Infectious Agents and JDM

In addition to temporal and seasonal differences, there may be regional differences in infectious agents identified in association with the first symptoms of JDM. Agents associated with the onset (and on occasion, flare) of JDM include group A beta hemolytic streptococci and the RNA picornaviruses. Other infections that have been implicated in the pathogenesis of JDM include parvovirus, influenza, parainfluenza, and Borellia , as well as parasites, such as Toxoplasmosis gondii , but no evidence of related DNA or RNA has been identified in affected JDM muscle. Enteroviral agents are the most tantalizing, when antibody studies are considered. Newly diagnosed children (1974–1980) from the Chicago area were tested and displayed an increased frequency of antibody—both neutralizing (N) and complement fixing (CF)—to the coxsackievirus B antigen. There may be wide variation in different years, because these data were not reproduced by the same laboratory in a study of 20 children with dermatomyositis from the same region with onset of disease in the years 1987 to 1992. In studies searching for genetic evidence of infection, enteroviral RNA was identified in the muscle of UK patients with PM/DM, which was not confirmed in a similar patient population living in Sweden. Echovirus has been linked to the development of inflammatory myopathy in children with hypogammaglobulinemia and growth hormone deficiency, which was exacerbated by administration of growth hormone. In contrast, evidence of viral RNA has not been identified in the muscle biopsies from patients with myositis living in the United States, either in Jo-1 positive adults or in newly diagnosed, untreated children with active JDM, who had the specific area of the inflamed muscle identified for biopsy by MRI scan. There is also a possible role for molecular mimicry. Evidence supporting this hypothesis is based on a report of a protein present in skeletal myosin (which has homology with the streptococcal type 5M protein), which stimulated peripheral blood mononuclear cells in vitro . Blood from children who had “flares” of their dermatomyositis symptoms following streptococcal infections show a higher proliferative response than blood from children without a known antigen exposure. In parallel studies, an epitope specific for rheumatic fever did not stimulate the peripheral blood mononuclear cells from children with JDM.

Early reports of JDM suggested that exposure to T. gondii or hepatitis B might initiate the inflammatory myopathy. However, antibody titers to these agents were not increased either in a case control regional study, which tested sera from children with JDM in the mid-1980s or in a national case control study of new onset JDM. Noninfectious agents and exposures currently posited as causative agents in JDM include vaccines (hepatitis B, measles-mumps-rubella vaccine, typhoid, cholera) which a recent thoughtful appraisal could not refute. These data contributed to the current ban on the administration of live viral vaccines to children with JDM, irrespective of the level of their disease activity. In addition, drugs such as d -penicillamine, growth hormone, and bone marrow transplants in which graft versus host myositis occurs as a component of immune activation have been invoked as contributing factors to the display of IIM symptoms. Of note, influenza B, which typically causes a short episode of pain in the calf muscles of young children has not been associated with the development of juvenile chronic myositis. Taken together, the above data suggest that the etiology of JDM appears to be multifactorial, and may encompass a specific epitope(s) and environmental conditions in individuals who have a genetic predisposition to develop IIM.

Genetic Data

Several lines of evidence indicate that there is a strong genetic component that contributes to JDM display of symptoms. Although JDM may occur sporadically in more than one family member, the disease has been reported in monozygotic twins in whom muscle-related abnormalities developed 2 weeks after an upper respiratory infection. Proteomic studies of monozygotic twins with autoimmune disease, including JDM, suggests that autoimmune diseases share common pathways. Specific genetic associations have focused on the region controlling autoimmunity on chromosome 6 and previous data have identified DR3*0301 and TNFα in linkage disequilibrium with DQA1*0501 and DQA*0301 in US white patients. The strong association of JDM/DM and JPM/PM with this specific region on chromosome 6 was confirmed by a Genome Wide Association Study (GWAS) of a large population of Western European adult and pediatric patients with these diseases ( Figure 42.4 ). However, this association appears to be modified by race. When 151 white American adults with idiopathic inflammatory myopathy (IIM) were compared with 50 Korean adults with IIM, the linked allele DQA1*0501 and DRB1 alleles sharing the first hypervariable region motif 9EYSTS13 were major genetic risk factors for the development of myositis in Americans. Although both the white and Korean patients had similar distributions of clinical characteristics, autoantibody profiles, and clinical groups, none of the HLA-DRB1 or DQA1 alleles or motifs was a risk factor for IIM in the Korean patients. These data support the currently held assumption that the genetic risk factors for the inflammatory myopathies are multifactorial and appear to be associated with the patient’s ethnicity.

Genome Wide Association Study (GWAS). Manhattan plot of 1178 patients (European) with dermatomyositis (matched controls=4724) showing p values for 242,876 SNPs successfully genotyped. The orange line=7.3 (p=5×10 ⁻⁸ ) and the blue line=4 (p=1×10 ⁻⁴ ). SNP, single nucleotide polymorphism (2).

Reproduced with permission from Miller et al. (2013).

When muscle from untreated children with definite JDM was examined, Wt-1 (Wilms Tumor 1) was found to be massively hypomethylated, in contrast to the age-matched healthy controls. Of note, this hypomethylation was also true for children with JIIM who had partial therapy or those with overlap or JPM, suggesting that less muscle wasting may occur in children because they still have the capacity to repair cell damage—controlled by Wt-1. Studies of microRNA (mi-RNA) arrays in untreated JDM muscle disclosed that the mi-12 was downregulated and controlled the inflammatory cytokine cascade via NFkB. In addition, downregulation of mi-12 was associated with increased von Willebrand Factor-antigen (vWF:Ag) in JDM sera, suggesting that this might be one of the inflammatory pathways that contribute to the widespread microvascular vascular damage seen in JDM.

Maternal factors also might be associated with susceptibility to JDM. Boys with JDM appear to be chimeric because 73% of the boys had peripheral blood mononuclear cells (PBMCs) that contained female (XX) cells. These cells were positive for HLA-DQA1*0501 and were activated by the host male cells, which suggests that this antigen (or related MHC antigen) may be an important indicator of predisposing factor(s) for JDM (see the following).

Cutaneous Findings

One of the early symptoms of JDM is an intermittent periorbital edema, which may be the only presenting sign. Periorbital erythema and edema ( Figure 42.1A ), and eyelid capillary vessel dilation may persist long after other signs and symptoms of disease activity have resolved; these are present in the majority of affected children. We have observed a flare in several children indicated only by erythema of the pinna of the ears, heralding the development of full-blown involvement of muscle and skin. As in children with systemic lupus erythematosus (SLE), the erythematous rash may cross the bridge of the nose and is malar in distribution. Sun exposure can precipitate exacerbation of symptoms (the children may sunburn easily) either initially, or once the disease has been diagnosed and treated. When rash is the first definite symptom of JDM, it is first observed in the summer months in 41% of newly diagnosed cases of JDM. Other areas of capillary involvement can be seen on inspection of the roof of the mouth, which shows dilated erythematous capillaries at the junction of the hard and soft palate, as well as swollen and often bleeding erythematous gums.

Proceeding distally, other cutaneous features include the neck, which may have a rash extending to the upper torso (the shawl sign) ( Figure 42.1B ). The examiner may find involvement of the extensor surfaces of the arms and legs, medial malleoli of the ankles, as well as the buttocks ( Figure 42.1C ), all of which may occur in the absence of elevated serum concentrations of muscle-derived enzymes. Skin over the knuckles (metacarpophalangeal joints and proximal interphalangeal joints) is often either hypertrophic or pale red (Gottron’s sign) and evolves into colorless bands of atrophic skin, which, during active disease, may have a papular, “alligator skin” type of appearance (Gottron’s papules) ( Figure 42.1D ). Pathologic calcifications occur at pressure points, which, if they break through the skin, offer a portal for infection (see Figure 42.1E and C ). Partial baldness may result as a consequence of chronic scalp inflammation ( Figure 42.5B ). The cuticle becomes dry and children frequently try to bite away the thickened skin at the base of the nailbeds. Other cutaneous signs found in JDM include paronychiae, often located on the lateral aspects of the nail of the great toe, which improve with symptomatic care and return of sufficient peripheral vascular blood flow. Livedo reticularis (lacy patterning on the skin) is frequent in children with Raynaud’s phenomenon and may indicate the presence of a hypercoagulable state as well as the presence of an antiphospholipid antibody. An excellent catalog of cutaneous manifestations in JDM is readily available. Newly diagnosed JDM parents, who were interviewed within 6 months of diagnosis, identified the rash of JDM before proximal muscle weakness in more than 50% of the children. The parents recognized the rash at the same time as the weakness in another 23% of children, and, in the remainder of the JDM children (27%), weakness was the first symptom reported by parents ( Table 42.4 ). Many children present with the amyopathic form of JDM (rash only) much later in their disease course. It is now recognized that anti-MDA5 antibody may be associated with malignancy in adults with amyopathic disease.

Features of chronic long-standing disease in JDM. ( A ) Lipoatrophy showing loss of fat over hand/fingers. ( B ) Scarring of the scalp following chronic inflammation with extensive hair loss. ( C ) Extension of pathological calcifications as seen on radiograph of the arm of a child with long-standing active disease.

The vascular features are one of the hallmarks of JDM. The upper eyelid margins frequently have a fringe of dilated capillaries ( Figure 42.2A ), some of which become thrombosed in active disease. The rash has a violaceous or heliotrope hue and is often most prominent on the eyelid where small infarctions can occur, as well as in the area of the medial canthi near the eyes in children who have a prominent component of necrotizing vasculopathy. Rarely, children with a chronic disease course can present with eyelid telangiectasia ( Figure 42.2B ). The spectrum of capillary changes in the nailfold is shown in Figure 42.2C1, 2, and 3 . The association with the number of nailfold capillary end row loops and the severity of the rash but not the muscle involvement is graphed in Figure 42.2D and the occlusion of capillaries and arterioles is demonstrated in the muscle biopsy ( Figure 42.2E ). If the active symptoms of JDM have been present for more than 1 year before treatment, there is greater likelihood that the lipodystrophy will be easy to detect ( Figure 42.5A ) (see information on chronic course later in this section).

Musculoskeletal Symptoms

Weakness is the first symptom in about 25% of cases ( Table 42.3 ) and is routinely evaluated using the Childhood Myositis Assessment Scale (CMAS). The evaluation of muscle strength is challenging in children, because it requires voluntary cooperation (see later section “Evaluation Tools for Disease Activity and Chronicity”). Proximal muscle weakness may be detected when the child has difficulty with climbing stairs, getting up from a chair, combing hair, or when using their hands to push off from the body in an attempt to stand up from the floor (Gowers’ sign). Weakness of the neck flexors, a particularly sensitive indicator of muscular impairment, is often the first area of impairment, and is frequently the last sign of weakness to normalize. Truncal weakness is common and can be demonstrated by asking the child to perform a sit-up (without a counterbalance to the feet) with the arms held in three positions: extended, crossed on the chest, and behind the head. However, even a healthy child younger than 5 years is often not able to clear the scapula; the endurance test of holding first the right arm and then the right leg off the examining table was not achievable by a good proportion of healthy children. More than 60% of children with JDM complain of pain on proximal, but not distal, compression of muscles, which is seen in PM and overlap syndromes, but it is less severe than the muscle pain in bacterial myopathies. Children with spinal muscular atrophy do not usually have muscle pain on compression. Fatigue is a common symptom of many dystrophies (especially Duchenne’s and Becker’s) and is not useful in differentiating children with JDM. Usually the child with an inflammatory myopathy is more comfortable when the limbs are held in the flexed position, promoting the development of flexion contractures, which may be difficult to reverse.

Cardiorespiratory Abnormalities

In more than half the children with definite JDM the electrocardiogram is abnormal at diagnosis. Asymptomatic conduction abnormalities predominate, with an occasional complete block of the right bundle branch, which usually resolves with control of the inflammatory process. Dilated cardiomyopathy can be a rare presenting complaint and usually resolves when all the indicators of immunologic activation have normalized. Tachycardia is common at diagnosis and when it continues during the disease course it reflects cardiac compromise, which can be detected by an increase in cardiac-specific indicators, such as troponin levels. Because the respiratory musculature in the trunk is almost always involved, most cases of untreated JDM have a restrictive ventilatory defect, accompanied by a decrease in ventilatory capacity. The decrease in ventilatory capacity can also be associated with diminished speech volume. A husky voice or vocal cord nodules, presumably as a result of the stress of trying to be heard, are present in approximately 3% of the over 600 children with JDM followed at our center. A study of long-term follow-up identified restrictive pulmonary impairment, associated with long-term JDM damage in 8% of patients, indicating a need for repetitive pulmonary follow-up in JDM patients.

Pulmonary Fibrosis

Pulmonary fibrosis is more commonly found in individuals who carry an antibody to the t-RNA synthetases, of which anti-Jo-1 is the most common. Children with JDM who have an antibody to Ro, or patients with an overlap syndrome with antibody to U1 RNP, or those with antibody to signal recognition particle (SRP) or anti-alanyl-tRNA synthetase (Pl-12), have a higher frequency of pulmonary fibrosis. They may develop a honeycomb appearance at the base of the lung, identified by high resolution computed tomography scan of the chest, and decreased diffusion of CO ₂ and FEV1 on pulmonary function testing. It is critical to identify ILD early in the disease course, for not only is ILD a cause of death in older patients with JDM, but if recognized and treated promptly with compliance in childhood, the fibrosis can be reversed.

Gastrointestinal Involvement

The most severe prognostic indicator is impairment of the flow of secretions associated with decreased esophageal motility. This can be demonstrated by a rehabilitation cookie swallow with radiographic contrast, which shows retention of barium in a widened atonic, pyriform sinus, which can be associated with a “stacked coin” appearance. This anatomic change could allow swallowed liquids to penetrate the adjacent unprotected airway. Esophageal reflux may result in aspiration pneumonia, and appropriate precautions should be taken (e.g. using thickened foods, raising the head of the bed, and giving attention to clearing the respiratory tree). Involvement of the masseter muscles ( Figure 42.1A ) may be associated with difficulty in chewing as well as with swelling of the cheek(s) and the gradual development (over weeks/months) of buccal fat atrophy characteristic of partial lipodystrophy.

Boys and girls with untreated JDM were shorter and lighter than national norms (p>0.0005 for both), perhaps reflecting decreased GI absorption secondary to inflammation, and nonwhite children were weaker than white children (p>0.0005). Older children had more dysphagia (p=0.017) and arthritis (p>0.001). Vasculopathy can affect any part of the gastrointestinal tract. In severe disease, in addition to weight loss, mucosal ulceration with melena can occur with the possibility of life-threatening perforation. Pneumatosis intestinalis can occur as well, requiring bowel rest and aggressive immunosuppression. In the young child, development of normal speech patterns can be disturbed; soft palate involvement is often revealed by nasal, high-pitched speech (e.g. identified by having the child say the letter “E”) and usually resolves with a decrease in the inflammatory component of the myositis. A dilated atonic esophagus can be associated not only with delayed gastric emptying but also with infectious or neoplastic diseases. Smooth muscle dysfunction can also result in decreased lower gastrointestinal motility, making constipation an early and easily ascertainable symptom that responds to a stool modifier, such as Marilax, although chronic intermittent diarrhea has also been reported by the children or their parents as well. If there is a family history of celiac disease or the physician has an increased index of suspicion, then a celiac panel should be obtained, which if positive, should be confirmed by gastrointestinal biopsy, before the children embark on a gluten-free diet because they are thought to have celiac disease.

Genitourinary Function

Severe inflammation can result in massive breakdown of muscle elements as well as primary compromise of the renal parenchyma itself, which may culminate in acute renal failure. This requires prompt hydration with monitoring of renal function. Necrosis of the ureter with calcifications has been reported, involving the middle (iliac) segment, because of the relatively sparse blood supply to this region compared with the upper (lumbar) or lower (pelvic) segments.

Reproductive function may be altered in acute or chronic disease: menses may cease during severe disease, only to resume after the active inflammation is controlled. One study identified delayed menarche with normal cycles and low follicular reserve in JDM patients. The girls with JDM had decreased progesterone levels suggesting an underlying subclinical corpus luteum dysfunction in this disease. Lipodystrophy can result in impairment of fertility in female patients, especially if severe disease onset is before puberty. In addition, JDM girls may have abnormal levels of LH and FSH.

With respect to pregnancy, if the JDM symptoms in the mother are relatively quiescent, then both mother and infant will do well, but a JDM disease flare during pregnancy can be problematic. Active JDM symptoms during pregnancy—muscle weakness, rash flare—can usually be managed with the use of modest doses of corticosteroids (both IV and PO), given with periodic IVIg without harm to the fetus. However, pregnancy in a mother with JDM may be associated with increased fetal wastage secondary to antibodies, such as anticardiolipin antibodies, which alter coagulation. Anticardiolipin antibodies have been identified in children with JDM (often with a negative lupus anticoagulant) and can be associated with fetal death, as well as vascular thrombosis. Birth control measures, such as oral contraceptives, should take into account the possibility of anticardiolipin antibodies. The type of birth control used should be discussed with the patient and her OB/GYN physician to diminish the possible risk of increased intravascular thrombosis.

Ophthalmologic Findings

Children with a more severe vasculopathy may display ulceration and infarction of tissue, often in the region of the medial canthus of the eye, which heal and leave a depressed scar. Within the eye, in active inflammation of JDM, transient retinal exudates and “cotton wool” spots may occur after the occlusion of small vessels, leading to intraretinal edema with injury to retinal nerve fibers, optic atrophy, and sustained visual loss. Neovascularization of the retina with spontaneous regression has also been reported. Central retinal vessel occlusion has been associated with anticardiolipin antibody. Disease of conjunctivae vessels can lead to an avascular zone with a potential for infarction. If there is a family history of red-green color blindness, the use of hydroxychloroquine should be avoided. Orbital myositis can be documented by MRI, either targeting a single fast-moving muscle, such as the superior oblique or as part of the spectrum of inflammatory myopathy which responds to corticosteroid administration or other immunosuppressant and may be part of the IgG4 syndrome (see later text). Children treated with steroids should be monitored for glaucoma (especially if there is a positive family history!) and for the development of sublenticular cataracts, which often resolve as the child improves.

Other Disease Manifestations

Vasculopathy involving the central nervous system may be associated with depression or wide mood swings, which may be exacerbated by steroid therapy (see “Psychological Aspects of Juvenile Myositis” below). Very few children with JDM present with Raynaud’s phenomenon; these symptoms are more frequently found as isolated phenomena in children with overlap syndromes or scleroderma.

Lipodystrophy

Three stages of lipodystrophy are now recognized: (1) localized lipodystrophy, occasionally following panniculitis that may be painful; (2) partial lipodystrophy targeting the areas over intense proximal muscle inflammation; and (3) generalized lipodystrophy, in which fat is lost over a larger part of the body, muscle atrophy is prominent, and joint contractures may be present. Several clinical features can provide clues to the duration of disease, for lipodystrophy occurs later in the disease course, reported 4.6 years after first symptom. Loss of subcutaneous fat over the masseter area and over the arms and legs, proximal<distal, gives a ropey appearance to the musculature, with clear definition of muscle groups that are not hypertrophied ( Figure 42.5A ). In contrast, abdominal muscle tone is diminished, so that the child or young adult has difficulty with sit-ups, even when muscle strength is normal elsewhere. This loss of abdominal tone is accompanied by increased abdominal fat, with the appearance of a “pot belly.” Another prominent feature of partial and general lipodystrophy is acanthosis nigricans, or speckled areas of increased pigment, which may be found in the skin folds of the neck, the axilla, behind the knee, or between the buttocks and appears like “dirty skin.” An additional phenotypic feature of this illness is coarsening of hair texture, or, if there is chronic inflammation of the scalp, loss of hair in the affected area ( Figure 42.5B ). If the JDM is still active before puberty, then there may be loss of fertility, with masculinization, reflected by increased facial hair and change in body habitus. The clinical features of lipodystrophy are not rare and occur in about 20% of our JDM population: more than 30% had some evidence of fat atrophy, 22% had increased insulin levels, elevated levels of triglycerides were present in 10%, and three tenths of those tested for glucose tolerance had evidence of insulin resistance.

Dystrophic Calcifications

Calcification in soft tissue is a consequence of the duration and severity of the active symptoms of JDM. Although the number of children with JDM with calcium deposits in the soft tissues has decreased when this disease is diagnosed more promptly and treated aggressively to 14%, the national average is still about 30% and, in South Africa, 70% of children with JDM develop calcinosis. The pathologic calcifications often follow delayed diagnosis or insufficient therapy. In children with the JDM rash only who were not given initial aggressive therapy, myositis often develops at a later date and may be complicated by pathologic calcifications. The calcifications may occur at pressure points, often the elbows or buttocks, but also can be found in fascia surrounding muscle ( Figure 42.1E and C ), as well as in palmar surface of the digits in children with overlap syndromes, such as Pm/Scl. The calcifications may change in appearance from massive accumulations to become thinner, more pancake-like collections, which then may resolve spontaneously, draining as a white cheesy or serosanguineous exudate containing macrophages and leaving dry, pitted scars ( Figure 42.1E ). In persistent, active myositis, the calcifications may progress to become a sheath, impairing flexion and function, breaking the barrier of the skin to form a portal for infection. Sepsis is not uncommon, frequently from staphylococci, and is a major contributor to the morbidity and mortality related to this disease. Children with JDM who have calcium deposits have three times higher urinary excretion of γ-carboxyglutamic acid (GLA), a component of the vitamin K-dependent coagulation pathway. An intriguing finding is that children with JDM without pathologic calcifications have GLA excretion that is twice normal, suggesting a prominent role of this protein in the pathophysiology of the disease. Further characterization of the calcifications show that they are not bone-like when studied with Fourier transform infrared spectroscopy, although they do have selective deposition of bone matrix proteins.

Calcification—Differential Diagnosis

It is important to differentiate the etiology of dystrophic calcinosis in JIIM from that in other syndromes such as in heterotopic calcinosis or that following trauma. Heterotopic calcinosis occurs in children with progressive osseous heteroplasia. In these individuals, there may be evidence of both intramembranous and endochondral ossification. In the cases of progressive osseous heterotopia described in the literature, the children presented at birth or within the first 6 months of age with only the cutaneous calcifications. This entity can be differentiated from fibrodysplasia ossificans progressiva, in which congenital malformations of the big toes are present at birth.

Disease Chronicity

Flexion contractures, hyperlipidemia, and cardiovascular disease are a few of the additional consequences of chronic inflammation. The position of comfort in the active phase of acute myositis is the flexed position which, if maintained for too long a period, becomes fixed with loss of both range of motion and of function; calcifications in the flexor tendons compound the problem. ILD is a leading cause of mortality in children with IIM. Short stature, present at diagnosis, is maintained for both boys and girls with JDM once they reach adulthood, when they are at increased risk for atherosclerotic heart disease and the metabolic syndrome, which may share features of the accelerated cardiovascular disease seen in adults with SLE as well as children.

Other Autoimmune Diseases

Many conditions must be considered in the differential diagnosis of inflammatory myopathy in children ( Table 42.5 ). Because myositis is often a component of other autoimmune rheumatic diseases, it is essential to exclude such conditions as SLE, mixed connective tissue disease, chronic arthritis in children (especially systemic onset juvenile rheumatoid arthritis [JRA] ), the spondyloarthropathies, Sjögren’s syndrome, and Kawasaki syndrome. They also may have a myositis specific antibody (MSA) that is often associated with a nonremitting disease course, such as Jo-1, the most common of the antibodies to the t-RNA synthetases ( Table 42.6 ). Furthermore, the inflammation can be concentrated in one specific muscle area (see “Other Myopathies” following), as in cases of orbital myositis ; it can be a nodular or proliferative process, or it can involve an eosinophilic infiltration of the fascia. Children with muscular dystrophy or a dysferlin deficiency associated with inflammation may present with muscle weakness (most often distal) as well as elevated levels of serum derived. Other conditions must also be excluded before the diagnosis of JDM is established. The endocrinopathies must also be included in the differential diagnosis. We have observed proximal and distal muscle weakness and elevated muscle enzymes in children with hypothyroidism, hyperthyroidism, and hyperparathyroidism.

Magnetic Resonance Imaging

Musculoskeletal inflammation at diagnosis and flare can be identified on magnetic resonance imaging (MRI), which guides the muscle biopsy, EMG, and other serologic assessments. The use of MRI to identify the specific area of often patchy inflammation in the muscle can direct the surgeon to the appropriate site for a muscle biopsy ( Figure 42.6 ). This approach minimizes error in sampling uninvolved areas in this focal disease and can serve, under very special circumstances, as an excellent monitor of a child’s response to therapy. The MRI findings may normalize several months later than the muscle enzymes. P31 magnetic spectroscopy has been used for the past few years and gives additional information about the child’s muscle strength and performance and has confirmed evidence of defective oxidative phosphorylation in diseased muscle.

( A ) Sagittal view of the MRI of a child positive for U1-RNP. The regions of muscle inflammation (white areas) are asymmetrical; the undirected biopsy of an area subsequently found not to be involved was read as “normal.” The MRI directed biopsy (white area) showed characteristic inflammation and muscle fiber damage. ( B ) Magnetic resonance image of a child with early symptoms of JDM and normal muscle enzymes. This T2 weighted image displays the patchy nature of the muscular involvement: the white areas (arrows) show the symmetrical edema of active inflammation surrounded by thickened fascia.

Muscle Enzymes

The standard muscle enzymes obtained for diagnosis are creatine kinase (CK), the transaminases aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT), lactate dehydrogenase (LDH), and aldolase. The highest concentration of CK is present in excitable tissues (muscle and nervous system) and occurs in three isoforms, MM, MB, and BB. In skeletal muscle, the MM form predominates (90% to 95%), whereas immature muscle may have increased concentrations of the MB form (20% to 30% in children younger than 1 year of age). AST is found primarily in the heart, liver, skeletal muscle, and kidney, and ALT is also found in skeletal muscle but in much lower concentrations. LDH catalyzes the intraconversion of lactate and pyruvate and is found in most of the tissues of the body. Aldolase is also widely distributed in the tissues of the body, and increased circulating levels of aldolase may be seen not only in myopathies but also in disorders of the liver, the hematologic tissue, and other diseases. The child who has moderately active JDM on muscle biopsy can have an elevated level of aldolase or any one of the other commonly tested muscle derived enzymes, while the others are in the normal range. Furthermore, these muscle enzymes may normalize by 4.5 months after the first JDM symptom, despite continuing disease activity, losing their value as a guide to therapy ( Table 42.7 ).

Electromyogram

Evidence of inflammatory myopathy on EMG is not specific to JDM. Inasmuch as 20% of EMGs not guided by MRI are “negative” or normal, it is prudent to use MRI or ultrasound to identify the specific area of inflammation in the muscle. Once the location of the electrodes has been chosen (not the site of a future biopsy), insertional irritability followed by spontaneous electrical activity at rest is often observed. This pattern can also be seen in the muscular dystrophies and in early acute myositis. Abnormal, early, full recruitment of muscle fibers with moderate effort occurs in about 45% of patients with JDM, and bizarre, high-frequency discharges occur in 15% to 20% of patients tested. Reduced motor unit activity is seen in Duchenne’s muscular dystrophy (DMD) as well as in JIIM. A comprehensive comparison of DMD and JPM showed that the JPM patients more frequently had complex repetitive discharges on electromyography and a complete response to treatment with prednisone or other immunosuppressive agents than dystrophy patients (44% versus 0%). Myasthenia gravis can coexist with an inflammatory myopathy, resulting in a greater degree of instability of motor-unit potential than is found in the uncomplicated inflammatory myopathies. Given the child’s variable acceptance of this procedure, we often reserve the EMG testing for the definition of cases that are not straightforward. Study of diagnostic testing of 384 children who were entered into the Children’s Arthritis and Rheumatology Research Alliance (CARRA) registry indicated that EMG results were most likely to show nondiagnostic results with 50% of the children requiring an additional diagnostic study to confirm JDM.

Muscle Biopsy

The vasculopathy of JDM may occur in the absence of a prominent inflammatory component. Capillaries and arteriole damage with loss of the capillary network results in structural change in the nailfold capillary bed as well as in muscle, with a subsequent decrease in the capillary-to-fiber ratio. Vascular compromise and capillary dropout, with perifasicular atrophy of both type I and type II fibers, are seen in the muscle pathology in JDM ( Figure 42.7 ). Multiple satellite cells are frequently found adjacent to atrophic fibers; focal repair occurs concomitantly with fiber atrophy. Low-grade ischemia may also be related to the increased expression of class I and class II major histocompatibility complex gene products. Greater than 50% expression of class I by muscle fibers is now considered as one diagnostic criterion for inflammatory myopathy. In contrast, in PM, there appears to be much less primary involvement of vessels; that is, they may be normal in number and structure. Some children with PM have the same histologic features as children with the rash of JDM (perifasicular atrophy, capillary occlusion), which may extend the spectrum of disease pathology for the diagnosis of JDM. Other children with PM and antisynthetase antibodies, such as SRP, may have areas of necrosis, in comparison with the documentation of apoptotic cell death in JDM muscle, which increases proportionally to the time that the inflammation is untreated.

Muscle histopathology in JDM with 8 months of untreated disease: Hematoxylin and eosin stain shows extensive connective tissue proliferation and fibrosis while muscle fiber size variation is evident. The hallmarks of the disease, perifasicular atrophy and occlusion of capillaries and arterioles, are seen. The active inflammatory infiltrate is composed of primarily mononuclear cells.

In JDM, even when the serum levels of muscle-derived enzymes are normal, the MRI-directed muscle biopsy can reveal active foci of inflammation. Children with active inflammation and normal muscle enzymes may also have elevated levels of vWF:AG and/or neopterin, which can be used to guide therapy (see later discussion).

Skin Involvement

Study of the skin in JDM can yield valuable information about disease pathophysiology. Adults with DM and cutaneous ulceration may develop malignancy, which is not true for children with JDM. DM patients with “mechanics hands” are at higher risk for ILD. Inflamed DM skin contains an infiltrate composed of C4 and CD8 T cells, plasmacytoid dendritic cells, neutrophils along with basal keratinocyte vacuolar alteration with apoptotic keratinocytes, and mucin deposition. Type 1 interferons are produced by plasmacytoid dendritic cells and genome-wide expression data documents a robust upregulation of IFN-inducible genes in DM skin, as well as evidence of other inflammation pathways, complement activation, and epidermal activation and differentiation. In JDM, mast cells were increased in the skin of the child, compared to their number in the inflamed muscle from the same child obtained by MRI directed biopsy. Unlike in SLE, children with JDM do not display immunoflorescent band-like immunoglobulin deposits at the derma-epidermal junction, which is an important point in differentiating the two similar clinical presentations.

Humoral Immunity

The complex immune system, consisting of innate and adaptive components, is essential to the pathophysiology of JDM tissue damage, but the complete sequence from immune activation to target damage has not yet been deciphered. Humoral immunity per se may be abnormal in a minority of patients with IIM: children with hypogammaglobulinemia may develop inflammatory myopathy associated with echovirus infection, and IgA deficiency has been identified in a few children with undefined inflammatory myopathy. In immunocompetent children, early in the disease course, the IgM and or/or IgG may be elevated.

Myositis Specific Antibodies

As presented in Table 42.6 the evolving serological classification of JIIM has provided insight into some of the factors contributing to clinical myositis disease heterogeneity. Several methods are used to detect myositis-specific antibodies (MSA). For example, ELIZA determinations of MSA may be confounded by false positives as opposed to immunodiffusion, radiolabelling, and immunoprecipitation methods, which yield protein bands of different migratory characteristics. The most common MSA antibody in children with inflammatory myositis is directed against a doublet protein, p155/140. Specific skin sensitivity and patterns of erythema are associated with p155/140 and the children frequently follow a chronic course. This antibody is not associated with malignancy in DM/JDM and differs from the p155/140 antibody directed against TIF-1-γ (antitranscription intermediary factor-1-γ/α (TIF-1-γ/α)) found in adults with DM/PM who harbor a malignancy. Anti-MJ occurs in 20–25% of patients, is directed against nuclear matrix protein 2 (NXP-2), and is associated with a monocyclic course, more severe disease manifestations, more frequent hospitalizations, and calcinosis. Only 2–4% of pediatric IIM patients have antibody to the aminoacyl-tRNA synthetases (Jo-1 and non-Jo-1 synthetases) present both in JPM (9%) and in overlap myositis (13%). These patients have frequent arthritis, and should be rigorously monitored for ILD, which results in the highest mortality of all the MSAs. Another marker of myositis refractory to treatment is anti-SPR (signal recognition protein), primarily found in JPM girls (18%) who are African-American. Anti-M2 (NuRD) is directed against the 218/240 kDa helicase family proteins and is associated with the hallmark cutaneous findings in JDM patients who are predominantly Hispanic and have a milder disease course. Anti-CADM-140 (MDA-5) is common in amyopathic DM patients (i.e. skin findings but no evidence of muscle involvement) who frequently have rapidly progressive ILD, cutaneous ulcerations, and palmar pustules, and who, in Japan, have a high mortality rate. Anti-SAE (small ubiquitin-like modifier activating enzyme) has been identified in children with JDM and adults with skin symptoms preceding muscle involvement and a low frequency of ILD.

Myositis Associated Antibodies

Myositis associated antibodies (MAAs) are primarily found in adults and in children with overlap myositis as well as in JPM and JDM and include the anti-U1-RNP, anti-Ro, anti-PM-Scl, anti-Ku specific antibodies as well as other, less frequently identified MAAs ( Table 42.6 ). Of note, newer, more sensitive methods of antibody detection have indicated that sera containing minute amounts of antibodies to Ro, La, RNP, and Sm can functionally activate the IFN-α pathway in children with JDM, suggesting that these antibodies may actively participate in perpetuating disease pathology. Finally, a large group of children are negative for known MSA or MAA antibodies, and may be either ANA positive or ANA negative. In addition, myositis antibody negative sera may contain precipitin bands against as-yet-unidentified proteins.

Type 1 Interferons

Current concepts in this fast-moving field concerning the driving force of the pediatric inflammatory myopathies center on the massively upregulated type1 interferon response, first identified in muscle of untreated children with active symptoms of JDM of all disease durations as similar to a massive antiviral response ; for example MXA (myxovirus A) was upregulated 96-fold ( Figure 42.8A ). Further study showed the disease duration did impact on many other aspects of gene expression, including vascular remodeling ( Figure 42.8B ). This type 1 driven interferon response was confirmed by others, both in children and in muscle from adults with DM and PM, but not in adults with IBM. There are at least three major types of interferons: type 1 (interferon-α and interferon-β), type 2 (IFN-γ), and type 3, including interferon-λ—which may antagonize IFN-α activity. Recent evidence in adults with DM has identified IFN-β as a strong component of their inflammatory response. Peripheral blood from children and adults with DM was tested which displayed specific upregulation of type 1 interferon induced genes and their proteins. However, not all the upregulated genes in the untreated muscle were expressed in mRNA from the same child with JDM’s peripheral blood mononuclear cells (PBMCs) obtained at diagnosis. MxA mRNA expression in JDM PBMC obtained at the initial clinic visit was elevated compared to controls and was positively correlated with Disease Activity Score (DAS) for muscle, but not with DAS for skin, suggesting that damage to skin and muscle in JDM may each have a discrete pathophysiology. Decrease in muscle symptoms was associated with a decrease in PBMC MxA mRNA expression. As type 1 interferons induce many genes including MXA , a phase I trial of a monoclonal antibody to type 1 interferon-α was executed, which documented both improved patient symptoms and diminished expression of type 1 interferon genes. The role of TNFα is presented in Figure 42.9 . A proposed scheme that integrates some of the environmental and genetic factors in the development of JDM is presented in Figure 42.10 .

Gene expression (GE) profile heat maps for type 1 interferon induced genes, comparing data from MRI directed muscle biopsies from ( A ) untreated children with definite symptoms JDM of 2 months or less duration, with ( B ) GE profiles from muscle biopsies of untreated children with JDM symptoms>2 months’ duration. B . Gene tree created by hierarchical clustering based on gene expression profiles. Upregulated genes were clustered into clusters C, D, and F, while downregulated genes were clustered into clusters A, B, and E, in girls with long (≥2 mo) vs. short (<2 mo) duration of active disease. The color codes represent the ratio between each of the JDM groups compared with the age- and sex-matched control samples. The complete list of genes in clusters A–F can be found in supplemental table 1 of Chen et al. Genes involved in vasculature and extracellular matrix remodeling, which is part of angiogenesis, were differentially expressed between patients with long and short duration of active disease. Interestingly, most of these genes cluster in cluster F, in which genes were downregulated more in patients with short duration of the disease (<2 mo). This finding suggests preferential misregulation of the expression of these specific genes in the early phase of the inflammatory disease process.

Reproduced with permission from Chen et al. (2008).

The association of a long duration of untreated disease and the TNFα-308A allele with a chronic disease course in white children with JDM. ( A ) Increased frequency of the TNFα-308A allele in white children with JDM compared with controls. ( B ) Both a long time period of untreated disease (>9 months before therapy given) and the TNFα-308A allele contribute to a subsequent chronic disease course in JDM. The DQA1*0501 allele, while increased in children with JDM, appears to be associated with disease susceptibility, not disease chronicity. ( C ) A chronic disease course is associated with increased production of TNFα by peripheral blood mononuclear cells. ( D ) The muscle fiber expression of TNFα on histochemistry in the diagnostic muscle biopsies from untreated JDM is increased in children with the TNFα-308 A allele. Surprisingly, more muscle fibers than macrophages are positive for TNFα, suggesting that this may be an important mechanism of localization of tissue damage.

Reproduced with permission from Pachman et al. (2001).

A proposed scheme for the pathophysiology of JDM. The Major Histocompatibility Locus, DR3 *0301 may serve as a disease susceptibility locus for microbial or other antigenic interactions, while the TNFα-308A allele is associated with increased production of TSP-1 which may play a role in vessel occlusion, as well as a chronic disease course which includes increased pathological calcifications.

T Cell Immunity

Children with active untreated JDM may be lymphopenic, and the duration of untreated disease may influence the lymphocyte phenotype. Studies of the cellular composition in the muscle of children with JDM identified CD4, CD8 positive cells and macrophages as well as mast cells—which were more prominent in matched skin samples. Perifasicular atrophy, one of the hallmarks of juvenile dermatomyositis, is characterized by infiltration of CD4+ T cells (dendritic cells) as well as the destruction of micro capillaries which contribute to muscle cell death. The native CD4+ T cells as well as plasmacytoid dendritic cells, which are also CD4 positive, are active producers of IFN-α (see the previous discussion). A possible local source of IFN-β may be immature muscle cells, which appear to be the target of activated DCs expressing IL-1 and IL-23, implicated in T cell polarization. In turn, the local production of IFN-β after TLR-3 activation in the presence of the Th1 cytokine IFN-γ may explain HLA class I overexpression by muscle fibers themselves—a hallmark of inflammatory myopathy.

Complement

A few studies that included children demonstrated complement activation: the membrane attack complex was localized to the intramuscular microvasculature in 10 of 12 patients and was correlated with the duration of the clinical disease. Complement components and immune complexes appear to participate in the pathophysiology of JDM with evidence of complement activation (C3d) accompanied by increased levels of fibrinopeptide A and vWF:Ag, which are synthesized by and released from damaged endothelial cells (see the following). In children with JDM, decreased levels of C4 protein are directly associated with fewer than normal 4A gene copy number, apparently in linkage disequilibrium with the “autoimmune locus” identified by the GWAS studies.

Cytokines and Chemokines

Investigation of this fast-changing field documents the complex interrelationships of the cytokine network. Many of the type 1 interferon inducible cytokine genes proceed through the NFkB pathway and are pro-inflammatory in nature. A longitudinal investigation of mRNA from adults with DM for analysis of the cytokine-induced gene expression for the signaling pathways of type 1 interferon, TNFα, IL-1β, granulocyte-monocyte colony-stimulating factor, IL-10, and IL-13 demonstrated only a type 1 interferon signature score in 21/24 patients. Similarly, the analysis of children with JDM (MSA specificity not given), showed upregulation of type 1 interferon induced cytokines ; analysis of the cytokine pattern was presented as a potential biomarker for disease activity. There is an increased frequency of the A allele in the TNFα-308 promoter region compared with age-matched controls ( Figure 42.9A ), which is associated with increased production of TNFα protein by peripheral blood mononuclear cells as well as the muscle fibers themselves in untreated children with JDM.

Neopterin

Neopterin is an indicator of macrophage activation and is increased in the serum of untreated children with JDM. Neopterin, a member of the pteridine family, is derived from guanosine triphosphate via guanosine triphosphate cyclohydrolase and is released from macrophages as a consequence of T-cell-dependent interactions involving interferon-γ (IFN-γ). Neopterin levels correlated with the clinical disease activity score in more than 65% of cases. The neopterin levels were not associated with peripheral blood mononuclear cell production of IFN-γ in vitro but with the number of macrophages in the muscle biopsy of the child with JDM; they both decrease in response to appropriate therapy. Measurement of urinary neopterin (first voided specimen) showed a good correlation with disease activity.

Acute Phase Reactants

In uncomplicated JM, the usual indicators of an acute-phase reaction, ESR and C-reactive protein, are often within normal limits, even in those children with ILD. However, ESR and C-reactive protein may be elevated in pediatric patients with severe active disease or infected sites of calcinosis, as well as in children with overlap syndromes, where these acute phase reactants are associated arthritis. Of note, if the child is given intravenous IgG therapy, an elevated ESR may be observed. The lymphopenia is not commonly accompanied by an abnormal platelet count, although mild microcytic anemia may be present.

Von Willebrand Factor Antigen

A sensitive indicator of vasculopathy, an elevated von Willebrand factor antigen (vWF:Ag) may precede a disease flare (when muscle enzyme data are normal), or it may remain elevated after the enzymes have normalized. Of note, the normal range for this antigen is blood group dependent: people with blood group “O” have lower normal ranges (36–157%) than those associated with other blood group antigens, such as blood group B, for which the normal range is 57% to 241%. In about 65% of children with JDM, levels of vWF:Ag are highly associated with a clinical score of disease activity (DAS). These clinical indicators of disease activity—the MRI findings, neopterin, and vWF:Ag levels—are easily available, but are imperfect guides to therapy. It is anticipated that accurate measurements of pro-inflammatory immune markers will help characterize the severity of the immunologically mediated inflammatory process, and become more accessible in the future.

Vitamin D Levels

The few studies reporting data from children with JDM at diagnosis comment that the levels of 25-hydroxy vitamin D are often below normal ranges. These low values are obtained before the children are strongly urged to limit sun exposure, for UVB will exacerbate not only the JDM rash on the exposed skin, but may trigger a full-blown flare in the inflammatory myopathy. It is important to obtain a vitamin D blood level at diagnosis so that appropriate supplementation with 2- or 3-hydroxy-vitamin D can begin concomitantly with the start of corticosteroids, along with supplemental doses of calcium.

Bone Mineral Density

Decreased bone density, frequent in untreated JDM, is measured by DXA, using a “Z score” normalized for age-matched healthy children, and is associated with a longer duration of untreated disease, depressed serum osteocalcin, and 25-hydroxy vitamin D insufficiency. This constellation of events places the child at risk for fracture prior to the initiation of glucocorticoid therapy, and this is escalated by the use of corticosteroids. Of note, untreated children with JDM have an elevated RANKL:OPG ratio at the time of diagnosis, resulting in expansion of the number of osteoclasts and activation of the bone resorptive function. This may lead to suppression of normal bone mineral accretion and a subsequent reduction in the lumbar spine bone mineral density (BMD) Z score. Therefore, children with a longer duration of untreated JDM may have lower than normal lumbar spine BMD Z scores. This risk is further augmented by steroid treatment, which impairs calcium absorption, and the child’s relative decrease in mobility because of weakness, which promotes calcium mobilization from bone.

Development of Consensus Driven Guidelines for Classification and Therapy

Specific investigation of the efficacy of the type, duration, and route of medication administered to children with JDM and the other less common inflammatory myopathies is a continuous process. Several consensus meetings developed guidelines for treatment: one for moderately severe JDM, another for moderate JDM. A concerted assessment of the use of corticosteroids in IIM, as there is in asthma, has not yet been organized. Several factors may confound the existing data. Active vasculopathy, which is often not evaluated, may inhibit oral absorption of the drug compared with the intravenous route. The age of the child may alter drug metabolism, once absorption has occurred, so that younger children may require a higher dose per square meter than their adult counterparts—which has been proven for methotrexate in children, and may apply to other forms of medication. Specific recommendations for therapy have to be considered in this context but are limited because of the lack of uniform assessment of age-dependent patient response during therapy. In addition, although there are some clues as to immunological specificity, these indicators of immunologic activity have not been widely tested to confirm that they have normalized at some point after therapy has been initiated.

Oral Corticosteroids

In general, the treatment of mild uncomplicated JDM consisted of oral prednisone (1 to 2 mg/kg) in conjunction with gastric protection ( Table 42.8 ). The child’s linear growth is arrested temporarily if the oral dosage of steroids exceeds 4 mg/m ² . Stunted growth combined with increased weight gain and IIM-associated decreased mobility proves a challenge for the body-image conscious child. For the adolescent, the increased weight gain and the development of steroid-induced acne when taking oral prednisone frequently pose problems with compliance, which can be circumvented to some extent by the intravenous administration of methylprednisolone. In children with microvascular damage which also occurs in the gastrointestinal tract, absorption of oral prednisone is impaired, providing the rationale for the use of high-dose intermittent methylprednisolone, as shown in Figure 42.11 , in which the absorption of 50 mg of prednisolone IV vs. PO was compared in children with JDM and decreased nailfold capillary end row loops.

Table 42.8

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