-I are the retroviruses more clearly associated with polymyositis and inclusion body myositis (62; 32; 63). Claims that other viruses, such as enteroviruses, can be causally connected with polymyositis are unproven (30; 41; 106). In some cases, however, polymyositis or necrotizing autoimmune myositis (NAM) has followed an acute viral illness. The same applies with SARS-Cov-19 during the present pandemic. A number of cases have been reported in connection with COVID-19, but few have been fully substantiated (55). Autopsy studies from patients hospitalized with severe pulmonary and systemic complications have shown some nonspecific endomysial inflammatory features mostly related to cytokine release and the strong inflammatory state triggered by the coronavirus; however, no convincing signs of SARS-Cov-19 have been detected in the muscle tissue and, like the other viruses, there is no evidence that SARS-Cov can infect the muscle fibers (55; 56; 57; 58).

Prior claims that cancer is considered to have increased association with polymyositis (139) or plays a role in its pathogenesis have not been substantiated (30). Cancer is, however, more frequently associated with dermatomyositis and necrotizing autoimmune myositis (04). Some reports suggesting patients with increased risk of cancer for all inflammatory myopathies have not taken into account the subtype of myopathy and other independent cancer-associated risk factors, such as long-term immunotherapy and increasing age (21; 85).

Eosinophilic myositis. This is a rare form of myositis characterized by eosinophilia in the peripheral blood and eosinophilic infiltrations in the endomysial tissue. The term “eosinophilic myositis” was coined by Layzer and colleagues in 1977 to describe cases in which eosinophils were the most prominent inflammatory cells within the endomysial infiltrate (105). Some of these patients may have involvement of other organs (heart, lungs, bone marrow, or skin) at some point in the course of their disease. Eosinophilic myositis can be seen in the context of parasitic infections, vasculitis (especially Churg-Strauss syndrome), mixed connective tissue disease, L-tryptophan-induced eosinophilia-myalgia syndrome (84; 92), toxic oil syndrome, or idiopathic hypereosinophilic syndrome (137). When the pathology is predominant in the fascia, the disease presents with skin induration and pain and is often referred to as “eosinophilic fasciitis” (Shulman syndrome) (138). At times, the skin is spared and the pathology predominates in the perimysium; such cases are referred to as “eosinophilic perimyositis” (91; 74; 104; 137; 147). Accordingly, an eosinophilic inflammatory muscle disease can present either as polymyositis with proximal muscle weakness or, most often, as fasciitis clinically manifesting as focal or generalized myalgia, muscle induration, tenderness, and cramps, with various involvements of the skin and the subcutaneous tissue. Eosinophilic myositis may overlap with hypereosinophilic syndrome, eosinophilic fasciitis, and eosinophilic perimyositis, implying a continuum of inflammatory involvement that extends from the fascia into the perimysium and endomysium. Several cases of eosinophilic myositis and fasciitis have been associated with drugs, such as tranilast (an antiasthmatic), phenobarbitol (101; 09), or contaminated L-tryptophan (84; 136; 92). Mutations in the calpain gene have also been associated with eosinophilic myositis, which often presents in young adults as hyperCKemia and minimal muscle weakness (102).

Macrophagic myofasciitis. This type of fasciitis seems to be a distinctive disorder identified years ago in French patients presenting with myalgias, early fatigue, and mild muscle weakness (80; 51). Muscle biopsy revealed pronounced infiltration of the connective tissue around the muscle (epimysium, perimysium, and perifascicular endomysium) by sheets of periodic acid-Schiff-positive macrophages and occasional CD8+ T cells. Creatine kinase or erythrocyte sedimentation may be at times elevated. Most patients respond to glucocorticoid therapy, and the overall prognosis is favorable. The pathology was almost always seen at the sites of previous vaccinations, even several months later, and had been linked almost exclusively in France to a type of aluminum component used as a substrate for preparation of their vaccines. Some evidence suggests that examination of the fascia along with the muscle may enhance the diagnostic yield for an overlapping myositis (108).

Necrotizing autoimmune myositis (NAM), also referred to as immune-mediated necrotizing myopathy (IMNM). Necrotizing autoimmune myositis is turning out to be the commonest subset among all the inflammatory muscle diseases, if inclusion-body myositis is excluded, based on the number of cases identified each year in busy referred clinics and reported in large series; accordingly, it should not be missed because it is potentially treatable if identified early (49; 154). NAM still, however, remains an overlooked entity, often misdiagnosed as polymyositis. The patients present with high CK, in the thousands; moderate to severe muscle weakness of acute or subacute onset; and histological features of muscle fiber necrosis mediated by macrophages as the main effector cell. There are no T-cell infiltrates or ubiquitous MHC-I expression as seen in polymyositis and inclusion body myositis, but the MHC-I expression is spotty (46; 47; 48; 49). In a number of patients, the muscle biopsies show deposition of complement on necrotic fibers and at times the blood vessels (83; 25; 01). Up to 65% of these patients have antibodies against signal recognition particles (SRP) or against a 100-kd autoantigen identified as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) (83; 25; 111).

The cause of NAM is multifactorial. A higher incidence of cancer has been observed in several cases (04) whereas others developed NAM during therapy with checkpoint inhibitors for advanced malignancies (96; 53; 93); some patients have an active viral infection (ie, HIV) and others may have a smoldering underlying autoimmune process, but still others have no other disease or apparent exposure to exogenous agents (48; 49). Some cases, however, have a statin exposure, which is implicated as a cause based on the assumption that statins, in addition to rarely causing a self-limited toxic myopathy, can also induce an autoimmune necrotizing myositis that persists after statin withdrawal (47; 111). Although the statin connection is widely accepted, a statin-triggered muscle autoimmunity remains still dubious among some critics (49; 31; 52; 53; 54; 05). NAM is probably an antibody-mediated disease, as implied by the presence of specific antibodies and complement with endomysial macrophages, which have been interpreted to represent an antibody-dependent cell-mediated cytotoxicity (ADCC) process (25; 01). This hypothesis, however, as discussed, lacks specificity because these antibodies are not pathogenic, whereas complement deposition and MHC-I expression are always associated with muscle fiber necrosis due to any cause, being ubiquitous in necrotic muscle fibers in all patients with nonimmune myopathies, such as muscular dystrophies (71; 97; 52; 53; 54; 55; 56). It has been proposed that NAM may differ from nonimmune-mediated toxic or dystrophic necrotizing myopathies by a strong expression of type 1 helper T cell (T1)/classically activated macrophage M1 and elevated level of interferon-γ, tumor necrosis factor-α, IL-12, and STAT1 levels in the muscle tissue (129).

The connection of necrotizing autoimmune myositis with statins has been based on a retrospective–over many years–historical chart review and the observation that anti-HMGCR antibodies were present in a number of these patients (111); because statins upregulate the expression of HMGCR in cultured cells, and HMGCR is the target of action of statins, this is a logical assumption. In this retrospective chart review, anti-HMGCR antibodies were detected in 45 of 750 patients (6%) with all types of myopathies, but among patients older than 50 years of age, 92.3% had at some point taken statins (111). This assumption did not, however, establish a causative role of statins and did not take into account that 25% of Americans above 40 years take statins. Subsequent studies from many centers throughout the world have now shown that anti-HMGCR autoantibodies are more often seen in statin-naïve patients with autoimmune necrotizing myositis (03; 69; 120; 02; 05; 98; 153), challenging a strict statin connection. Considering that NAM is now one of the commonest inflammatory myopathies and more than 25% of Americans above 40 years take statins, the association between statins and NAM needs to be objectively viewed as to whether it represents a chance phenomenon (53; 54; 55; 56). Some authors have proposed that the term “statin myopathy” should not be used (05) because only a minority of NAM patients had statin exposure and, most importantly, they develop NAM many years after statin initiation that makes their causative role dubious. These reservations are of general practical significance because in the author’s experience many patients with preexisting myopathic weakness, even genetic myopathies, or even just hyperCKemias, are deprived of statins by their primary care physicians fearing worsening of muscle weakness.

Because statins have immunomodulatory potential in autoimmune diseases, an interesting controlled study showed that simvastatin 20 mg/kg in an experimental mouse model of autoimmune myositis decreased the severity of the disease and significantly improved muscle strength and histopathology compared to placebo-treated mice (110). A trend towards higher serum Th17 percentage population was also noted in statin-treated and improved mice. These authors concluded that simvastatin can be a candidate as a disease-modifying agent in inflammatory myopathies.

“Antisynthetase syndrome” or “overlap myositis” or “anti-Jo-1 syndrome”. Anti-Jo-1 antibodies, the commonest among the anti-antisynthetases, directed against the histidyl-transfer RNA synthetase, define the now distinct antisynthetase or “overlap myositis” syndrome, characterized by: (a) myositis with prominent pathologic changes at the periphery of the fascicles and the perimysial connective tissue in the form of necrotizing perimysial and perifascicular myositis with actin myonuclear inclusions (115; 140); (b) interstitial lung disease; (c) arthritis; (d) Raynaud phenomenon; (e) fever; and (f) mechanic’s hands. The association of this clinicopathological phenotype with anti-Jo-1 antibodies appears strong in defining this distinct myositis subset, even if the Jo-1 antibodies are not pathogenic.

Presence of autoantibodies. Various autoantibodies against nuclear (antinuclear antibodies) or cytoplasmic antigens are found in as many as 20% of patients with inflammatory myopathies. The antibodies to cytoplasmic antigens are directed against ribonucleoproteins that are involved in translation and protein synthesis and include various synthetases and translation factors, including Jo-1, PL-7, PL-12, OJ, EJ, PMS1, and PMS2 (145; 94; 82; 02). Of these, anti-Jo-1, directed against the histidyl-transfer RNA synthetase, accounts for 75% of all the antisynthetases and is clinically useful in defining the distinct subset mentioned above. Overall, however, these antibodies may not be muscle-specific or pathogenic because: (1) they are directed against ubiquitous intracellular targets; (2) their exact myopathogenicity has not been defined; (3) they are almost always associated with interstitial lung disease or seen in patients with interstitial lung disease who do not have active myositis; and (4) they also can occur in inclusion body myositis and dermatomyositis, despite the clinical and immunopathologic differences of these disorders. Other autoantibodies are seen when myositis is associated with connective tissue disease and are the hallmarks of the other disease, such as Ro/SSA, La/SSB, Ki/SL in Sjögren; or tRNA, ANA, LE, or a 56 kDanRNP in lupus. The autoantibodies associated with scleroderma and mixed connective tissue concern only patients with dermatomyositis, the only form of inflammatory myopathy that overlaps with these two conditions (as discussed in the related article). Because these antibodies recognize ubiquitously expressed molecules and seem to be associated with some distinct clinical phenotypes, it has been suggested that the targeted tissue itself might regulate the phenotype-specific immune response owing to altered structure of tissue autoantigens during periods of cell stress, apoptosis, or acquisition of adjunct proteins (141). This hypothesis remains to be tested. As mentioned above, two autoantibodies, anti-SRP and anti-HMGCR, appear to be good markers of necrotizing myositis, and they are of diagnostic value because they are detected in up to 65% of patients with NAM (25), regardless of statin exposure. Claims that these antibodies may be pathogenic because they can cause muscle fiber atrophy and affect regeneration in vitro are not of direct relevance to the mechanism of the disease because the main causative characteristic of NAM is a macrophage-mediated muscle fiber necrosis with devastating muscle destruction and not muscle fiber atrophy (10; 53; 54; 55; 56).

Immunopathology. In polymyositis, original studies provided evidence suggesting a T cell-mediated cytotoxic process directed against unidentified muscle antigens in a pattern identical to the one described and studied in inclusion body myositis. Considering that polymyositis is very rare, it is conceivable that some of the studied specimens might have been from patients with inclusion body myositis, which is often erroneously diagnosed as polymyositis. The immunology and immunopathology have been, however, of extraordinary scientific value in understanding the role of cytotoxic T cells and, even if polymyositis is now rare, the information is applicable to all forms of autoimmune myopathies, hence, the need to be reviewed.

The T cell-mediated process is supported by the presence of CD8+ cells that, along with macrophages, initially surround healthy, nonnecrotic muscle fibers and eventually invade and destroy them (07; 08; 72; 70; 88). Muscle fibers, either next to or remote from the areas of inflammation, strongly express the class I major histocompatibility complex antigen, which is absent from the sarcolemma of normal muscle fibers (97). Cytotoxic T cells recognize antigenic targets in association with class I major histocompatibility complex antigen; these findings indicate that in polymyositis the primary immunopathologic mechanism is T cell-mediated and class I major histocompatibility complex antigen-restricted process. In one case, gamma/delta cytotoxic T cells were responsible for the muscle fiber injury (89); in vitro studies have further shown that this patients' circulating T lymphocytes are sensitized and exert cytotoxic effect to their homologous myotubes (87).

The specificity of the T cells has been examined by studying the gene rearrangement of the T cell receptors of the autoinvasive T cells, with similar findings in both polymyositis and inclusion body myositis. In patients with polymyositis, as well as inclusion body myositis, only certain T cells of specific T cell receptor alpha and T cell receptor beta families are recruited to the muscle from the circulation (112; 124; 15). Cloning and sequencing the amplified endomysial or autoinvasive T cell receptor gene families has demonstrated a restricted use of the J-beta gene with conserved amino acid sequence in the CDR3 region, indicating that CD8+ cells are specifically selected and clonally expanded in situ by muscle-specific autoantigens (112; 124; 15). Studies combining immunocytochemistry with polymerase chain reaction and sequencing of the most prominent T cell receptor families have shown that only the autoinvasive, not the perivascular, endomysial CD8+ cells are clonally expanded (15). Comparison of the T cell receptor repertoire between polymyositis and dermatomyositis with spectral type has confirmed that perturbations of the T cell receptor families occur among the peripheral blood lymphocytes, and they are specific for polymyositis and inclusion body myositis but not dermatomyositis (16). Further, among the circulating T cells, clonal expansion occurs only of the cytotoxic CD8+ cells that express genes for perforin and infiltrate the major histocompatibility complex-I-expressing muscle fibers (122). The clonal restriction of the autoinvasive T cells was confirmed with laser microdissection studies followed by sequencing of the T cell receptor gene families (86).

In order for antigen presentation and recognition by the T cells to occur, the muscle fibers and the autoinvasive CD8+ T cells need to coexpress the costimulatory molecules (B7-1, B7-2, BB1, CD40, or ICOS-L) and the respective counter-receptors [CD28, CTLA-4 (cytotoxic T lymphocyte antigen 4), CD40L or ICOS]. Several studies have now confirmed that the MHC-I-positive muscle fibers express BB1 (CD80) and make cell-to-cell contact with their CD28 or CTLA-4 ligands on the autoinvasive CD8+ T cells (14; 35). The CD40 molecule is also upregulated in muscle fibers, and the CD40 ligand is expressed in the infiltrating T cells (142). Further, there are ICOS/ICOS-L interactions between the autoinvasive CD8+ cytotoxic T cells and the MHC-I-expressing muscle fibers (157; 158; 156; 134).

Finally, cytokines, chemokines, and metalloproteinases (fundamental molecules for T cell activation, trafficking, antigen recognition, and T cell attachment) are upregulated in the muscle tissue of polymyositis patients. The mRNA of IL-1, IL-2, tumor necrosis factor-alpha and its receptor, tumor necrosis factor and its receptor, INF-gamma, T cell growth factor beta, granulocyte-macrophage colony-stimulating factor, IL-6, and IL-10 have been amplified from the muscle of most polymyositis and inclusion body myositis patients (146; 34; 67). Some of these cytokines, such as INF-gamma, ILI-1 beta, and tumor necrosis factor-alpha exert a direct cytotoxic effect on the muscle fibers (95; 40; 49; 50). Chemokines, a class of small cytokines participating in the leukocyte recruitment, trafficking, and activation, are also upregulated in polymyositis and inclusion body myositis. Among them, the chemokines interleukin-8, RANTES (regulated on activation, normal T cell expressed and secreted), monocyte chemoattractant protein 1, macrophage inflammatory protein 1a (MIP-1a), and IP-10 and its receptors are expressed in the endomysial inflammatory cells and in the neighboring extracellular matrix (26; 68; 66; 131). Adhesion of lymphocytes to muscle may be facilitated by metalloproteinases, a family of calcium-dependent zinc endopeptidases involved in the remodeling of the extracellular matrix. Among metalloproteinases, the metalloproteinase-9 and metalloproteinase-2 are upregulated in the nonnecrotic and major histocompatibility complex-I-expressing muscle fibers of patients with polymyositis and inclusion body myositis (24; 100). The metalloproteinase-2 is expressed on the autoinvasive CD8+ T cells that make cell-to-cell contact with the muscle fibers.

The release of cytokines and chemokines upregulates the expression of vascular cell adhesion molecule-I and intracellular adhesion molecule-I in the endothelial cells (32). These molecules serve as ligands for the integrins VLA-4 and lymphocyte function associated antigen-I that are expressed in T cells and facilitate their exit through the blood vessel wall into the perimysial and endomysial spaces.

Molecules, receptors, and ligands involved in exiting of the T cells through the endothelial cell wall and recognizing muscle antigens on the surface ...

Sequentially, (1) LFA-1-intracellular adhesion molecule-1 binding anchors the cytoskeletal molecules in the nascent immunological synapse. This allows (2) the interaction of T cell receptor-MHC with the sampling of MHC-peptides co...

Plasma cells and myeloid dendritic cells, which are potent antigen-presenting cells, are also seen among the endomysial infiltrates of patients with polymyositis, as well as inclusion body myositis and dermatomyositis and may play a significant role (81). Myeloid dendritic cells can be candidate cells for antigen presentation to surrounding T cells. Based on their immunoglobulin gene isotype, the endomysial plasma cells appear to mature and expand in situ implying an antigen-driven response (20). Because the same cells also have been found in inclusion body myositis and dermatomyositis, they may reflect a peculiarity of the inflammatory response within the closed muscle microenvironment. Similar clusters have been seen in the target organs of other autoimmune diseases, such as the synovium in rheumatoid arthritis or the brains of patients with multiple sclerosis.

Because in polymyositis, similarly to inclusion body myositis, the MHC-I is expressed in all fibers, regardless of if they are invaded by T cells, and the MHC-I remains strong throughout the disease; it was proposed that the MHC-I upregulation may exert a stress effect to the endoplasmic reticulum of the myofiber independent of T cell-mediated cytotoxicity (121). The assembly and folding of MHC-I occurs in the endoplasmic reticulum and matures only when binds to an antigenic peptide synthesized in the cytosol. A system of chaperone proteins, including calnexin, calreticulin, GRP94, GRP78, and ERP72, that form the MHC-loading complex ensure the proper maturation of MHC for antigen processing (42). If the “MHC-class-I loading complex,” does not bind to suitable antigens, the heavy chain glycoprotein is misfolded and removed from the endoplasmic reticulum to the cytosol for degradation. In polymyositis as well as inclusion body myositis, the muscle fibers are overloaded by MHC molecules, and the antigenic peptides cannot undergo proper conformational change to bind to MHC-I complex leading to endoplasmic reticulum stress. This is supported by upregulation of the aforementioned chaperone proteins and the activation of NF-kB, a means by which the cells protect themselves from endoplasmic reticulum stress. Such stressor effects are also seen in MHC-I transgenic mice, suggesting that overexpression of MHC-I alone may be sufficient to induce endoplasmic reticulum stress (121). This hypothesis is reasonable in explaining the continuous MHC-expression and chronic inflammation as seen in polymyositis and inclusion body myositis (42), but needs to be tested further.

The factors triggering the T cell-mediated process in polymyositis remain unclear. Viruses, especially the retroviruses HIV and HTLV-I, have been etiologically connected with the disease in infected individuals (62; 118; 32; 41; 92; 107), but these viruses are visible only on some infiltrating macrophages and not within the muscle fibers (44). Viral-specific T cells have been seen among the endomysial infiltrates in polymyositis and inclusion body myositis (63). The most interesting triggering factor is now becoming the immune-check-point inhibitors, which are directed against: (1) CTLA-4 (ipilimumab); (2) PD-1 (pembrolizumab and nivolumab); and (3) PD-L1 (atezollizumab, avelumab, and durvalumab). These drugs are used for advanced malignancy and prevent the CTLA-4 or PD-1 from binding to their respective receptors CD80/86 and PDL-1 and, by doing so, inhibit the “inhibitory” costimulatory interactions between T cells and tumor cells, resulting in positive costimulation and strong cell activation, like taking the “brakes off” the immune system (53). This blockade allows T cells to kill tumor cells, but the resulting enhanced costimulation causes an uncontrolled T cell activation that disrupts immune tolerance, resulting in immune-related events against muscle, mainly expressed as polymyositis and NAM, which at times occurs concurrently with myasthenia gravis (96; 53). Eosinophilic fasciitis and orbital myositis have been also seen.

New work on anti-synthetase syndrome myositis patients using proteomic analysis on peripheral blood cells concluded that a B-cell-driven pathology with persistence of a specific subtype of plasma cells is involved in self-perpetuating chronicity of the myositis process (130). Although the endomysial cells were not studied, the information indirectly suggests that B cells and plasma cells may be considered as therapeutic targets.

The triggering factors in eosinophilic myositis are also unclear, but trauma, drugs, or viral infections have been implicated. The cytokine interleukin-5 may play a role in inducing eosinophilia (148). Activated eosinophils infiltrate tissues and degranulate, releasing cytotoxic factors such as cytotoxic granule protein, major basic protein, and eosinophil cationic protein (155; 92; 99; 148). Eosinophil granule proteins are known to be toxic to cultured cardiac muscle (143) and may induce a similar effect in the skeletal muscle. Eosinophilic infiltration of skeletal muscle, however, does not account for all the parenchymal destruction because in many cases, in spite of peripheral eosinophilia, the eosinophilic infiltrates have been rare or transient within the muscle. Perimysial deposition of major basic protein has been demonstrated in some cases and is thought to contribute to tissue damage (92; 99). The rarity of these syndromes has precluded a systematic study of their immunopathogenesis. In macrophagic myofasciitis, the triggering factors have been thought to be aluminum-containing vaccines (13).

Diagnostic workup

The clinical suspicion of polymyositis, overlap myositis, or necrotizing autoimmune myositis is bolstered by evaluation of serum muscle enzymes and by electromyography and is confirmed by a diagnostic muscle biopsy.

Serum muscle enzymes. The most sensitive enzyme is creatine kinase, which in polymyositis can be as much as 50 times higher than normal whereas in NAM can be more than 50 times the upper limit of normal, often in the thousands. Although creatine kinase usually parallels disease activity, it can be normal in chronic polymyositis and chronic NAM. Creatine kinase may also be normal in patients with polymyositis and in a setting of a connective tissue disease (“overlap myositis”), reflecting the preference of the pathologic process for the intramuscular vessels and the perimysium. Along with creatine kinase, serum SGOT and SGPT, and LDH may also be elevated. The presence of high SGOT, SGPT, and LDH levels in a patient with early disease and minimal weakness often suggests the diagnosis of liver disease leading to an unnecessary liver biopsy if the creatine kinase level is not concurrently checked. If SGOT is higher than SGPT, a myogenic cause should be suspected; when SGPT is higher than SGOT and the gamma-GT is also elevated, liver disease is more likely.

Electromyography. Needle electromyography shows myopathic potentials characterized by short-duration, low-amplitude polyphasic units on voluntary activation and increased spontaneous activity with fibrillations, complex repetitive discharges, and positive sharp waves. This electromyographic pattern occurs in a variety of acute, toxic, and active myopathic processes and should not be considered diagnostic for the inflammatory myopathies. In fact, no pattern is characteristic of polymyositis. Mixed myopathic and neurogenic potentials (polyphasic units of short and long duration) are more often seen in inclusion body myositis, but they can be seen in both polymyositis and dermatomyositis due to muscle fiber regeneration and the chronic nature of the disease. Electromyographic studies are generally useful to exclude neurogenic disorders and to assess whether the myopathy is active or inactive

Muscle biopsy. Muscle biopsy is the definitive test not only to establish the diagnosis of polymyositis but also to exclude other neuromuscular diseases. In what is referred to as polymyositis, the presence of inflammation is the histologic hallmark of the disease. The endomysial infiltrates are mostly in foci within the fascicles (endomysially) initially surrounding healthy muscle fibers but eventually resulting in phagocytosis and muscle fiber necrosis. The inflammatory infiltrates may be so small and multifocal that they are missed in a small-size muscle biopsy specimen. Occasionally, inflammation can be better seen in longitudinal sections. In polymyositis, as in inclusion body myositis, the inflammation is primary, a term used to indicate that CD8+ cells invade histologically healthy fibers that express MHC-I antigen. We refer to this lesion as the “CD8/MHC-I complex” (40) and have proposed it to be a specific lesion for polymyositis that secures the histologic diagnosis. Eosinophils are rare, but, if abundant, the diagnosis of eosinophilic myositis should be considered; in cases of suspected fasciitis or perimyositis, a biopsy of skin, fascia, or muscle in a wedge-like fashion is most informative. The perifascicular atrophy and prominent perivascular infiltrates seen in dermatomyositis are not present in polymyositis, and the blood vessels are normal. When the disease is chronic, the connective tissue is increased. In polymyositis, there should be no vacuolated fibers with cytoplasmic inclusions, typical of inclusion body myositis. Magnetic resonance imaging (MRI) is helpful for diagnosis when muscle edema is present or myofasciitis is suspected. MRI can be also helpful in identifying the most affected muscles and guide the diagnostic biopsy (49).

In necrotizing autoimmune myositis, there are abundant necrotic fibers invaded or surrounded by macrophages. Lymphocytic infiltrates are sparse, and MHC class 1 upregulation is spotty but sometimes prominent beyond the necrotic fibers. Necrotizing autoimmune myositis seems mediated, in the majority of the patients, by specific antibodies against SRP or HMGCR, which are seen in up to 65% of these patients; although not pathogenic, they are very good markers. Complement deposits are frequent but not unexpected because based on classic immunopathology studies, all necrotic fibers in nonimmune myopathies, such as muscular dystrophies, unambiguously activate complement, which in turn stimulates cellular infiltrates and macrophages (71).

Primary intramuscular inflammatory response is an invariable feature of polymyositis, and absence of inflammation early in the illness should raise a critical concern about the diagnosis. In the old diagnostic criteria introduced by Bohan and Peter (17; 18), the main diagnostic features of proximal muscle weakness, myopathic findings on the electromyogram, elevated creatine kinase levels, and inflammation in the muscle biopsy had equal diagnostic weight. Further, the diagnosis of polymyositis was acceptable even without the presence of muscle biopsy findings specific for the disease. Consequently, inclusion body myositis was overlooked, and various noninflammatory myopathies were erroneously diagnosed as polymyositis, as repeatedly emphasized (30; 36; 40). This has prompted the introduction of diagnostic criteria (30; 49; 40). The diagnosis of polymyositis is definite when a patient has: (1) acquired, subacute myopathy fulfilling the exclusion criteria described earlier and lacking the distribution of weakness typically seen in inclusion body myositis; (2) elevated creatine kinase; (3) a muscle biopsy with the histologic features of polymyositis, including the MHC-I/CD8 lesion (40); and (4) exclusion of inflammatory dystrophies and NAM. The diagnosis is probable polymyositis if the muscle biopsy shows nonspecific myopathic features but widespread MHC-I expression without apparent T cell infiltrates, macrophages, or vacuoles and the patient does not have the clinical phenotype of inclusion-body myositis (see relevant MedLink Neurology article for Inclusion-body myositis). A repeat muscle biopsy from another site may prove informative in these cases and might be considered to secure a definitive diagnosis.

The most common erroneous practice that impacts investigative and therapeutic decisions is the failure to distinguish PM from IBM, NAM, and inflammatory dystrophies (ie, Duchenne muscular dystrophy, dysferlinopathy, calpainopathy, merosin deficient sarcoglycanopathy), owing to erroneous pathologic interpretation of the biopsy and the failure to correlate the histology with the clinical phenotype. The muscle fiber necrosis in PM is due to invasion of seemingly intact muscle fibers by cytotoxic lymphocytes; in contrast, the invasion of muscle fibers in dystrophies is mostly by macrophages. However, in cases where endomysial infiltration is associated with lymphocytes, these cells lack the MHC/CD8 complex that is typical of PM and IBM as noted above. Some observations have confirmed that up to 15% of biopsies from patients with typical clinical features of IBM demonstrate only inflammation, like that seen in PM, but without the classic vacuoles (22). These patients labeled as PM/IBM or probable IBM need to be distinguished from PM on the basis of the typical clinical phenotype and the large number of COX-negative and “ragged-blue” fibers seen in the biopsy. In NAM the predominant cell invading muscle fibers are macrophages but, in contrast with dystrophies where the disease manifests slowly over years, NAM evolves acutely or within weeks and is often associated with antibodies. Errors can be avoided by a combined evaluation of the clinical with the histologic and immunopathologic findings.

Management

The treatment of polymyositis, NAM, and anti-synthetase syndrome remains empirical, and separate large-scale, prospective, controlled clinical studies have not been performed (30; 36; 37; 39; 46; 49; 36; 40; 114). In most old series, patients had not been screened to exclude inclusion body myositis, which appears to resist all therapies.

The main goal of therapy in all three myositis groups is to improve function in activities of daily living by improving muscle strength. Although improvement in strength is usually accompanied by a fall in serum creatine kinase, decreases of serum creatine kinase alone need to be interpreted with caution because most immunosuppressive therapies lower serum muscle enzyme levels without necessarily improving muscle strength. Unfortunately, this has been misinterpreted as "chemical improvement" and has formed the basis for the common habit of "chasing" or "treating" the creatine kinase level instead of monitoring muscle strength, a practice that has led to prolonged use of unnecessary immunosuppressive drugs and erroneous assessment of their efficacy (33; 46). The most commonly used drugs are steroids and nonsteroidal immunosuppressive agents.

Corticosteroids. Prednisone is the first-line drug of this empirical treatment.

Response to prednisone determines whether or not stronger immunosuppressive drugs will be needed; therefore, one may prefer an aggressive approach with high-dose prednisone beginning early in the disease (33; 46; 2015a). A high, single-daily, morning dose of 60 to 80 mg for an initial period of 3 to 4 weeks is preferable. Prednisone is then tapered over a 6 to 8-week period to an 60 to 80 mg single dose every other day by gradually reducing the "off-day" dose by 10 mg per week or faster, if side effects occur (though this carries a greater risk of breakthrough of disease). If there is evidence of efficacy and no serious side effects, then the dosage is reduced gradually until the lowest possible dose that controls the disease is reached. If by the time the dosage has been reduced to every other day and no objective benefit (defined as increased muscle strength) has been observed, the patient may be considered unresponsive to prednisone; tapering may be then accelerated while a second-line therapy is considered (28).

The merits of a single-dose, alternate-day program in minimizing side effects (cushingoid appearance, diabetes, obesity, high blood pressure, osteoporosis, avascular necrosis of the hip, retarded growth in children) while adequately controlling the underlying disease have been previously discussed (28; 30).

Sometimes the long-term use of prednisone may cause increased weakness with a normal or unchanged creatine kinase level, a situation often referred to as "steroid myopathy." This condition is rather uncommon with prednisone but more often seen with dexamethasone. In a patient who has previously responded to high doses of prednisone, the development of increased weakness may be related to steroid-induced myopathy or to disease activity that either will respond to a higher dose of steroids or has become resistant to steroids. It may be difficult to distinguish one situation from the other because the two can coexist or be complicated by other factors, such as decreased mobility, infection, or associated systemic illnesses. In these circumstances, the decision to raise or lower the prednisone dosage may be influenced by reviewing changes in the patient’s muscle strength during the preceding two months in connection with mobility, serum creatine kinase levels, and changes in medications. If none of these are informative, then prednisone dosage can be adjusted (increased or decreased) arbitrarily. The cause of the weakness may be evident in the ensuing 2 to 8 weeks, based on the changes in the patient's strength.

Prednisone failures and nonsteroidal therapies. Almost all patients with polymyositis, NAM, and anti-synthetase syndrome myositis respond to steroids to some degree and for some period of time. The rationale for starting another immunosuppressive drug in those patients is based on the following criteria: (1) the need for a "steroid-sparing" drug when the patient has developed significant complications despite steroid responsiveness, (2) repeated relapses when attempting to lower a high steroid dosage, (3) ineffectiveness of an adequate dose of prednisone for at least a 2- to 3-month period, and (4) rapidly progressive disease with evolving severe weakness and respiratory failure. The preference for selecting the next-in-line immunosuppressive therapy is, however, empirical. The choice is typically based on a physician's own bias, personal experience with each drug, and assessment of the relative efficacy to safety ratio. The following immunomodulating or immunosuppressive therapies are used in the treatment of these patients.

Azathioprine. Although low doses (1.5 to 2 mg/kg/day) are commonly used, one may prefer higher doses up to 3 mg/kg for more effective immunosuppression in difficult cases. This drug is well tolerated and has fewer side effects than others, but it acts slowly (effects are not seen until 3 to 6 months of treatment). It follows that patience is required before concluding that the drug is ineffective. Azathioprine, metabolized by xanthine oxidase, can be severely toxic to the liver or bone marrow if given concurrently with allopurinol; therefore, combined use should be avoided.

Mycophenolate mofetil. Mycophenolate mofetil is an immunosuppressive drug that inhibits the purine pathway on the T cells with promising results (135), although control studies have not been performed. It has the advantage of working faster than azathioprine, and it is well tolerated. Doses up to 2000 to 3000 mg per day in two divided doses are recommended.

Methotrexate. Methotrexate is preferred by some practitioners because it acts faster than azathioprine. It can be given orally, starting at 7.5 mg weekly for the first three weeks (given in a total of three doses, 2.5 mg every 12 hours), increasing it gradually by 2.5 mg/week up to a total of 15 to 25 mg weekly. An important very rare side effect is methotrexate-pneumonitis, which can be difficult to distinguish from the interstitial lung disease accompanying some of these patients, especially those with Jo-1 antibodies, as described above.

Cyclophosphamide. Preferably, cyclophosphamide is given intravenously at doses of 0.5 to 1 gm/m2 per month. Cyclophosphamide has shown promising results in some patients (19). Although in our hands it was ineffective in patients with severe disease, the drug may be helpful in a subset of patients with interstitial lung disease (27).

Cyclosporine. The advantage of cyclosporine, although used with limited success, is that it acts faster than azathioprine, and its toxicity can be monitored by measuring optimal trough serum levels (which vary between 100 and 250 ng/mL).

Plasmapheresis. Plasmapheresis was not helpful in a double-blind, placebo-controlled study that we conducted (117).

Tacrolimus. Acting as a calcineurin inhibitor, tacrolimus has shown promise in the treatment of difficult cases. However, the experience with this drug is limited.

Rituximab. Rituximab, the first anti-CD20 monoclonal antibody that causes depletion of B cells, is promising in some polymyositis, NAM, and anti-synthetase syndrome patients based on a series of anecdotal reports. However, a completed controlled study comparing rituximab-early and rituximab-late (given 8 weeks later and serving as a placebo arm) groups showed no difference between the two arms in the time to achieving the definition of improvement during the 44-week period (123). Eighty-three percent of patients in both groups, however, met the definition of improvement. Although the nature of the study design does not allow conclusions on efficacy of this drug versus placebo, the observation that patients in both groups improved suggests that rituximab may play a role in patients resistant to therapies (49).

Intravenous immunoglobulin. In a double-blind study, intravenous immunoglobulin was effective in patients with refractory dermatomyositis (32; 35) and has been effective in the majority of polymyositis and NAM patients tried (23; 35; 113; 79; 56). However, controlled data are lacking. Subcutaneous immunoglobulin was also shown to be of benefit (127; 64; 65).

Recommended therapeutic approach.

Considering all the aforementioned therapies, our step-by-step approach is as follows (40; 46; 49):

Step 1: High-dose prednisone (oral or intermittent intravenous)

Step 2: Initial or subsequent optional immunosuppressant, ie, mycophenolate, azathioprine, or methotrexate, only for steroid-sparing effect

Step 3: If steps 1 and 2 fail, high-dose intravenous immunoglobulin

Step 4: If Step 3 fails, consider a trial, with guarded optimism, of rituximab. If interstitial lung disease is present, one of the following agents, chosen according to the patient’s age, degree of disability, tolerance, experience with the drug and general health, are additional options: cyclosporin, cyclophosphamide, or tacrolimus. Other agents, mostly in the form of monoclonal antibodies or fusion proteins, seem now very promising, especially anti-B cell agents like rituximab, a B-cell-depleting monoclonal antibody (42; 43; 44; 49).

New biologics. New biologics may becoming promising therapeutic options. JAK kinase inhibitors, such as tofacitinib (103; 126) and ruxolitinib (90) seem effective, probably by affecting circulating cytokine levels and regulating the activation of dendritic cells and T lymphocytes, known to be activated in the disease (124). Monoclonal antibodies directed against complement, such as eculizumab directed against C5 blocking the generation of C5a and the membrane attack complex assembly, are being tested in these patients (55; 56; 57). A double-blind study in patients with NAM and anti-synthetase syndrome is ongoing.

References

01: Allenbach Y, Arouche-Delaperche L, Preusse C, et al. Necrosis in anti-SRP+ and anti-HMGCR+myopathies: Role of autoantibodies and complement. Neurology 2018;90(6):e507-17. PMID 29330311
02: Allenbach Y, Benveniste O. Diagnostic utility of auto-antibodies in inflammatory muscle diseases. J Neuromusc Dis 2015;2(1):13-25. PMID 28198709
03: Allenbach Y, Drouot L, Rigolet A, et al. Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin. Medicine (Baltimore) 2014;93(3):150-7. PMID 24797170
04: Allenbach Y, Keraen J, Bouvier AM, et al. High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody. Brain 2016;139(Pt 8):2131-5. PMID 27086869
05: Alshehri A, Choksi R, Bucelli R, Pestronk A. Myopathy with anti-HMGCR antibodies: Perimysium and myofiber pathology. Neurol Neuroimmunol Neuroinflamm 2015;2(4):e124. PMID 26090508
06: Amato AA, Griggs RC. Unicorns, dragons, polymyositis, and other mythological beasts. Neurology 2003;61:288-9. PMID 12913184
07: Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. II. Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol 1984;16:209-15. PMID 6089646
08: Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. V. Identification and quantitation of T8+ cytotoxic and T8 suppressor cells. Ann Neurol 1988;23:493-9. PMID 2968776
09: Arase S, Kato S, Nakanishi H, et al. Eosinophilic polymyositis induced by tranilast. J Dermatol 1990;17(3):182-6. PMID 1693928
10: Arouche-Delaperche L, Allenbach Y, Amelin D, et al. Pathogenic role of anti-signal recognition protein and anti-3-Hydroxy-3-methylglutaryl-CoA reductase antibodies in necrotizing myopathies: Myofiber atrophy and impairment of muscle regeneration in necrotizing autoimmune myopathies. Ann Neurol 2017;81(4):538-48. PMID 28224701
11: Atlas E, Novak SN, Duray PH, Steere AC. Lyme myositis: muscle invasion by Borrelia burgdorferi. Ann Intern Med 1988;109:245-6. PMID 3389608
12: Banker BQ. Parasitic myositis and other inflammatory myopathies. In: Engel AG, Banker BQ, editors. Myology. New York: McGraw-Hill, 1986:1467-524.
13: Bassez G, Authier FJ, Lechapt-Zalcman E, et al. Inflammatory myopathy with abundant macrophages (IMAM): a condition sharing similarities with cytophagic histiocytic panniculitis and distinct from macrophagic myofasciitis. J Neuropathol Exp Neurol 2003;62:464-74. PMID 12769186
14: Behrens L, Kerschensteiner M, Misgeld T, et al. Human muscle cells express a functional costimulatory molecule distinct from B7.1 (CD80) and B7.2 (CD86) in vitro and in inflammatory lesions. J Immunol 1998;161:5943-51. PMID 9834075
15: Bender A, Ernst N, Iglesias A, et al. T cell receptor repertoire in polymyositis: clonal expansion of autoaggressive CD8+ T cells. J Exp Med 1995;181:1863-8. PMID 7722460
16: Benveniste O, Cherin P, Maisonobe T, et al. Severe perturbations of the blood T cell repertoire in polymyositis, but not dermatomyositis patients. J Immunol 2001;167:3521-9. PMID 11544346
17: Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975a;292(7):344-7. PMID 1090839
18: Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med 1975b;292(8):403-7. PMID 1089199
19: Bombardieri S, Hughes GR, Neri R, Del Bravo P, Del Bono L. Cyclophosphamide in severe polymyositis. Lancet 1989;1(8647):1138-9. PMID 2566079
20: Bradshaw EM, Orihuela A, McArdel SL, et al. A local antigen-driven humoral response is present in the inflammatory myopathies. J Immunol 2007;178(1):547-56. PMID 17182595
21: Buchbinder R, Forbes A, Hall S, Dennett X, Giles G. Incidence of malignant disease in biopsy-proven inflammatory myopathy. A population-based cohort study. Ann Intern Med 2001;134:1087-95. PMID 11412048
22: Chahin N, Engel AG. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM. Neurology 2008;70(6):418-24. PMID 17881720
23: Cherin P, Herson S, Weschsler B, et al. Intravenous immunoglobulin for polymyositis and dermatomyositis. Lancet 1990;336:116. PMID 1697394
24: Choi YC, Dalakas MC. Expression of matrix metalloproteinases in the muscle of patients with inflammatory myopathies. Neurology 2000;54:65-71. PMID 10636127
25: Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010;62(9):2757-66. PMID 20496415
26: Confalonieri P, Bernasconi P, Megna P, et al. Increased expression of beta-chemokines in muscle of patients with inflammatory myopathies. J Neuropathol Exp Neurol 2000;59:164-9. PMID 10749105
27: Cronin ME, Miller FW, Hicks JE, Dalakas M, Plotz PH. The failure of intravenous cyclophosphamide therapy in refractory idiopathic inflammatory myopathy. J Rheumatol 1989;16(9):1225-8. PMID 2681763
28: Dalakas M. Treatment of polymyositis and dermatomyositis. Curr Opin Rheumatol 1989;1(4):443-9. PMID 2702045
29: Dalakas M. Pharmacologic concerns of corticosteroids in the treatment of patients with immune-related neuromuscular diseases. Neurol Clin 1990;8(1):93-118. PMID 2181270
30: Dalakas MC. Polymyositis, dermatomyositis, and inclusion-body myositis. N Engl J Med 1991;325:1487-98. PMID 1658649
31: Dalakas MC. Necrotizing autoimmune myositis (NAM): antibodies seem to be specific markers aiding diagnosis. J Neurol Neurosurg Psychiatry 2016;87(10):1037. PMID 27151962
32: Dalakas MC. Retroviruses and inflammatory myopathies. Baillieres Clin Neurol 1993;2:658-91. PMID 8156147
33: Dalakas MC. Intravenous immune globulin therapy for neurologic diseases. Ann Intern Med 1997;126(9):721-30. PMID 9139559
34: Dalakas MC. Molecular immunology and genetics of inflammatory muscle diseases. Arch Neurol 1998;55:1509-12. PMID 9865793
35: Dalakas MC. Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines. Muscle Nerve 1999;22:1479-97. PMID 10514226
36: Dalakas MC. Progress in inflammatory myopathies: good but not good enough. Editorial. J Neurol Neurosurg Psychiatry 2001a;70:569-73. PMID 11309448
37: Dalakas MC. The molecular and cellular pathology of inflammatory muscle diseases. Curr Opin Pharmacol 2001b;1:300-6. PMID 11712755
38: Dalakas MC. Polymyositis, dermatomyositis and inclusion body myositis. In: Braunwald E, Fauci AS, Kasper DL, et al, editors. Harrison’s principles of internal medicine. 15th edition. New York: McGraw-Hill, 2001d;2524-9.
39: Dalakas MC. Muscle biopsy findings in inflammatory myopathies. Rheum Dis Clin North Am 2002;28(4):779-98, vi. PMID 12506772
40: Dalakas MC. Therapeutic approaches in patients with inflammatory myopathies. Sem Neurol 2003;23:199-206. PMID 12894385
41: Dalakas MC. Viral related muscle disease. In: Engel AG, editor. Myology. New York: McGraw Hill, 2004.
42: Dalakas MC. Treatment of polymyositis and dermatomyositis. Signaling pathways and immunobiology of inflammatory myopathies. Nature Clinic Practice Rheumatol 2006a;2:219-27. PMID 16932688
43: Dalakas MC. Therapeutic targets in patients with inflammatory myopathies: present approaches and a look to the future. Neuromuscular Disord 2006b;16:223-36. PMID 16542836
44: Dalakas MC. Inflammatory, immune and viral aspects of Inclusion Body Myositis. Neurology 2006c;66(Suppl):533-8. PMID 16432143
45: Dalakas MC. Toxic and drug-induced myopathies. J Neurol Neurosurg Psychiatry 2009;80(8):832-8. PMID 19608783
46: Dalakas MC. Advances in the treatment of myositis. Nature Review Rheumatol 2010a:129-37.
47: Dalakas MC. Inflammatory muscle diseases: a critical review on pathogenesis and therapies. Curr Opin Pharmacol 2010b;10(3):346-52. PMID 20409756
48: Dalakas MC. An update on inflammatory and autoimmune myopathies. Neuropathol and Appl Neurobiol 2011;37(3):226-42. PMID 21155862
49: Dalakas MC. Inflammatory muscle diseases. N Engl J Med 2015a:372(18):1734-47. PMID 25923553
50: Dalakas MC. Polymyositis, dermatomyositis and inclusion body myositis. In: Kasper DL, Fauci AS, Hauser S, et al, editors. Harrison’s principles of internal medicine. 19th edition. New York: McGraw-Hill, 2015b;2194-202.
51: Dalakas MC. Inflammatory muscle diseases [Letter to the editor]. N Engl J Med 2015c;373(4):393-4. PMID 26200989
52: Dalakas MC. Are autoantibodies pathogenic in necrotizing myopathy? Nat Rev Rheumatol 2018a;14(5):251-2. PMID 29651118
53: Dalakas MC. Neurological complications of immune checkpoint inhibitors: what happens when you 'take the brakes off' the immune system. Ther Adv Neurol Disord 2018b;11:1756286418799864. PMID 30245744
54: Dalakas MC. Case 22-2019: a 65-year-old woman with myopathy. N Engl J Med 2019;381(17):1693. PMID 31644862
55: Dalakas MC. Inflammatory myopathies: update on diagnosis, pathogenesis and therapies, and COVID-19-related implications. Acta Myologica 2020;39(4):289-301. PMID 33458584
56: Dalakas MC. Update on intravenous immunoglobulin in neurology: modulating neuro-autoimmunity, evolving factors on efficacy and dosing and challenges on stopping chronic IVIg therapy. Neurotherapeutics 2021;18(4):2397-418. PMID 34766257
57: Dalakas MC. Complement in autoimmune inflammatory myopathies, role of myositis-associated antibodies, COVID19-associations and muscle amyloid deposits. Expert Rev Clin Immunol 2022a;18(4):413-23. PMID 35323101
58: Dalakas MC. Unconvincing evidence of SARS-CoV-2-related myositis in autopsied muscles. JAMA Neurology 2022b;79(1):92.** PMID 34807230
59: Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003;362:1762-3. PMID 14511932
60: Dalakas MC, Illa I, D'Ambrosia JM, et al. A controlled study of intravenous immunoglobulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993-2000. PMID 8247075
61: Dalakas MC, Karpati G. Inflammatory myopathies. In: Karpati G, Hilton-Jones, Bushby K, Griggs RC, editors. Disorders of voluntary muscle. 8th edition. Cambridge, UK: Cambridge University Press, 2010;427-52.
62: Dalakas MC, Pezeshkpour GH, Gravell M, Sever JL. Polymyositis in patients with AIDS. JAMA 1986;256:2381-3. PMID 3464769
63: Dalakas MC, Rakocevic G, Shatunov A, Goldfarb L, Salajegheh M. Inclusion body myositis with human immunodeficiency virus infection: four cases with clonal expansion of viral-specific T cells. Ann Neurol 2007;61(5):466-75. PMID 17366634
64: Danieli MG, Pettinari L, Moretti R, Logullo F, Gabrielli A. Subcutaneous immunoglobulin in polymyositis and dermatomyositis: a novel application. Autoimmun Rev 2011;10(3):144-9. PMID 20858553
65: Danieli MG, Verga JU, Mezzanotte C, et al. Replacement and immunomodulatory activities of 20% subcutaneous immunoglobulin treatment: a single-center retrospective study in autoimmune myositis and CVID patients. Front Immunol 2022;12:805705. PMID 35111165
66: De Bleecker JL, De Paepe B, Vanwalleghem IE, Schroder JM. Differential expression of chemokines in inflammatory myopathies. Neurology 2002;58:1779-85. PMID 12084877
67: De Bleecker JL, Meire VI, Declercq W, Van Aken HE. Immunolocalization of tumor necrosis factor-alpha and its receptors in inflammatory myopathies. Neuromusc Disord 1999;9:239. PMID 10399751
68: De Rossi M, Bernasconi P, Baggi F, de Waal Maleft R, Mantegazza R. Cytokines and chemokines are both expressed by human myoblasts: possible relevance for the immune pathogenesis of muscle inflammation. Intl Immunol 2000;12:1329-35. PMID 10967028
69: Drouot L, Allenbach Y, Jouen F, et al. Exploring necrotizing autoimmune myopathies with a novel immunoassay for anti-3-hydroxy-3-methyl-glutaryl-CoA reductase autoantibodies. Arthritis Res Ther 2014;16(1):R39. PMID 24484965
70: Emslie-Smith AM, Arahata K, Engel AG. Major histocompatibility complex class-I antigen expression, immunolocalization of interferon subtypes and T-cell mediated cytotoxicity in myopathies. Hum Pathol 1989;20:224-31. PMID 2470663
71: Engel AG, Biesecker G. Complement activation in muscle fiber necrosis: demonstration of the membrane attack complex of complement in necrotic fibers. Ann Neurol 1982;12(3):289-96. PMID 6753731
72: Engel AG, Arahata K. Mononuclear cells in myopathies: quantitation of functionally distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies. Hum Pathol 1986;17:704-21. PMID 3459704
73: Engel AG, Emslie-Smith AM. Inflammatory myopathies. Curr Opin Neurol Neurosurg 1989;2:695-700.
74: Fang MA, Verity MA, Paulus HE. Subacute perimyositis. J Rheumatol 1988;15(8):1291-3. PMID 3184078
75: Fauci AS. Human B lymphocyte function: cell triggering and immunoregulation. J Infect Dis 1982a;145:602-12. PMID 6176659
76: Fauci AS. The syndrome of Kaposi's sarcoma and opportunistic infections: an epidemiologically restricted disorder of immunoregulation. Ann Intern Med 1982b;96(1):777-9. PMID 7091942
77: Gao AF, Saleh PA, Kassardjian CD, Vinik O, Munoz DG. Brachio-cervical inflammatory myopathy with associated scleroderma phenotype and lupus serology. Neurol Neuroimmunol Neuroinflamm 2017;5(1):e410. PMID 29114565
78: Gaut P, Wong PK, Myer RD. Pyomyositis in a patient with the acquired immunodeficiency syndrome. Arch Intern Med 1988;148:1608-10. PMID 3382306
79: Genevay S, Saudan-Kister A, Guerne PA. Intravenous gammaglobulins in refractory polymyositis: lower dose for maintenance treatment is effective. Ann Rheum Dis 2001;60:635-6. PMID 11350855
80: Gherardi RK, Coquet M, Cherin P, et al. Macrophagic myofasciitis: an emerging entity. Groupe d'Etudes et Recherche sur les Maladies Musculaires Acquises et Dysimmunitaires (GERMMAD) de l'Association Francaise contre les Myopathies (AFM). Lancet 1998;352(9125):347-52. PMID 9717921
81: Greenberg SA, Pinkus GS, Amato AA, Pinkus JL. Myeloid dendritic cells in inclusion-body myositis and polymyositis. Muscle Nerve 2007;35(1):17-23. PMID 16969836
82: Hengstman GJ, Brouwer R, Vree Egberts WT, et al. Clinical and serological characteristics of 125 Dutch myositis patients. J Neurol 2002;249:69-75. PMID 11954871
83: Hengstman GJ, van Engelen BG, van Venrooij WJ. Myositis specific autoantibodies: changing insights in pathophysiology and clinical associations. Curr Opin Rheumatol 2004;16(6):692-9. PMID 15577606
84: Hertzman PA, Blevins WL, Mayer J, Greenfield B, Ting M, Gleich GJ. Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990;322:869-73. PMID 2314421
85: Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 2001;357:96-100. PMID 11197446
86: Hofbauer M, Wiesener S, Babbe H, et al. Clonal tracking of autoaggressive T cells in polymyositis by combining laser microdissection, single-cell PCR and CDR3 spectratype analysis. Proc Natl Acad Sci USA 2003;100(7):4090-5. PMID 12651958
87: Hohlfeld R, Engel AG. Coculture with autologous myotubes of cytotoxic T cells isolated from muscle in inflammatory myopathies. Ann Neurol 1991;29:498-507. PMID 1830466
88: Hohlfeld R, Engel AG. The immunobiology of muscle. Immunol Today 1994;15:269-74. PMID 8068173
89: Hohlfeld R, Engel AG, Kunio Li, Harper MC. Polymyositis mediated by T lymphocytes that express the gamma/delta receptor. N Engl J Med 1991;3324:877-81. PMID 1705662
90: Hornung T, Janzen V, Heidgen FJ, Wolf D, Bieber T, Wenzel J. Remission of recalcitrant dermatoymyositis treated with ruxolitinib. N Engl J Med 2014;371(26):2537-8. PMID 25539124
91: Huang KW, Chen XH. Pathology of eosinophilic fasciitis and its relation to polymyositis. Can J Neurol Sci 1987;14(4):632-7. PMID 3690437
92: Illa I, Dinsmore S, Dalakas MC. Immune-mediated mechanisms and immune activation of fibroblasts in the pathogenesis of eosinophilia-myalgia syndrome induced by L-tryptophan. Hum Pathol 1993;24:702-9. PMID 8100551
93: Johansen A, Christensen SJ, Scheie D, Højgaard JLS, Kondziella D. Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies: systematic review. Neurology 2019;92(14):663-74. PMID 30850443
94: Jury EC, D’Cruz D, Morrow WJ. Autoantibodies and overlap syndromes in autoimmune rheumatic disease. J Clin Pathol 2001;54:340-7. PMID 11328831
95: Kalovidouris AE, Plotkin Z. Synergistic cytotoxic effect of interferon gamma and tumor necrosis factor alpha on cultured human muscle cells. J Rheumatol 1995;22:1698-703. PMID 8523348
96: Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti–programmed death 1 (PD-1) antibodies. JAMA Neurol 2017;74(10):1216-22. PMID 28873125
97: Karpati G, Pouliot Y, Carpenter S. Expressions of immunoreactive major histocompatibility complex products in human skeletal muscles. Ann Neurol 1988;23:64-72. PMID 3278673
98: Kassardjian CD, Lennon VA, Alfugham NB, Mahler M, Milone M. Clinical features and treatment outcomes of necrotizing autoimmune myopathy. JAMA Neurol 2015;72(9):996-1003. PMID 26192196
99: Kaufman LD, Kephart GM, Seidman RJ, et al. The spectrum of eosinophilic myositis. Clinical and immunopathogenic studies of three patients, and review of the literature [Review]. Arthritis Rheum 1993;36(7):1014-24. PMID 8318029
100: Kieseier BC, Schneider C, Clements JM, et al. Expression of specific matrix metalloproteinases in inflammatory myopathies. Brain 2001;124:341-51. PMID 11157561
101: Knutsen AP, Shah M, Schwartz KB, Tsai CC. Graft versus host-like illness in a child with Phenobarbital hypersensitivity. Pediatrics 1986;78(4):581-4. PMID 3763264
102: Krahn M, Lopez de Munain A, Streichenberger N, et al. CAPN3 mutations in patients with idiopathic eosinophilic myositis. Ann Neurol 2006;59:905-11. PMID 16607617
103: Kurtzmam DJ, Wright NA, Lin J, et al. Tofacitinib citrate for refractory cutaneous dermatomyositis: an alternative treatment. JAMA Dermatol 2016;152(8):944-5. PMID 27120749
104: Lakhanpal S, Duffy J, Engel AG. Eosinophilia associated with perimyositis and pneumonitis. Mayo Clin Proc 1988;63(1):37-41. PMID 3336240
105: Layzer RB, Shearn MA, Satya-Murti S. Eosinophilic polymyositis. Ann Neurol 1977;1:65-71. PMID 889290
106: Leon-Monzon M, Dalakas MC. Absence of persistent infection with enteroviruses in muscles of patients with inflammatory myopathies. Ann Neurol 1992;32:219-22. PMID 1324633
107: Leon-Monzon M, Lamperth L, Dalakas MC. Search for HIV proviral DNA and amplified sequences in the muscle biopsies of patients with HIV-polymyositis. Muscle Nerve 1993;16:408-13. PMID 8455655
108: Lim J, Eftimov F, Raaphorst J, Aronica E, van der Kooi AJ. Diagnostic value of additional histopathological fascia examination in idiopathic inflammatory myopathies. Eur J Neurol 2019;26(12):1494-6. PMID 31220379
109: Loarce-Martos J, Lilleker JB, Parker M, McHugh N, Chinoy H. Polymyositis: is there anything left? A retrospective diagnostic review from a tertiary myositis centre. Reumatology (Oxford) 2021;60(7):3398-403. PMID 33367878
110: Maalouly G, Hajal J, Saliba Y, et al. Beneficial role of simvastatin in experimental autoimmune myositis. Int Immunopharmacol 2020;79:106051. PMID 31863923
111: Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011;63(3):713-21. PMID 21360500
112: Mantegazza R, Andreetta F, Bernasconi P, et al. Analysis of T cell receptor repertoire of muscle-infiltrating T lymphocytes in polymyositis: restricted V alpha/beta rearrangements may indicate antigen-driven selection. J Clin Invest 1993;91:2880-6. PMID 8514895
113: Mastaglia FL. Treatment of autoimmune inflammatory myopathies. Curr Opin Neurol 2000;13:507-9. PMID 11073355
114: Mastaglia FL, Garlepp MJ, Phillips BA, Zilko PJ. Inflammatory myopathies: clinical, diagnostic and therapeutic aspects. Muscle Nerve 2003;27:407-25. PMID 12661042
115: Mescam-Mancini L, Allenbach Y, Hervier B, et al. Anti-Jo-1 antibody-positive patients show a characteristic necrotizing perifascicular myositis. Brain 2015;138(Pt 9):2485-92. PMID 26198592
116: Messina S, Fagiolari G, Lamperti C, et al. Women with pregnancy-related polymyositis and high serum CK levels in the newborn. Neurology 2002;58:482-4. PMID 11839858
117: Miller FW, Leitman SF, Cronin ME, et al. Controlled trial of plasma exchange and leukapheresis in polymyositis and dermatomyositis. N Engl J Med 1992;326(21):1380-4. PMID 1472183
118: Morgan OS, Rodgers-Johnson P, Mora C, Char G. HTLV-I and polymyositis in Jamaica. Lancet 1989;2:1184-7. PMID 2572904
119: Murata K, Dalakas MC. Expression of the costimulatory molecule BB-1, the ligands CTLA-4 and CD28 and their mRNA in inflammatory myopathies. Am J Pathol 1999;155:453-60. PMID 10433938
120: Musset L, Miyara M, Benveniste O, et al. Analysis of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase using different technologies. J Immunol Res 2014;2014:405956. PMID 24741598
121: Nagaraju K, Casciola-Rosen L, Lundberg I, et al. Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum 2005;52:1824-35. PMID 15934115
122: Nishio J, Suzuki M, Miyasaka N, Kohsaka H. Clonal biases of peripheral CD8 T cell repertoire directly reflect local inflammation in polymyositis. J Immunol 2001;167:4051-8. PMID 11564826
123: Oddis CV, Reed AM, Aggarwal R, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum 2013;65(2):314-24. PMID 23124935
124: O’Hanlon TP, Dalakas MC, Plotz PH, Miller FW. Predominant TCR-alpha-beta variable and joining gene expression by muscle-infiltrating lymphocytes in the idiopathic inflammatory myopathies. J Immunol 1994;152:2569-76. PMID 8133064
125: Otero C, Dalakas MC. Onset of polymyositis (PM) and dermatomyositis (DM) during pregnancy: report of 4 cases. Ann Neurol 1992;32:282.
126: Paik JJ, Casciola-Rosen L, Shin JY, et al. Study of tofacitinib in refractory dermatomyositis: an open-label pilot study of ten patients. Arthritis Rheumatol 2021;73(5):858-65. PMID 33258553
127: Patrick C, Jean-Christophe D, Jean-Charles C, Odile C. High-dose subcutaneous immunoglobulins for the treatment of severe treatment-resistant polymyositis. Case Rep Rheumatol 2014;2014:458231. PMID 25140268
128: Pestronk A, Kos K, Lopate G, Al-Lozi MT. Brachio-cervical inflammatory myopathies: clinical, immune, and myopathologic features. Arthritis Rheum 2006;54(5):1687-96. PMID 16646041
129: Preube C, Goebel HH, Held J, et al. Immune-mediated necrotizing myopathy is characterized by a specific Th1-M1 polarized immune profile. Am J Pathol 2012;181(6):2161-71. PMID 23058368
130: Preube C, Paesler B, Nelke C, et al. Skeletal muscle provides the immunological micro‑milieu for specific plasma cells in anti‑synthetase syndrome‑associated myositis. Acta Neuropathologica 2022;144(2):353-72. PMID 35612662
131: Raju R, Vasconcelos OM, Semino-Mora C, Granger RP, Dalakas MC. Expression of interferon-gamma inducible chemokines in the muscles of patients with inclusion body myositis. J Neuroimmunol 2003;141:125-31. PMID 12965263
132: Rowland LP. Polymyositis, inclusion body myositis and related myopathies. In: Rowland LP, editor. Merrit's textbook of neurology. 9th edition. Philadelphia: Lea & Febiger, 1995;798-802.
133: Schmidt J, Dalakas MC. Pathomechanisms of inflammatory myopathies: recent advances and implications for diagnosis and therapies. Expert Opin Med Diagn 2010;4(3):241-50. PMID 23488533
134: Schmidt J, Rakocevic G, Raju R, Dalakas MC. Upregulated inducible costimulator and ICOS-ligand in inclusion body myositis muscle: significance for CD8+ T cell cytotoxicity. Brain 2004;127(Pt 5):1182-90. PMID 15047591
135: Schneider C, Gold R, Schäfers M, Toyka KV. Mycophenolate mofetil in the therapy of polymyositis associated with a polyautoimmune syndrome. Muscle Nerve 2002;25:286-8. PMID 11870700
136: Seidman RJ, Kaufman LD, Sokoloff L, Miller F, Iliya A, Peress NS. The neuromuscular pathology of the eosinophilia-myalgia syndrome. J Neuropathol Exp Neurol 1991;50(1):49-62. PMID 1985153
137: Serratrice G, Pellissier JF, Roux H, Quilichini P. Fasciitis, perimyositis, myositis, polymyositis and eosinophilia [Review]. Muscle Nerve 1990;13(5):385-95. PMID 2189069
138: Shulman LE. Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome. J Rheumatol 1984;11(5):569-70. PMID 6542592
139: Siguergeirsson B, Lindelof B, Edhag O, Allander E. Risk of cancer in patients with dermastomyositis and polymyositis. N Engl J Med 1992;326:363-7.
140: Stenzel W, Preuße C, Allenbach Y, et al. Nuclear actin aggregation is a hallmark of anti-synthetase syndrome-induced disimmune myopathy. Neurology 2015;84(13):1346-54. PMID 25746564
141: Suber TL, Casciola-Rosen L, Rosen A. Mechanisms of disease: autoantigens as clues to the pathogenesis of myositis. Nat Clin Pract Rheumatol 2008;4(4):201-9. PMID 18319710
142: Sugiura T, Kawaguchi Y, Harigai M, et al. Increased CD40 expression on muscle cells of polymyositis and dermatomyositis: role of CD40-CD40 ligand interaction in IL-6, IL-8, IL-15 and monocyte chemoattractant protein-1 production. J Immunol 2000;164:6593-600. PMID 10843719
143: Tai PC, Hayes DJ, Clark JB, Spry CJ. Toxic effects of human eosinophil secretion products on isolated rat heart cells in vitro. Biochem J 1982;204:75-80. PMID 7115333
144: Tanboon J, Uruha A, Stenzel W, Nishino I. Where are we moving in the classification of idiopathic inflammatory myopathies? Curr Opin Neurol 2020;33(5):590-603. PMID 32852298
145: Targoff IN. Update on myositis-specific and myositis-associated autoantibodies. Curr Opin Rheumatol 2000;12:475-81. PMID 11092195
146: Tews DS, Goebel HH. Cytokine expression profile in idiopathic inflammatory myopathies. J Neuropathol Exp Neurol 1996;55:342-7. PMID 8786392
147: Trueb RM, Becker-Wegerich P, Hafner J, Wuthrich B, Burg G. Relapsing eosinophilic perimyositis. BR J Dermatol 1995;133(1):109-14. PMID 7669620
148: Trueb RM, Lubbe J, Toricelli R, Panizzon RG, Wuthrich B, Burg G. Eosinophilic myositis with eosinophilic cellulitis-like skin lesions. Association with increased serum levels of eosinophil cationic protein and interleukin-5. Arch Dermatol 1997;133(2):203-6. PMID 9041834
149: Vattemi G, Marini M, Di Chio M, Colpani M, Guglielmi V, Tomelleri G. Polymyositis in solid organ transplant recipients receiving tacrolimus. J Neurol Sci 2014;345(1-2):239-43. PMID 25130930
150: Wagner E. Fall einer seltnen Muskelkrankheit. Arch Heilkd 1863;4:288.
151: Walton JN, Adams RD. Polymyositis. London: E and S Livingston, 1938.
152: Warner CL, Fayad PB, Heffner RR Jr. Legionella myositis. Neurology 1991;41:750-2. PMID 2027497
153: Watanabe Y, Suzuki S, Nishimura H, et al. Statins and myotoxic effects associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies: an observational study in Japan. Medicine (Baltimore) 2015;94(4):e416. PMID 25634171
154: Watanabe Y, Uruha A, Suzuki S, et al. Clinical features and prognosis in anti-SRP and anti-HMGCR necrotizing myopathy. J Neurol Neurosurg Psychiatry 2016;87(10):1038-44. PMID 27147697
155: Weller PF. The immunobiology of eosinophils. N Engl J Med 1991;324:1110-8. PMID 2008184
156: Wiendl H, Hohlfeld R, Kieseier BC. Immunobiology of muscle: advances in understanding an immunological microenvironment. Trends Immunol 2005;26:373-80. PMID 15922662
157: Wiendl H, Mitsdoerffer M, Hofmeister V, et al. The nonclassical MHC molecule HLA-G protects human muscle cells from immune-mediated lysis: implications for myoblast transplantation and gene therapy. Brain 2003a;126:176-85. PMID 12477705
158: Wiendl H, Mitsdoerffer M, Schneider D, et al. Muscle fibers and cultured muscle cells express the B7.1/2 related costimulatory molecule ICOSL: implications for the pathogenesis of inflammatory myopathies. Brain 2003b;126:1026-35. PMID 12690043

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Polymyositis, necrotizing autoimmune myositis, myofasciitis, and overlap-myositis

Associated Disorders

AIDS
Collagen vascular diseases
Granulomatous diseases
Interstitial lung disease
Sarcoidosis
- Systemic immune-medicated disorders

Differential Diagnosis

hereditary neuromuscular disease
muscular dystrophies
metabolic myopathies
endocrinopathies
electrolyte disturbances
- mitochondriopathies
- systemic illness
- malabsorption syndromes
- alcoholism
- cancer
- vasculitis
- systemic infection
- sarcoidosis
- granulomatous disease
- treatment with myotoxic drugs
- neurogenic muscular dystrophies
- neurogenic conditions
- biochemical muscle disease
- inclusion body myositis
- necrotizing autoimmune myositis

Also Relevant

Dermatomyositis
Inclusion body myositis
Limb-girdle muscular dystrophies
Myositis and cancer
Neurologic complications of the hepatitis viruses
- Trichinosis
- Viral and retroviral myositis

Polymyositis, necrotizing autoimmune myositis, myofasciitis, and overlap-myositis …

Polymyositis, necrotizing autoimmune myositis, myofasciitis, and overlap-myositis

Introduction

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

Recommended therapeutic approach.

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Drug-induced myasthenic syndromes

Neuromyotonia and myokymia

Viral and retroviral myositis

Becker muscular dystrophy

Collagen VI–related dystrophies: Ullrich congenital muscular dystrophy, Bethlem muscular dystrophy, and intermediate COL6-RD

Bell palsy

Vogt-Koyanagi-Harada syndrome

Neuromyelitis optica spectrum disorders

Polymyositis, necrotizing autoimmune myositis, myofasciitis, and overlap-myositis

Introduction

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

Recommended therapeutic approach.

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Drug-induced myasthenic syndromes

Neuromyotonia and myokymia

Viral and retroviral myositis

Becker muscular dystrophy

Collagen VI–related dystrophies: Ullrich congenital muscular dystrophy, Bethlem muscular dystrophy, and intermediate COL6-RD

Bell palsy

Vogt-Koyanagi-Harada syndrome

Neuromyelitis optica spectrum disorders

This is an article preview.
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to access the full version.