Treatment and Management of Autoimmune Myopathies

Dermatomyositis

DM occurs in both children and adults. It is a distinct clinical entity because of a characteristic rash that accompanies or, more often, precedes muscle weakness. The skin manifestations include a heliotrope rash (blue-purple discoloration) with edema on the upper eyelids, a flat red rash on the face and upper trunk, and erythema of the knuckles with a raised violaceous scaly eruption (Gottron rash) ( Fig. 22.1 ) ( ; , ; ). The erythematous rash can also occur on other body surfaces, including the knees, elbows, malleoli, neck and anterior chest (often in a V sign), and back and shoulders (shawl sign), and may be exacerbated after exposure to the sun. The initial erythematous lesions may result in scaling of the skin, accompanied by pigmentation and depigmentation, giving a shiny appearance at times. Dilated capillary loops at the base of the fingernails are also characteristic of DM. The cuticles may be irregular, thickened, and distorted, and the lateral and palmar areas of the fingers may become rough and cracked, with irregular, “dirty” horizontal lines, resembling “mechanic’s hands.” DM in children resembles the adult disease. An early abnormality in children is “misery,” defined as an irritable child who feels uncomfortable, has a red flush on the face, is fatigued, does not feel like socializing, and has varying degrees of muscle weakness ( ). A tiptoe gait due to flexion contracture of the ankles is not unusual. In DM, the affected muscles are predominantly proximal, but the degree of weakness varies. It can be mild, moderate, or severe, leading to quadriparesis. In advanced cases, atrophy of the affected muscles takes place. Ocular and facial muscles remain normal even in advanced cases; if these muscles are affected, the diagnosis of inflammatory myopathy should be in doubt. The pharyngeal and neck extensor muscles can be involved, causing dysphagia and difficulty holding up the head. The tendon reflexes are preserved but may be absent in severely weakened or atrophied muscles. The respiratory muscles are rarely affected, but respiratory symptoms may not be uncommon due to interstitial lung disease. Myalgia and muscle tenderness may occur early in the disease, especially when DM occurs in the setting of a connective tissue disorder. In patients with DM who have severe muscle pain, involvement of the fascia should be suspected.

Some patients with the classic skin lesions may have clinically normal strength, even 3 to 5 years after onset. This form of DM, referred to as dermatomyositis sine myositis or amyopathic dermatomyositis ( ), has a better overall prognosis. Although in these cases the disease appears limited to the skin, the muscle biopsy shows significant perivascular and perimysial inflammation with immunopathologic features identical to those seen in classic DM, suggesting that the amyopathic and myopathic forms are part of the range of DM affecting skin and muscle to varying degrees ( ; ).

DM usually occurs alone, but it may overlap with scleroderma and mixed connective tissue disease. Fasciitis and skin changes similar to those found in DM have occurred in patients with eosinophilia-myalgia syndrome caused by the ingestion of contaminated l -tryptophan and in patients with eosinophilic fasciitis or macrophagic myofasciitis. In up to 15% of adult patients, the DM has a paraneoplastic association. Ovarian cancer is most frequent, followed by intestinal, breast, lung, and liver cancer. In Asian populations, nasopharyngeal cancer is more common ( ). Because tumors are often uncovered at autopsy or on the basis of abnormal findings on medical history and physical examination, blind radiologic searches are rarely fruitful. A complete annual physical examination with breast, pelvic, and rectal examinations (including colonoscopy in high-risk patients); urinalysis; complete blood cell count; blood chemistry tests; and chest radiograph is usually sufficient and is highly recommended, especially for the first 3 years.

Extramuscular manifestations may also be prominent in some patients with DM and include (1) dysphagia; (2) subcutaneous calcifications ( Fig. 22.2 ), sometimes opening onto the skin and causing ulcerations and infections, especially in children ( ); (3) contractures of the joints, especially in the childhood form; (4) pulmonary involvement due to interstitial lung disease, especially in patients who have anti-Jo-1 antibodies, as discussed later; (5) gastrointestinal ulcerations, due to vasculitis or infections; (6) general systemic disturbances, such as fever, malaise, weight loss, and arthralgia; and (7) Raynaud phenomenon, especially when DM is associated with a connective tissue disorder.

Polymyositis

PM has no unique clinical features, and it is often a diagnosis of exclusion ( , ; ; ; ). PM is a rare disorder that, by all accounts, is the most overdiagnosed acquired myopathy. The study of PM 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 two more common entities, the IBM and the NAM, are not overlooked ( ). If all other myopathies are carefully excluded, PM may not even exist today as a distinct entity (Dalakas,2020). For historical reasons, PM is best defined as an inflammatory myopathy of subacute onset (weeks to months) and steady progression that occurs in adults who do not have rash on the face, trunk, or fingers, as seen in DM; involvement of eye and facial muscles; family history of a neuromuscular disease; endocrinopathy; history of exposure to myotoxic drugs or toxins; and another myopathy such as dystrophy, metabolic myopathy, or IBM. Unlike DM, in which the rash secures early recognition, the actual onset of PM cannot be easily determined and the disease may exist for several months before the patient seeks medical advice.

Patients with PM commonly present with proximal and often symmetrical muscle weakness that develops over weeks to months, and rarely acutely. An acute onset should raise the suspicion of a necrotizing myopathy. Fine-motor movements that depend on the strength of distal muscles are affected only late in the disease. If these muscles are affected from the outset or early in the course of the disease, the diagnosis of IBM should be suspected. In advanced cases, atrophy of the affected muscles takes place. Ocular muscles remain normal even in advanced cases; if these muscles are affected, the diagnosis of inflammatory myopathy should be in doubt. In contrast with IBM, in which the facial muscles are affected in the majority of patients, in PM, the strength of the facial muscles remains normal except in rare advanced cases. The pharyngeal and neck extensor muscles can be involved, causing dysphagia and difficulty holding up the head. The tendon reflexes are preserved but may be absent in severely weakened or atrophied muscles. The respiratory muscles are rarely affected, but respiratory symptoms are not uncommon owing to interstitial lung disease, especially in patients with anti-Jo-1 antibodies or antibodies to various ribonucleoproteins ( , ; ; ; ). Although myalgia may occur early in the disease, most often, in the setting of a coexisting connective tissue disorder, severe muscle pain should raise the suspicion of fasciitis even if there are no overt signs of skin induration and thickness.

PM is extremely rare in childhood, and if a diagnosis is made in patients younger than 16 years, a careful review is needed to exclude another disease, especially one of the inflammatory dystrophies.

PM appears to be a syndrome of diverse causes. As a stand-alone clinical entity, it may not probably exist based on recent evidence (Dalakas, 2020). It is more frequently seen in association with connective tissue disorders, systemic autoimmune diseases, or viral infections, such as Sjögren syndrome, rheumatoid arthritis, Crohn disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult celiac disease, chronic graft-versus-host disease, discoid lupus, ankylosing spondylitis, Behçet 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, immunoglobulin A deficiency, and acquired immunodeficiency syndrome (AIDS). Among viruses, human immunodeficiency virus (HIV) and human T-lymphotrophic virus type I (HTLV-I) are the only viruses convincingly associated with PM. Claims that other viruses, such as enteroviruses, can be causally connected with PM are unproved. In contrast to DM, PM is not more frequently associated with cancer compared to other chronic autoimmune disorders treated with immunosuppressants.

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” ( ). 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, can now be seen in patients with AIDS. Certain bacteria, such as Borrelia burgdorferi of Lyme disease and Legionella pneumophila of legionnaires’ disease may infrequently be the cause of PM.

Drugs do not cause PM. The only drug that could change immunoregulation and trigger PM is d -penicillamine ( , ). Zidovudine and the cholesterol-lowering drugs can be myototoxic, but they cause a mitochondrial or a necrotizing myopathy that lacks the features of primary T-cell-mediated endomysial inflammation as seen in PM. In these cases, the muscle fibers demonstrate prominent mitochondrial or necrotic features with macrophages.

Necrotizing Autoimmune Myositis (Also Referred to as Immune-Mediated Necrotizing Myopathy)

NAM is turning out to be the most common subset among all the inflammatory muscle diseases, if IBM 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 ( , ; ). However, NAM still remains an overlooked entity, often misdiagnosed as PM. 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 major histocompatibility complex class I (MHC-I) expression as seen in PM and IBM, but the MHC-I expression is spotty. Up to 65% of these patients have antibodies against signal recognition particles (SRPs) or against a 100-kd autoantigen identified as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) ( , ; ).

Antisynthetase Syndrome” or “Overlap Myositis” or “Anti-Jo-1 Syndrome”

Anti-Jo-1 antibodies, directed against the histidyl-transfer RNA synthetase, the most common among the antisynthetases, define the “antisynthetase” or “overlap myositis” syndrome, which has now evolved into a distinct entity. It is 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 ( , , ; ; ; ); (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 ( , ; ; ; ).

Inclusion Body Myositis

IBM is the most common of the inflammatory myopathies. It affects men more often than women and is the most commonly acquired myopathy in men older than 50 years. Although IBM may be suspected when a patient with presumed PM does not respond to therapy, involvement of distal muscles, especially foot extensors and deep finger flexors in almost all cases ( Fig. 22.3 ), should be a clue to an early clinical diagnosis ( ; , , ; ; ; ; ; ; ; ). Some patients present with falls because their knees collapse owing to early weakness of the quadriceps muscles. Others present with weakness in the small muscles of the hands, especially the long finger flexors, and complain of inability to hold certain objects such as golf clubs, play the guitar, turn a key, or tie a knot. The weakness and the accompanying atrophy can be asymmetrical, with preferential involvement of the quadriceps ( Fig. 22.3A – C ), iliopsoas, triceps, biceps, and finger flexors in the forearm. This involvement is in contrast to the hereditary or familial quadriceps-sparing IBM ( ; , ), in which the quadriceps remains strong in spite of the weakness in the other muscles. The selective involvement of the flexor digitorum profundus has been confirmed with magnetic resonance imaging ( ). Dysphagia is quite common, occurring in up to 60% of the patients, especially late in the disease. Because of the distal and at times asymmetrical weakness and atrophy and the early loss of the patellar reflex, a lower motor neuron disease is occasionally suspected, especially since serum CK activity is either not elevated or only moderately increased ( ). Sensory examination is generally normal except for a mildly diminished vibratory sensation at the ankles, presumably related to the patient’s age. Contrary to early suggestions, the distal weakness does not represent neurogenic involvement but is part of the distal myopathic process, as confirmed with macro-electromyography (EMG) ( ). In contrast to PM and DM, in which facial muscles are spared, mild facial muscle weakness is very common and is noted in more than 60% of IBM patients ( ).

Sporadic IBM (s-IBM) can be associated with systemic autoimmune or connective tissue diseases in up to 33% of affected patients ( ; ). An increased frequency of DRb10301 and DQb10201 alleles associated with DR and DQ phenotypes has been documented in up to 75% of patients ( ). A frequent association with HLA-B8-DR3 haplotype has been also observed ( ). Familial aggregation of IBM with the typical clinical phenotype of s-IBM, and with histologic and immunopathologic features identical to the sporadic form, can also occur, as seen in other autoimmune disorders ( ). Our group has designated this as familial inflammatory IBM and emphasized that it should be distinguished from hereditary inclusion body myopathy (h-IBM), a noninflammatory vacuolar myopathy that spares the quadriceps ( ; ) and occurs mostly in Iranian Jews but also in other ethnic groups ( ; ). This disorder results from mutations in the uridine diphosphate- N -acetylglucosamine 2-epimerase/ N -acetylmannosamine kinase ( GNE ) gene ( ).

Progression of s-IBM is slow but steady. Data from 86 patients studied consecutively by the author’s group revealed that progression is faster when the disease begins later in life. Patients whose disease began in their 60s required an assistive device many years later compared with those whose disease began in their 70s, presumably because of lesser reserves ( ).

Eosinophilic Syndromes and Fasciitis

Prominent presence of eosinophilic polymorphonuclear leukocytes in muscle (or fascia) can occur in isolation or with systemic eosinophilia and is due to parasitic infection, vasculitis, hypereosinophilic syndrome, or toxic factors. In eosinophilic PM ( ; ), muscle involvement is part of a systemic hypereosinophilic syndrome. A marked systemic eosinophilia is present. Proximal limb muscles show stiffness, pain, and variable weakness. An important feature is thickening of the skin, mimicking scleroderma ( ). Serum CK activity is moderately elevated. The pathologic picture is similar to that of idiopathic PM, except that there is a conspicuous presence of eosinophilic polymorphonuclear leukocytes in the inflammatory infiltrates. Certain patients with genetically defined calpain-gene mutations were reported to have eosinophilic infiltrates in their muscle ( ). The frequency of this phenomenon and the role of eosinophils in myopathy remain unclear.

In eosinophilic fasciitis, the inflammatory reaction is restricted to the fascia and is best shown by a biopsy of the fascia lata. Eosinophilia-myalgia syndrome was also described in patients after prolonged oral intake of large doses of a contaminated l -tryptophan preparation taken as a therapeutic over-the-counter agent ( ). There was marked systemic eosinophilia with generalized myalgia and moderate muscle weakness ( ). The lymphocytic inflammatory infiltrates (CD8+ cytotoxic cells) also included either abundant or few eosinophilic polymorphonuclear leukocytes, mainly in the perimysial region and less often in the interstitial space of muscle ( ; ). Coexisting peripheral neuropathy was also noted. The pathogenic factor was a contamination of l -tryptophan with an acetaldehyde ditryptophan derivative, which seems to induce autosensitization. A distinctive inflammatory myofasciitis was also identified in up to 80 French patients who presented with myalgias, fatigue, and mild muscle weakness ( ). Muscle biopsy revealed pronounced infiltration of the connective tissue around the muscle (epimysium, perimysium, and perifascicular endomysium) by sheets of periodic acid–Schiff base-positive macrophages and occasional CD8+ T cells. The serum CK or erythrocyte sedimentation rate may at times be elevated. Most patients respond to glucocorticoid therapy, and the overall prognosis is favorable. The pathologic change is almost always seen at the sites of previous vaccinations, even several months later, and has been linked to a type of aluminum component used as a substrate for preparation of the vaccines. Macrophagic myofasciitis has been reported exclusively from France.

Diagnosis and Evaluation

The diagnosis of these disorders is based on the combination of clinical history, serum muscle enzymes, EMG, and muscle biopsy. The CK is elevated in all three subsets, but it can be normal or only slightly elevated in DM and IBM. The EMG is myopathic in all three and, although useful to exclude neurogenic disorders, it is insensitive to differentiate an inflammatory myopathy from other toxic or dystrophic myopathic processes. The muscle biopsy shows inflammatory features distinct for each subset and remains the most sensitive diagnostic tool. In DM, the inflammation is perivascular or at the periphery of the fascicle and is often associated with perifascicular atrophy ( Fig. 22.4 ); in PM and IBM, the inflammation is in multiple foci within the endomysial parenchyma ( Fig. 22.5 ) and consists predominantly of CD8+ T cells that invade healthy muscle fibers expressing the MHC-I antigen ( ). The MHC/CD8 complex is characteristic and useful for the diagnosis of PM and IBM ( ; , ). Plasma cells and dendritic cells are frequent among the infiltrates in all three disorders ( ). An additional feature in IBM is the presence of vacuoles containing 12- to 16-nm tubulofilaments with tiny deposits of amyloid and amyloid-related proteins ( Fig. 22.6 ) ( ; ). In IBM, the presence of 15- to 18-nm tubular filamentous masses in nuclei or cytoplasm of muscle fibers can be demonstrated with extensive ultrastructural scrutiny ( ). These filamentous masses are not disease specific but have been reported to be identical to the paired helical filaments found in neurons in Alzheimer disease ( ). The blue granules, located in or along the wall of the vacuoles, correspond to whorls of cytomembranes or myelin figures, detectable by electron microscopy ( ). Most important, congophilic material, best visualized by Texas-red fluorescent optics, can be found in a variable number of fibers usually in or near rimmed vacuoles ( ; ; ). Other degeneration-associated molecules such as beta-amyloid and its precursor protein, alpha-chymotrypsin, tau proteins, ubiquitin, apolipoprotein E, prion protein, and others are also found in a small percentage of fibers ( ; ). Although they help toward confirming the histologic diagnosis of IBM, they are not specific because they have been found in other myopathies ( ) or even in chronic neurogenic conditions such as the postpolio syndrome ( ). In IBM, the beta-amyloid appears targeted for lysosomal degradation via macroautophagy, as specific studies indicate ( ). Ragged red, cytochrome oxidase–negative muscle fibers with mitochondrial excess and multiple mitochondrial DNA deletions have been demonstrated in most examined cases ( ). Uniform expression of class I MHC products at the surface of most muscle fibers is characteristic of PM, IBM, and, in most cases, NAM, whereas in DM, this phenomenon may be evident only in the perifascicular or other random regions ( ; ). Ubiquitous expression of MHC-I does not occur in limb girdle dystrophy, denervating diseases, or metabolic myopathies (except in regenerating fibers or in fiber invaded by macrophages and lymphoid cells), which makes MHC immunostaining a very helpful diagnostic tool for PM, NAM, and IBM ( ).

Immunopathology

The cause of PM, DM, and IBM is unknown, but an autoimmune pathogenesis is strongly implicated.

Immunopathology of Dermatomyositis

In DM, there is evidence of a complement-mediated process based on immunopathologic studies performed on muscle biopsy specimens. The primary antigenic targets appear to be components of the endothelium of the blood vessels in the endomysium and probably the skin. Alterations in the endothelial cells consisting of pale and swollen cytoplasm with microvacuoles and tubuloreticular aggregates appear early in the disease. These changes are caused by immune complexes immunolocalized in the endomysial blood vessels along with the C5b-9 membranolytic attack complex, the lytic component of the complement pathway. The membranolytic attack complex and the early complement components C3b and C4b are deposited on the capillaries early in the disease and precede the signs of inflammation or structural changes in the muscle fibers ( , ; ; ; ). These complement fragments are also detected in the serum and correlate with disease activity. The disease probably begins when putative antibodies or other factors activate complement C3, C3b, and C4b fragments that lead to the formation of membranolytic attack complex, which is deposited in the endomysial microvasculature and leads to osmotic lysis of the endothelial cells and capillary necrosis ( , ; ; ; ). As a result, there is reduction in the number of capillaries per muscle fiber, impaired perfusion, and dilatation of the loop of the remaining capillaries in an effort to compensate for the ischemic process. Larger intramuscular blood vessels are also affected in the same pattern, leading to muscle fiber destruction (often resembling microinfarcts) and inflammation. The perifascicular atrophy often seen in more chronic stages is probably a reflection of the endofascicular hypoperfusion that is prominent distally.

The activation of complement induces the release of cytokines and chemokines such as interleukins (IL-1, IL-6) and tumor necrosis factor (TNF), which, in turn, upregulate the expression of VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) on the endothelial cells and facilitate the transmigration of activated T cells to the perimysial and endomysial spaces. Immunophenotypic analysis of the lymphocytic infiltrates demonstrates B cells, CD4+ cells, and plasmacytoid dendritic cells in the perimysial and perivascular regions, supporting the view that a humoral-mediated mechanism plays the major role in the disease. In the perifascicular regions, there is also upregulation of various molecules such as cathepsins and signal transduction and activation of transducer molecules, probably triggered by interferon-γ, TGF-β (transforming growth factor-beta), and myxovirus resistance protein MxA induced by α/β interferon, which is probably secreted by the large number of plasmacytoid dendritic cells ( ). Based on gene arrays, a number of adhesion molecules, cytokines, and chemokine genes are also upregulated in the muscles of DM patients. Most notable among those genes are the X-linked Kallmann syndrome-1 protein (KAL-1) adhesion molecule ( ) and genes induced by α/β interferon ( ). KAL-1 is upregulated by TGF-β and may have a deleterious role in DM by inducing fibrosis. Of interest, KAL-1, along with TGF-β, is downregulated in the muscles of DM patients who improved after therapy, and it is most clinically relevant ( ). A summary of the immunopathology of DM is shown in Fig. 22.7 .

Immunopathology of Polymyositis and Inclusion Body Myositis

PM and IBM may be some of the best studied or prototypic T cell–mediated disorders in which cytotoxic T cells directed against heretofore unidentified muscle antigens form an immunologic synapse with the MHC-I antigen expressed on the surface of muscle fibers. The cytotoxicity of the autoinvasive T cells has been supported by the presence of perforin granules that are directed toward the surface of the muscle fiber and lead to muscle fiber necrosis on release. The specificity of the T cells has been further examined by studying the gene rearrangement of the T-cell receptors (TCRs) of the autoinvasive T cells ( ; ). In patients with PM, as well as IBM, only certain T cells of specific TCR-alpha and TCR-beta families are recruited to the muscle from the circulation. Cloning and sequencing of the amplified endomysial TCR gene families have demonstrated a restricted use of the J-beta gene with conserved amino acid sequence in the CDR3 region, the antigen-binding region of the TCR, indicating that CD8+ cells are specifically selected and clonally expanded in situ by muscle-specific autoantigens. Studies combining laser microdissection, immunocytochemistry, polymerase chain reaction (PCR), and sequencing of the most prominent TCR families have shown that only the autoinvasive, not the perivascular, endomysial CD8+ cells are clonally expanded. Comparison of the TCR repertoire between PM and DM with spectratyping has confirmed that perturbations of the TCR families occur only in PM but not DM. Further, among the circulating T cells, clonal expansion occurs only in the cytotoxic CD8+ cells that express genes for perforin and infiltrate the MHC-I-expressing muscle fibers ( Fig. 22.8 ).

The clonally expanded CD8+ T cells form immunologic synapses with the muscle fibers they invade, as supported by the coexpression of costimulatory molecules B7-1, B7-2, BB1, CD40, or inducible costimulator (ICOS) ligand (ICOS-L) on the muscle fibers and the respective counterreceptors CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), CD40 ligand (CD40L), or ICOS on autoinvasive T cells ( ; ; ). Cytokines, chemokines, and metalloproteinases (fundamental molecules for T-cell activation, trafficking, antigen recognition, and T-cell attachment) are also upregulated in the muscle tissue. Some of these cytokines, such as interferon-γ, IL-1β, and TNF, may exert a direct cytotoxic effect on the muscle tissue. Unique to the muscle is the observation that the various cytokines and chemokines can also stimulate the muscle fibers to endogenously produce certain proinflammatory cytokines, such as interferon-γ, which enhances and perpetuates the immune response.

In PM, MHC-I is expressed in all fibers, even in those not invaded by T cells, often throughout the course of the disease. Such a chronic MHC-I upregulation may be exerting a deleterious stress effect to the endoplasmic reticulum (ER) of the myofiber, independent of T cell–mediated cytotoxicity, as discussed next.

The factors triggering the T cell–mediated process in PM and IBM remain unclear. Viruses may be responsible for breaking tolerance, and several of the common viruses, including coxsackievirus, influenza virus, paramyxoviruses, cytomegalovirus, and Epstein-Barr virus, have been directly associated with chronic and acute myositis ( ). Very sensitive PCR studies, however, have repeatedly failed to confirm the presence of such viruses in these patients’ muscle biopsies ( ; ).

The best evidence of possible viral connection in PM and IBM is with the retroviruses. Monkeys infected with the simian immunodeficiency virus and humans infected with HIV and HTLV-I develop PM or IBM. In humans infected with HIV or HTLV-I, an isolated inflammatory myopathy may occur as the initial manifestation of the retroviral infection or myositis may develop later in the disease course ( ; ; ; ; ; ; ; ; ; ; ; ). The association of retroviruses with s-IBM is more than a coincidence because large numbers of HIV/HTLV-I positive patients with IBM have been now reported from many centers worldwide ( ; ; , ; ). In these seropositive patients, the disease appears before the age of 50 but several years after the first manifestations of the retroviral infection, suggesting that in HIV-positive patients who live longer and harbor the virus for several years, the disease is more frequently recognized. The clinical phenotype and muscle histologic findings in HIV-IBM patients are identical to the retroviral-negative IBM ( ; ). Using in situ hybridization, PCR, immunocytochemistry, and electron microscopy, viral antigens could not be detected within the muscle fibers but only in occasional endomysial macrophages ( ; ; ; , ; , ; ). Molecular immunologic studies using tetramers have shown that retrovirus-specific cytotoxic T cells, whose TCR contains amino acid residues for specific HLA/viral peptides, are recruited within the clonally expanded T cells and invade muscle fibers ( ; ). We have interpreted these observations to suggest that in HIV and HTLV-I IBM, there is no evidence of persistent infection of the muscle fibers with the virus or viral replication within the muscle but rather that the chronic retroviral infection, in genetically susceptible individuals, triggers a persistent inflammatory process that leads to s-IBM ( ; ).

Humoral factors also seem to play a role in IBM as exemplified by observations of isolated single plasma cells from muscle sections. A series of recombinant immunoglobulins reconstructed from these cells recognized self-antigens expressed by cell lines and in muscle tissue homogenates. One of the putative antigens is identified as the 5’-nucleotidase 1A (anti-cN1A), an enzyme involved in nucleotide metabolism that is highly expressed in skeletal muscle. Anti-cN1A antibodies were detected in 33% to 50% of patients with IBM ( ; ). Although these antibodies do not have distinct specificity for IBM as they are also observed with lower frequency in other autoimmune diseases ( ), their presence strengthens the view of a humoral immune response in IBM.

Immunopathology of Necrotizing Autoimmune Myositis

The cause of NAM is multifactorial. A higher incidence of cancer has been observed in several cases ( ), while others developed NAM during therapy with checkpoint inhibitors for advanced malignancies ( ); some patients have an active viral infection (i.e., HIV); others may have a smoldering underlying autoimmune process; and still others have no other disease or apparent exposure to exogenous agents ( ). Recently, in the setting of COVID19 viral infection, a number of patients with clinical features on NAM and very high CK levels have been observed ( ). Some cases have been thought to have a statin exposure ( ; ) based on the assumption that statins, in addition to rarely causing an acute self-limited toxic myopathy, can also induce an autoimmune necrotizing myositis that persists after statin withdrawal, although a connection with statin-triggered autoimmunity has never been established ( ). It is likely that NAM could be an antibody-mediated disease, as implied by the presence of specific antibodies and complement deposits, even though the pathogenic role of these antibodies has not been established ( ; , , ). It is still unclear if the recruitment of macrophages represents an antibody-dependent cell-mediated cytotoxicity process ( ; ).

The connection of NAM with statins has been strongly promoted by one group based on retrospective—over many years—historical chart review, which revealed anti-HMGCR autoantibodies in 45 of 750 patients (6%) with all myopathies, and among those patients aged 50 years and older, 92.3% had at some point taken statins ( ). Because statins upregulate the expression of HMGCR in cultured cells and HMGCR is the target of action of statins, a possible triggering cause was formulated and the term “statin myopathy” was coined. Such cause-and-effect relationship was never, however, substantiated , nor did it take into account that 25% of Americans above 40 years take statins. Further, 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, challenging the statin connection ( ; ). Considering that NAM is now one of the most common inflammatory myopathies and millions of people above 40 years take statins, the association between statins and NAM is likely a chance phenomenon, especially since their role in inducing NAM has not been proven ( , ). Some authors correctly proposed that the term “statin myopathy” should not be used because only a minority of NAM patients had statin exposure and, most importantly, they developed NAM many years after statin initiation, which makes their causative role dubious.