Developments in the Classification and Treatment of the Juvenile Idiopathic Inflammatory Myopathies




This review updates recent trends in the classification of the juvenile idiopathic inflammatory myopathies (JIIM) and the emerging standard of treatment of the most common form of JIIM, juvenile dermatomyositis. The JIIM are rare, heterogeneous autoimmune diseases that share chronic muscle inflammation and weakness. A growing spectrum of clinicopathologic groups and serologic phenotypes defined by the presence of myositis autoantibodies are now recognized, each with differing demographics, clinical manifestations, laboratory findings, and prognoses. Although daily oral corticosteroids remain the backbone of treatment, disease-modifying anti-rheumatic drugs are almost always used adjunctively and biologic therapies may benefit patients with recalcitrant disease.


Key points








  • Juvenile dermatomyositis is the most common clinicopathologic form of the juvenile idiopathic inflammatory myopathies (IIM), but juvenile polymyositis and overlap myositis are additional distinct groups with higher morbidity and mortality rates.



  • Myositis-specific and myositis-associated autoantibodies define several distinct serologic subgroups of juvenile myositis, which share many features with those of patients with adult IIM with the same autoantibodies. Of these, anti-p155/140 and anti-MJ autoantibodies are the most common in juvenile IIM.



  • Based on expert consensus and a randomized controlled trial, the combination of daily prednisone with methotrexate is the initial treatment of choice for moderately active juvenile dermatomyositis. Other agents, including intravenous methylprednisolone, intravenous immunoglobulin, and cyclosporine, may be used in combination with them or may serve as alternative agents to methotrexate.



  • Early evidence primarily from open-label studies and one randomized controlled trial suggest a role for additional drug and biologic therapies in treatment-refractory patients.




The juvenile idiopathic inflammatory myopathies (JIIM) are heterogeneous immune-mediated disorders characterized by chronic skeletal muscle inflammation but often include characteristic skin rashes and involvement of other organs. The diagnosis of these conditions remains based on the clinical and laboratory criteria of Bohan and Peter, with acknowledged limitations that many pediatric patients with characteristic rashes do not undergo electromyography or muscle biopsy. These disorders can be classified based on clinicopathologic features or on the presence of autoantibodies found almost exclusively in patients with myositis, known as the myositis autoantibodies. This subclassification of JIIM assists in understanding patients who share demographic and clinical features, laboratory abnormalities, responses to therapy, and prognoses. The authors now present an update to our understanding of the classification of juvenile myositis from work first published more than 15 years ago and an update on recent advances in the treatment of JIIM, reflecting collaborative multicenter studies and the introduction of biologic therapies for these diseases.




Clinicopathologic classification of JIIM


The recent classification has been achieved by large registry studies that have better defined the features of the most common phenotypes and additional case series and reports that have enhanced our understanding of the spectrum of the rarer clinical phenotypes. The classification of JIIM, based on clinical and histologic features, has been recognized both in adults and children with myositis, with the finding that the same clinical subgroups exist in JIIM as adult IIM but with different relative frequencies and slight differences in manifestations and prognoses. Although JIIM is 5-fold less common than adult IIM, in children, dermatomyositis (DM) is the most frequent of the IIMs, whereas polymyositis (PM) is relatively more frequent in adults than in children. Inclusion body myositis (IBM) and cancer-associated myositis are almost exclusively seen in adults. Since the authors’ first proposal of clinicopathologic groups for JIIM, several new forms of IIM have been recognized, including macrophagic myofasciitis and immune-mediated necrotizing myopathy, and the spectrum of amyopathic DM has expanded to include hypomyopathic DM ( Table 1 ). Infantile polymyositis is no longer recognized as a subgroup of JIIM but was found to be a muscular dystrophy (laminin alpha2 or merosin deficiency).



Table 1

A clinicopathologic classification of the JIIM















































































Clinicopathologic Phenotype Frequency in JIIM (%) Associations & Comments References
DM 85 Most common form of JIIM in children with median age at onset of 7.5 y and female predominance; characterized by Gottron papules or heliotrope rash, and CD4+ T cells and dendritic cells in perivascular distribution in muscle with a type I interferon signature; approximately 50%–60% of patients have a chronic course, and 24%–40% have a monocyclic course of illness; up to 25% have skin or gastrointestinal ulcerations; calcinosis seen in 25%–40% and lipodystrophy in ∼10%, with a spectrum of other associated manifestations
Overlap myositis 6–12 Patients meet criteria for another autoimmune disease, most frequently systemic sclerosis, systemic lupus erythematosus, juvenile idiopathic arthritis, localized scleroderma, Sjögren syndrome, or type I diabetes; Raynaud phenomenon, interstitial lung disease, arthritis, sclerodactyly, and calcinosis are more frequent in this subgroup; mortality is high, often related to lung disease
PM 4–8 Defined by the absence of the characteristic DM rashes; pathogenesis involves CD8+ endomysial infiltration in muscle; patients tend to be older (preteen or teenage), have higher CK levels, and more severe illness onset, with frequent falling episodes as a sign of distal weakness, myalgias, more frequent cardiac involvement, and intermediate mortality
Amyopathic or hypomyopathic DM 1 DM skin rashes, either without muscle weakness or with subclinical muscle weakness detected only by additional testing (eg, elevated serum muscle enzymes or abnormal EMG, muscle biopsy, or MRI); approximately 25% of patients develop JDM within 3 y; calcinosis has been reported in only 4%, and cutaneous ulcerations and interstitial lung disease are very rare; none of the children have malignancy, in contrast to adults with clinically amyopathic DM whereby these associated features are common.
IBM Rare Characterized by slowly progressive proximal and distal weakness, low serum CK level, and rimmed vacuoles on trichrome stain of muscle biopsy, with poor responses to immunosuppressive therapy; only a few case reports in teenage boys, whereas IBM is a major clinical subgroup in adults, suggesting a degenerative pathogenesis and/or environmental triggers that are present only in older adults or that have long latency
Cancer-associated myositis <1 Malignancy in association with JIIM is so uncommon that routine screening for cancer is generally not warranted, in contrast to adults with DM and PM whereby a malignancy screen is routinely performed because of a paraneoplastic association within 2 y of myositis onset; atypical illness features, such as prominent adenopathy, hepatosplenomegaly, palpable masses, and atypical rashes, have been proposed as part of a profile of indicators that may indicate an underlying associated malignancy that has been observed in most of the 17 reported cases of cancer associated with JIIM; most common cancers in children include lymphoma, leukemia, and solid organ tumors
Focal myositis 1–2 Characterized by a subacute, often painful intramuscular swelling or mass in a single muscle group, sometimes preceded by trauma, with histologic features of myositis; most common sites of involvement are the thigh muscles, gastrocnemius, brachialis, and sternocleidomastoid; lesions often spontaneously resolve, but immunosuppressive therapy or surgical resection may be beneficial in refractory cases
Orbital myositis 1–2 A focal myositis of the rectus muscles, which presents with ocular pain, headache, diplopia, proptosis, ocular injection, limited ocular mobility, and periorbital edema; children may have atypical presentations, including emesis, anorexia, lethargy, abdominal pain, and weight loss; inflammation of an orbital muscle must be distinguished clinically from thyroid-associated orbitopathy, but the differential diagnosis also includes rhabdomyosarcoma, lymphoproliferative disease, IgG4-related disease, or histiocytosis X; pediatric cases also differ from their adult counterparts in that they are more likely to be bilateral on presentation or associated with uveitis, disc edema, or eosinophilia; orbital myositis may be seen following an infection, such as group A streptococcus, or in the setting of other autoimmune conditions, including inflammatory bowel disease, linear scleroderma, or Kawasaki disease
Immune-mediated necrotizing myopathy 1 PM or DM in which the muscle biopsy demonstrates prominent muscle necrosis and little inflammation; thought to be mediated by autoantibodies, including anti–signal recognition particle or anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase
Macrophagic myofasciitis <1 An inflammatory myopathy thought to be related to aluminum-adjuvant vaccines; presents with prominent macrophagic infiltrates and aluminum detectable in the muscle; symptoms include myalgias, arthralgias, muscle weakness, chronic fatigue, and fever; in children, additional features include hypotonia, motor delay with an inability to stand or walk, and failure to thrive; typically, vaccination predates the diagnosis by 2–12 mo, and childhood-onset cases are generally in the first 5 y
Eosinophilic myositis <1 Prominent eosinophilic infiltrates on muscle biopsy, often accompanied by peripheral eosinophilia; may be idiopathic and true polymyositis or focal in nature; may also be drug induced, related to a parasitic infection, or to an underlying hypereosinophilic syndrome; in children, it is particularly important to exclude muscular dystrophies, including calpainopathy, Becker dystrophy, and gamma sarcoglycanopathy (LGMD2 C), which have been reported to present with eosinophilic myositis
Granulomatous myositis <1 Granulomas prominent in the muscle, which may be idiopathic or seen in association with Wegener vasculitis, sarcoidosis, or tuberculosis
Proliferative myositis Rare A very rare benign pseudosarcomatous lesion of skeletal muscle; may be diagnosed with fine-needle aspiration cytology, which shows hypercellular and polymorphic lesional cells and distinctive ganglion cell-like cells; most lesions resolve spontaneously within 4 mo; surgical resection is used for the remaining lesions
Graft-versus-host myositis Rare Polymyositis with weakness, myalgias, and elevated CK, which rarely occurs as part of graft-versus-host disease following stem cell and bone marrow transplantation; responds to prednisone and cyclosporine

Abbreviations: CK, creatine kinase; DM, dermatomyositis; EMG, electromyogram; Ig, immunoglobulin; MRI, magnetic resonance imaging; PM, polymyositis.


The most common clinical phenotype of myositis in children, constituting approximately 85% of all patients with JIIM, is juvenile DM (JDM), which is characterized by symmetric proximal muscle weakness and the presence of characteristic rashes (ie, Gottron papules [erythematous plaques overlying the extensor joint surfaces] or heliotrope rash [a purplish or erythematous rash over the eyelids]). One of the hallmarks of JDM, vasculopathy, is evident by examining the periungual capillaries, which are often dilated, tortuous, and decreased in density because of an immune-mediated attack, which is distinct from vasculitis. Several national registry studies have expanded our understanding of the clinical spectrum of JDM as a systemic autoimmune disease. Patients with JDM have a median age at onset of 7.5 years; in addition to the characteristic skin rashes, they have frequent malar rash, photosensitivity, linear extensor erythema, and other cutaneous findings. Their creatine kinase (CK) levels are elevated but they tend to be lower. The prognosis of JDM is variable, with a low overall mortality of 2% to 3%, and approximately 24% to 40% of patients having a monocyclic course, recovering with appropriate therapy within a 2-year period. However, the majority (50%–60%) of patients with JDM experience a chronic illness course. Persistent periungual capillary abnormalities and active skin disease have been associated with a chronic illness course. Patients with a chronic illness course and poor prognosis might also have cutaneous or gastrointestinal ulcerations or, less commonly, pulmonary or gastrointestinal tract air leaks (pneumomediastinum or pneumatosis intestinalis), indicating severe vasculopathy. Calcinosis occurs in 20% to 40% of patients, with a lower prevalence in patients treated more aggressively who enter remission more rapidly. Calcium and phosphate precipitate in the subcutaneous tissues and muscles as carbonate apatite, perhaps as a result of a loss of mineralization inhibitors. The risk factors for calcinosis include delay to diagnosis, cardiac involvement, the need for additional immunosuppressive therapy, as well as a prolonged and/or severe illness course. Another complication of JDM, lipodystrophy, occurs in up to 10% of patients and is characterized by progressive loss of subcutaneous fat in a localized, partial (ie, only in the extremities), or widespread distribution. Lipodystrophy has been associated with calcinosis, muscle atrophy, joint contractures, and facial rash and should be recognized early because of its association with metabolic sequelae of insulin resistance, diabetes, and hyperlipidemia, with frequencies proportionate to the degree of fat loss.


Overlap myositis , in which patients meet the criteria for JIIM as well as another autoimmune disease, is the next most common clinical phenotype of JIIM, occurring in 6% to 11% of patients. Raynaud phenomenon, interstitial lung disease, arthritis, and malar rash are more frequent illness features in this subgroup. Patients with overlap myositis are more likely to have JDM than juvenile PM (JPM), more often have myositis-associated autoantibodies, and are more often nonwhite. Among the JIIM subgroups, overlap myositis has a relatively higher mortality rate, which is often related to lung disease. The most common overlapping autoimmune conditions include systemic lupus erythematosus, juvenile idiopathic arthritis, systemic sclerosis, and localized scleroderma. Although organ-specific autoantibodies, including those for autoimmune thyroid disease and hepatitis, type I diabetes, and celiac disease, have been observed in 2% to 15% of patients with JDM, these autoantibodies were not accompanied by overt organ-specific overlapping autoimmune diseases in one population.


JPM, which is seen in about 4% to 8% of patients with JIIM, is characterized by both proximal and distal muscle weakness but lacks the characteristic rashes of JDM. The pathologic findings also differ from JDM, with frequent endomysial infiltrates in affected muscles. Patients with JPM tend to be older, with the onset in preteen or teenage years, have higher CK levels, more myalgias, and a more severe illness onset. They often have frequent falling episodes, a sign of distal weakness; cardiac involvement occurs in approximately one-third of patients with JPM. Mortality is intermediate between JDM and overlap myositis. A muscle biopsy is required for diagnosis because JPM is often misdiagnosed in patients who actually have other noninflammatory myopathies, particularly muscular dystrophies, which have more frequent myopathic features on biopsy and clinical muscle atrophy. Patients with JPM also frequently have myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs), particularly anti–aminoacyl-tRNA synthetase (antisynthetase) and anti–signal recognition particle (SRP) autoantibodies.


The other clinicopathologic phenotypes of the JIIM are uncommon (see Table 1 ). Of these, true DM sine myositis without evidence of muscle involvement is rare. However, hypomyopathic DM is occasionally observed, in which DM skin rashes are present for at least 6 months in patients who have no detectable weakness but have evidence of muscle inflammation on testing (including elevated serum muscle enzyme levels, or an abnormal electromyogram, muscle biopsy, or muscle magnetic resonance imaging [MRI]). A thorough review of 68 cases of juvenile-onset, clinically amyopathic DM, which encompasses both DM sine myositis and hypomyopathic DM, showed that 26% of the patients subsequently developed classic JDM and that this disease progression occurred up to several years later. At the onset, only 4% of those patients had an elevated CK level; of those with a normal CK level, only a minority had an abnormal electromyogram, muscle biopsy, or MRI, suggesting that these patients can be treated symptomatically for their cutaneous disease, with close clinical monitoring for progression to muscle involvement. Calcinosis was reported in only 4%, and none had ulcerations, interstitial lung disease, or malignancy, which are the manifestations that are often associated with amyopathic DM in adults. A case report noted cutaneous ulcerations and interstitial lung disease in a lethal case of juvenile clinically amyopathic DM. The outcome of hypomyopathic DM seems to be good; for example, in 24 patients, 65% recovered spontaneously without therapy, and 5 of 10 patients treated with systemic therapy entered remission.


Malignancy in association with JIIM is so uncommon that routine screening for cancer is generally not warranted. In contrast, adults with DM and PM routinely undergo malignancy screening because of an increased risk for malignancy within 2 years of myositis onset. Nevertheless, a tumor may present with an autoimmune, myositis-like picture in childhood. In a Brazilian registry of 189 patients with JIIM, there was an associated malignancy in 2 (1.1%) cases ; but in other large JIIM registry studies, coexisting cancer was not reported. Atypical illness features, including prominent adenopathy, hepatosplenomegaly, palpable masses, and atypical rashes, have been proposed to be part of a profile of indicators that might indicate an underlying malignancy because at least one of those features was observed in most of the 17 reported cases of cancer in association with JIIM. The most common associated cancers in children have included lymphoma, leukemia, and solid organ tumors.


Focal myositis , alternatively termed an inflammatory pseudotumor or focal nodular myositis , is characterized by an often painful intramuscular swelling or mass in a single muscle group that develops over several weeks or months, sometimes preceded by trauma. The most common sites of involvement are the thigh muscle groups, gastrocnemius, brachialis, and sternocleidomastoid; but any muscle may be affected. This disorder must be distinguished from malignant tumors and infectious causes, including Lyme disease. Although typically an isolated phenomenon, it can be associated with other rheumatic diseases. Histologic changes include fibrosis and intramuscular inflammation, particularly infiltration of macrophages that are occasionally accompanied by prominent eosinophils and CD4+ lymphocytes. Cases with severe inflammation have elevated B cells and plasmacytoid dendritic cells. Limited follow-up found spontaneous resolution in several cases, with immunosuppressive therapy or surgical resection used for refractory disease. A higher CK level or erythrocyte sedimentation rate, or limb atrophy may signal an increased risk of recurrence or progression to multifocal IIM.


Macrophagic myofasciitis (MMF) is an inflammatory myopathy that is thought to be related to aluminum-adjuvant vaccines. MMF often has an active lesion at the immunization site; systemic symptoms include myalgias, arthralgias, muscle weakness, chronic fatigue, and fever. In children, additional features include hypotonia, motor delay with an inability to stand or walk, and failure to thrive. Scanning electron microscopy with energy dispersive spectroscopy has been used to detect aluminum in tissue specimens. Histologically, granulomas comprised of periodic acid-Schiff–positive and CD68-positive macrophages are generally seen. Typically, vaccination predates the diagnosis by 2 to 12 months but has been as long as 10 years prior. MMF often occurs in individuals who have genetic susceptibility, particularly the human leukocyte antigen (HLA)-DRB1*01 allele.


Other clinicopathologic forms of JIIM are rare and are described in Table 1 .




Clinicopathologic classification of JIIM


The recent classification has been achieved by large registry studies that have better defined the features of the most common phenotypes and additional case series and reports that have enhanced our understanding of the spectrum of the rarer clinical phenotypes. The classification of JIIM, based on clinical and histologic features, has been recognized both in adults and children with myositis, with the finding that the same clinical subgroups exist in JIIM as adult IIM but with different relative frequencies and slight differences in manifestations and prognoses. Although JIIM is 5-fold less common than adult IIM, in children, dermatomyositis (DM) is the most frequent of the IIMs, whereas polymyositis (PM) is relatively more frequent in adults than in children. Inclusion body myositis (IBM) and cancer-associated myositis are almost exclusively seen in adults. Since the authors’ first proposal of clinicopathologic groups for JIIM, several new forms of IIM have been recognized, including macrophagic myofasciitis and immune-mediated necrotizing myopathy, and the spectrum of amyopathic DM has expanded to include hypomyopathic DM ( Table 1 ). Infantile polymyositis is no longer recognized as a subgroup of JIIM but was found to be a muscular dystrophy (laminin alpha2 or merosin deficiency).



Table 1

A clinicopathologic classification of the JIIM















































































Clinicopathologic Phenotype Frequency in JIIM (%) Associations & Comments References
DM 85 Most common form of JIIM in children with median age at onset of 7.5 y and female predominance; characterized by Gottron papules or heliotrope rash, and CD4+ T cells and dendritic cells in perivascular distribution in muscle with a type I interferon signature; approximately 50%–60% of patients have a chronic course, and 24%–40% have a monocyclic course of illness; up to 25% have skin or gastrointestinal ulcerations; calcinosis seen in 25%–40% and lipodystrophy in ∼10%, with a spectrum of other associated manifestations
Overlap myositis 6–12 Patients meet criteria for another autoimmune disease, most frequently systemic sclerosis, systemic lupus erythematosus, juvenile idiopathic arthritis, localized scleroderma, Sjögren syndrome, or type I diabetes; Raynaud phenomenon, interstitial lung disease, arthritis, sclerodactyly, and calcinosis are more frequent in this subgroup; mortality is high, often related to lung disease
PM 4–8 Defined by the absence of the characteristic DM rashes; pathogenesis involves CD8+ endomysial infiltration in muscle; patients tend to be older (preteen or teenage), have higher CK levels, and more severe illness onset, with frequent falling episodes as a sign of distal weakness, myalgias, more frequent cardiac involvement, and intermediate mortality
Amyopathic or hypomyopathic DM 1 DM skin rashes, either without muscle weakness or with subclinical muscle weakness detected only by additional testing (eg, elevated serum muscle enzymes or abnormal EMG, muscle biopsy, or MRI); approximately 25% of patients develop JDM within 3 y; calcinosis has been reported in only 4%, and cutaneous ulcerations and interstitial lung disease are very rare; none of the children have malignancy, in contrast to adults with clinically amyopathic DM whereby these associated features are common.
IBM Rare Characterized by slowly progressive proximal and distal weakness, low serum CK level, and rimmed vacuoles on trichrome stain of muscle biopsy, with poor responses to immunosuppressive therapy; only a few case reports in teenage boys, whereas IBM is a major clinical subgroup in adults, suggesting a degenerative pathogenesis and/or environmental triggers that are present only in older adults or that have long latency
Cancer-associated myositis <1 Malignancy in association with JIIM is so uncommon that routine screening for cancer is generally not warranted, in contrast to adults with DM and PM whereby a malignancy screen is routinely performed because of a paraneoplastic association within 2 y of myositis onset; atypical illness features, such as prominent adenopathy, hepatosplenomegaly, palpable masses, and atypical rashes, have been proposed as part of a profile of indicators that may indicate an underlying associated malignancy that has been observed in most of the 17 reported cases of cancer associated with JIIM; most common cancers in children include lymphoma, leukemia, and solid organ tumors
Focal myositis 1–2 Characterized by a subacute, often painful intramuscular swelling or mass in a single muscle group, sometimes preceded by trauma, with histologic features of myositis; most common sites of involvement are the thigh muscles, gastrocnemius, brachialis, and sternocleidomastoid; lesions often spontaneously resolve, but immunosuppressive therapy or surgical resection may be beneficial in refractory cases
Orbital myositis 1–2 A focal myositis of the rectus muscles, which presents with ocular pain, headache, diplopia, proptosis, ocular injection, limited ocular mobility, and periorbital edema; children may have atypical presentations, including emesis, anorexia, lethargy, abdominal pain, and weight loss; inflammation of an orbital muscle must be distinguished clinically from thyroid-associated orbitopathy, but the differential diagnosis also includes rhabdomyosarcoma, lymphoproliferative disease, IgG4-related disease, or histiocytosis X; pediatric cases also differ from their adult counterparts in that they are more likely to be bilateral on presentation or associated with uveitis, disc edema, or eosinophilia; orbital myositis may be seen following an infection, such as group A streptococcus, or in the setting of other autoimmune conditions, including inflammatory bowel disease, linear scleroderma, or Kawasaki disease
Immune-mediated necrotizing myopathy 1 PM or DM in which the muscle biopsy demonstrates prominent muscle necrosis and little inflammation; thought to be mediated by autoantibodies, including anti–signal recognition particle or anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase
Macrophagic myofasciitis <1 An inflammatory myopathy thought to be related to aluminum-adjuvant vaccines; presents with prominent macrophagic infiltrates and aluminum detectable in the muscle; symptoms include myalgias, arthralgias, muscle weakness, chronic fatigue, and fever; in children, additional features include hypotonia, motor delay with an inability to stand or walk, and failure to thrive; typically, vaccination predates the diagnosis by 2–12 mo, and childhood-onset cases are generally in the first 5 y
Eosinophilic myositis <1 Prominent eosinophilic infiltrates on muscle biopsy, often accompanied by peripheral eosinophilia; may be idiopathic and true polymyositis or focal in nature; may also be drug induced, related to a parasitic infection, or to an underlying hypereosinophilic syndrome; in children, it is particularly important to exclude muscular dystrophies, including calpainopathy, Becker dystrophy, and gamma sarcoglycanopathy (LGMD2 C), which have been reported to present with eosinophilic myositis
Granulomatous myositis <1 Granulomas prominent in the muscle, which may be idiopathic or seen in association with Wegener vasculitis, sarcoidosis, or tuberculosis
Proliferative myositis Rare A very rare benign pseudosarcomatous lesion of skeletal muscle; may be diagnosed with fine-needle aspiration cytology, which shows hypercellular and polymorphic lesional cells and distinctive ganglion cell-like cells; most lesions resolve spontaneously within 4 mo; surgical resection is used for the remaining lesions
Graft-versus-host myositis Rare Polymyositis with weakness, myalgias, and elevated CK, which rarely occurs as part of graft-versus-host disease following stem cell and bone marrow transplantation; responds to prednisone and cyclosporine

Abbreviations: CK, creatine kinase; DM, dermatomyositis; EMG, electromyogram; Ig, immunoglobulin; MRI, magnetic resonance imaging; PM, polymyositis.


The most common clinical phenotype of myositis in children, constituting approximately 85% of all patients with JIIM, is juvenile DM (JDM), which is characterized by symmetric proximal muscle weakness and the presence of characteristic rashes (ie, Gottron papules [erythematous plaques overlying the extensor joint surfaces] or heliotrope rash [a purplish or erythematous rash over the eyelids]). One of the hallmarks of JDM, vasculopathy, is evident by examining the periungual capillaries, which are often dilated, tortuous, and decreased in density because of an immune-mediated attack, which is distinct from vasculitis. Several national registry studies have expanded our understanding of the clinical spectrum of JDM as a systemic autoimmune disease. Patients with JDM have a median age at onset of 7.5 years; in addition to the characteristic skin rashes, they have frequent malar rash, photosensitivity, linear extensor erythema, and other cutaneous findings. Their creatine kinase (CK) levels are elevated but they tend to be lower. The prognosis of JDM is variable, with a low overall mortality of 2% to 3%, and approximately 24% to 40% of patients having a monocyclic course, recovering with appropriate therapy within a 2-year period. However, the majority (50%–60%) of patients with JDM experience a chronic illness course. Persistent periungual capillary abnormalities and active skin disease have been associated with a chronic illness course. Patients with a chronic illness course and poor prognosis might also have cutaneous or gastrointestinal ulcerations or, less commonly, pulmonary or gastrointestinal tract air leaks (pneumomediastinum or pneumatosis intestinalis), indicating severe vasculopathy. Calcinosis occurs in 20% to 40% of patients, with a lower prevalence in patients treated more aggressively who enter remission more rapidly. Calcium and phosphate precipitate in the subcutaneous tissues and muscles as carbonate apatite, perhaps as a result of a loss of mineralization inhibitors. The risk factors for calcinosis include delay to diagnosis, cardiac involvement, the need for additional immunosuppressive therapy, as well as a prolonged and/or severe illness course. Another complication of JDM, lipodystrophy, occurs in up to 10% of patients and is characterized by progressive loss of subcutaneous fat in a localized, partial (ie, only in the extremities), or widespread distribution. Lipodystrophy has been associated with calcinosis, muscle atrophy, joint contractures, and facial rash and should be recognized early because of its association with metabolic sequelae of insulin resistance, diabetes, and hyperlipidemia, with frequencies proportionate to the degree of fat loss.


Overlap myositis , in which patients meet the criteria for JIIM as well as another autoimmune disease, is the next most common clinical phenotype of JIIM, occurring in 6% to 11% of patients. Raynaud phenomenon, interstitial lung disease, arthritis, and malar rash are more frequent illness features in this subgroup. Patients with overlap myositis are more likely to have JDM than juvenile PM (JPM), more often have myositis-associated autoantibodies, and are more often nonwhite. Among the JIIM subgroups, overlap myositis has a relatively higher mortality rate, which is often related to lung disease. The most common overlapping autoimmune conditions include systemic lupus erythematosus, juvenile idiopathic arthritis, systemic sclerosis, and localized scleroderma. Although organ-specific autoantibodies, including those for autoimmune thyroid disease and hepatitis, type I diabetes, and celiac disease, have been observed in 2% to 15% of patients with JDM, these autoantibodies were not accompanied by overt organ-specific overlapping autoimmune diseases in one population.


JPM, which is seen in about 4% to 8% of patients with JIIM, is characterized by both proximal and distal muscle weakness but lacks the characteristic rashes of JDM. The pathologic findings also differ from JDM, with frequent endomysial infiltrates in affected muscles. Patients with JPM tend to be older, with the onset in preteen or teenage years, have higher CK levels, more myalgias, and a more severe illness onset. They often have frequent falling episodes, a sign of distal weakness; cardiac involvement occurs in approximately one-third of patients with JPM. Mortality is intermediate between JDM and overlap myositis. A muscle biopsy is required for diagnosis because JPM is often misdiagnosed in patients who actually have other noninflammatory myopathies, particularly muscular dystrophies, which have more frequent myopathic features on biopsy and clinical muscle atrophy. Patients with JPM also frequently have myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs), particularly anti–aminoacyl-tRNA synthetase (antisynthetase) and anti–signal recognition particle (SRP) autoantibodies.


The other clinicopathologic phenotypes of the JIIM are uncommon (see Table 1 ). Of these, true DM sine myositis without evidence of muscle involvement is rare. However, hypomyopathic DM is occasionally observed, in which DM skin rashes are present for at least 6 months in patients who have no detectable weakness but have evidence of muscle inflammation on testing (including elevated serum muscle enzyme levels, or an abnormal electromyogram, muscle biopsy, or muscle magnetic resonance imaging [MRI]). A thorough review of 68 cases of juvenile-onset, clinically amyopathic DM, which encompasses both DM sine myositis and hypomyopathic DM, showed that 26% of the patients subsequently developed classic JDM and that this disease progression occurred up to several years later. At the onset, only 4% of those patients had an elevated CK level; of those with a normal CK level, only a minority had an abnormal electromyogram, muscle biopsy, or MRI, suggesting that these patients can be treated symptomatically for their cutaneous disease, with close clinical monitoring for progression to muscle involvement. Calcinosis was reported in only 4%, and none had ulcerations, interstitial lung disease, or malignancy, which are the manifestations that are often associated with amyopathic DM in adults. A case report noted cutaneous ulcerations and interstitial lung disease in a lethal case of juvenile clinically amyopathic DM. The outcome of hypomyopathic DM seems to be good; for example, in 24 patients, 65% recovered spontaneously without therapy, and 5 of 10 patients treated with systemic therapy entered remission.


Malignancy in association with JIIM is so uncommon that routine screening for cancer is generally not warranted. In contrast, adults with DM and PM routinely undergo malignancy screening because of an increased risk for malignancy within 2 years of myositis onset. Nevertheless, a tumor may present with an autoimmune, myositis-like picture in childhood. In a Brazilian registry of 189 patients with JIIM, there was an associated malignancy in 2 (1.1%) cases ; but in other large JIIM registry studies, coexisting cancer was not reported. Atypical illness features, including prominent adenopathy, hepatosplenomegaly, palpable masses, and atypical rashes, have been proposed to be part of a profile of indicators that might indicate an underlying malignancy because at least one of those features was observed in most of the 17 reported cases of cancer in association with JIIM. The most common associated cancers in children have included lymphoma, leukemia, and solid organ tumors.


Focal myositis , alternatively termed an inflammatory pseudotumor or focal nodular myositis , is characterized by an often painful intramuscular swelling or mass in a single muscle group that develops over several weeks or months, sometimes preceded by trauma. The most common sites of involvement are the thigh muscle groups, gastrocnemius, brachialis, and sternocleidomastoid; but any muscle may be affected. This disorder must be distinguished from malignant tumors and infectious causes, including Lyme disease. Although typically an isolated phenomenon, it can be associated with other rheumatic diseases. Histologic changes include fibrosis and intramuscular inflammation, particularly infiltration of macrophages that are occasionally accompanied by prominent eosinophils and CD4+ lymphocytes. Cases with severe inflammation have elevated B cells and plasmacytoid dendritic cells. Limited follow-up found spontaneous resolution in several cases, with immunosuppressive therapy or surgical resection used for refractory disease. A higher CK level or erythrocyte sedimentation rate, or limb atrophy may signal an increased risk of recurrence or progression to multifocal IIM.


Macrophagic myofasciitis (MMF) is an inflammatory myopathy that is thought to be related to aluminum-adjuvant vaccines. MMF often has an active lesion at the immunization site; systemic symptoms include myalgias, arthralgias, muscle weakness, chronic fatigue, and fever. In children, additional features include hypotonia, motor delay with an inability to stand or walk, and failure to thrive. Scanning electron microscopy with energy dispersive spectroscopy has been used to detect aluminum in tissue specimens. Histologically, granulomas comprised of periodic acid-Schiff–positive and CD68-positive macrophages are generally seen. Typically, vaccination predates the diagnosis by 2 to 12 months but has been as long as 10 years prior. MMF often occurs in individuals who have genetic susceptibility, particularly the human leukocyte antigen (HLA)-DRB1*01 allele.


Other clinicopathologic forms of JIIM are rare and are described in Table 1 .




Serologic classification of JIIM


An alternative classification of the JIM is by the presence of myositis autoantibodies. Two classes of autoantibodies include MSAs, which are present almost exclusively in patients with myositis, and MAAs, which are present in patients with myositis and in patients with other autoimmune diseases ( Table 2 ). As the recognition of myositis autoantibodies has increased recently, this has enabled the identification of a myositis autoantibody in approximately 70% of patients with JIIM. These myositis autoantibodies define more homogeneous groups of patients with similar clinical features, responses to therapy, and prognoses. Of the autoantibodies studied in both children and adults, generally the same myositis autoantibodies have been seen, although some of them differ in frequency between children and adults. For example, anti-p155/140 and anti-MJ autoantibodies seem to be more prevalent in JDM than adult DM; conversely, the anti-synthetase autoantibodies, which are seen in approximately 5% of patients with JIIM, are present in 25% to 40% of patients with adult IIM. There are also many similarities in the clinical and demographic features, laboratory findings, and prognoses between patients with JIIM and patients with adult IIM with the same myositis autoantibodies. Myositis autoantibodies are most accurately detected by validated protein and RNA immunoprecipitation assays, with certain autoantibodies, particularly anti-p155/140 and anti-MJ, requiring additional confirmation by reverse immunoprecipitation-immunoblotting or immunodepletion methods. A line-blot assay is almost as sensitive and specific as protein immunoprecipitation in detecting the traditional MSAs and MAAs.



Table 2

A serologic classification of the JIIM
































































































Serologic Group Frequency (%) Clinical Subgroup Association in JIIM Comments References
MSA
Anti-p155/140 (TIF1-γ) 23–30 JDM and JDM with overlap myositis Associated with extensive photosensitive skin rashes, including the characteristic rashes of JDM, malar rash, V-sign and shawl-sign rashes, and linear extensor erythema, as well as periungual capillary changes, skin ulceration, and generalized lipodystrophy; patients frequently have a chronic illness course; not associated with cancer-associated myositis, which differs from patients with adult IIM with this autoantibody
Anti-MJ (NXP-2) 20–25 Primarily JDM Frequent muscle cramps, dysphonia, joint contractures, and a monocyclic illness course; this autoantibody group seems to have more severe illness, with some reports of increased calcinosis, frequent muscle atrophy, more frequent hospitalizations and gastrointestinal ulceration
Anti–aminoacyl-tRNA synthetases (Jo1 & non-Jo1 synthetases) 2–4 JDM, JPM, & overlap myositis More common in JPM (9%) and patients with juvenile overlap myositis (8%–13%); frequent ILD, arthritis, Raynaud phenomenon, fevers, and mechanic’s hands, similar to adults with these autoantibodies; among the MSA phenotypes, this group has the highest mortality caused by ILD
Anti-SRP 1 JPM More common in JPM (18%); seen primarily in African American girls with JPM who have severe to profound proximal and distal muscle weakness, frequent falling episodes, Raynaud phenomenon, very high CK levels, wheelchair use, and a chronic illness course; cardiac disease is also likely associated, and these patients are refractory to several therapies, similar to patients with adult IIM with anti-SRP autoantibodies
Anti-Mi-2 (NuRD) 2–13 JDM & overlap myositis JDM with classic cutaneous findings of Gottron papules, heliotrope rash, and malar rash; predominantly seen in Hispanic patients; mild disease, but children have higher CK levels than adults with this autoantibody
Anti-CADM-140 (MDA-5) Unknown JDM Associated with DM and clinically amyopathic DM in adults who frequently have rapidly progressive ILD, cutaneous ulceration, and palmar papules, with a high fatality rate; 7 patients with JDM or amyopathic JDM and ILD have been reported with this autoantibody; to date, most reports are from Japan, and mortality has been high
Anti-SAE 0.2 JDM Associated with DM cutaneous manifestations, which predate development of muscle symptoms, an absence of constitutional manifestations, and low frequency of ILD
MAA
Anti-U1-RNP 5–10 JDM, JPM, & overlap myositis More common in JPM (12%) and overlap myositis (20%–27%); associated with arthritis, Raynaud phenomenon, and sclerodactyly
Anti-Ro 2–6 JDM, JPM, & overlap myositis More common in overlap myositis (8%–15%); little known about the associated clinical features; associated with impaired lung function in 1 report; in adults, patients respond well to prednisone alone; may be seen in association with anti-Jo1 autoantibodies
Anti-PM-Scl 1–4 JDM, JPM, & overlap myositis More common in JPM (6%) and overlap myositis (10%–25%); based on adult cohorts, this autoantibody is associated with Raynaud phenomenon, arthritis, ILD, and esophageal dysmotility; most frequent in Caucasian patients with an HLA DRB1*0301 immunogenetic association
Anti-Ku 0.2 JDM, JPM, & overlap myositis More common in overlap myositis (2%); based on adult cohorts, frequently associated manifestations include arthralgia, Raynaud phenomenon, myalgias, dysphagia, and less commonly, ILD; patients respond well to corticosteroids alone, except those with lung disease
Other MAAs: anti-U2-, U3- or U5-RNP; anti-La; anti-Sm; anti-Th <1 JDM, JPM, & overlap myositis Each autoantibody is present more frequently in overlap myositis (1%–10%); little known, primarily associated with overlap myositis
Myositis autoantibody negative 28–57 JDM, JPM, & overlap myositis Relatively mild disease in this subgroup; this group is likely heterogeneous, with several different unrecognized autoantibody groups contained within

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Developments in the Classification and Treatment of the Juvenile Idiopathic Inflammatory Myopathies

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