Juvenile Dermatomyositis

Juvenile-onset amyopathic dermatomyositis refers to characteristic skin changes without muscle weakness or elevated muscle enzymes for longer than 6 months. One quarter of patients may progress to clinically significant myositis.[10]

Unlike adults, juvenile polymyositis is less common than JDM, and inclusion body myositis is rare in children.[3]

Overlap myositis occurs in conjunction with other connective tissue diseases such as scleroderma, systemic lupus erythematosus (SLE), juvenile idiopathic arthritis, vasculitis, Kawasaki disease, and psoriasis.[2] Overlap myositis generally demonstrates a milder muscle disease with favorable treatment response.

In contrast to adult dermatomyositis, cancer-associated myositis and interstitial lung disease is uncommon in children.[2, 11, 3] Cancers described have included lymphoma and leukemia.[2]

For patient education, parents and patients may visit the following websites:

• The Myositis Association

• The Childhood Arthritis & Rheumatology Research Alliance (CARRA)

• The Arthritis Foundation

• The Paediatric Rheumatology European society (PRES)

The current model of the pathogenesis of JDM involves both humoral and cell-mediated mechanisms that cause vascular and muscle damage. Autoantibodies directed against an unknown endothelial antigen may cause vascular injury, resulting in ischemia and subsequent muscle damage with increased expression of major histocompatibility complex (MHC) class I and II.[12, 13, 14, 15, 16, 17]

CD4+ T cells, B cells, plasmacytoid dendritic cells (pDCs), and macrophages are arranged in a perivascular and perifascicular distribution, with capillary thrombosis and deposition of membrane attack complex and complement.[12, 13, 14, 16, 18] Immune complex deposition mediates vascular injury, resulting in activation of complement and muscle inflammation.[19, 20, 15, 17]

T cells, as well as B cells, play a dominant role in disease pathogenesis. TH 17 cells are a subset of CD4 cells that have been found with neutrophils in inflammatory infiltrates and are producers of interleukin (IL)–17 found in inflamed tissues of JDM patients.[21] IL-17 induces MHC class I and IL-6 (a proinflammatory cytokine) expression in myoblasts in concert with IL-1 (a proinflammatory cytokine).[21, 22, 23] B cells have been found in the primary follicles of lymph nodes and lymphoid tissues forming germinal centers and are also found in perivascular infiltrates in patients newly diagnosed with JDM.[24]

Emerging research suggests that type I interferon-alpha/beta inducible genes of the innate immune system play a central role in the pathogenesis of dermatomyositis.[17] These genes mediate upregulation of MHC class I, induction of proinflammatory cytokines and chemokines, and dendritic cell maturation.[25, 26]

Plasmacytoid dendritic cells are involved in the innate immune system and produce large amounts of interferon-alpha (α) and beta (β) in vivo after viral stimulation.[27, 28] They have been found in the muscle, peripheral blood, and epidermis of skin lesions in patients with dermatomyositis.[18, 29] Overproduction of interferon alpha/beta proteins may lead to endothelial and myofiber damage.[28]

In a study that assessed family histories from 304 families of children with JDM, Niewold et al found that 51% of these families reported at least one additional member affected by an autoimmune disease.[30] Higher serum interferon-alpha values were found in untreated subjects with JDM who had a family history of SLE, suggesting that interferon-alpha may be a pathogenic factor shared by these autoimmune diseases.

Juvenile polymyositis is mediated by cytotoxic CD8+ T cells, activated macrophages, and expression of MHC-I.[13, 12, 20]

The etiology of JDM is incompletely understood. Evidence suggests a complex interplay of the innate and adaptive immune systems with environmental triggers in a genetically susceptible host.

Seasonal clustering of JDM in the months of April and May suggests the role of environmental triggers in the onset or exacerbation of the disease.[31] Infectious agents include viruses, parasites, and bacterial antigens that may produce a break in self-tolerance. Infectious agents implicated include the following[32, 33, 34, 35, 36] :

• Coxsackie B virus

• Parvovirus B19

• Enteroviruses

• Streptococcus species

Several mechanisms for infection-triggered autoimmunity have been proposed, including molecular mimicry, induction of anti-idiotypic antibodies, and modification of self-antigens through microbial proteins.[37, 38]

Type I interferon-alpha/beta genes are overexpressed in dermatomyositis.[39, 28, 40] Gene expression profiles of untreated patients may provide indirect evidence of an activated immune response, with an upregulation of interferon alpha/beta genes associated with viral and microbial antigens.[25, 39] Type I interferons can up-regulate MHC class I expression, promote T-cell survival, induce proinflammatory cytokine elaboration and dendritic cell maturation.[41]

levels of type I interferon gene expression in peripheral blood mononuclear cells therefore may be a marker for increased disease activity.[39, 40] Downregulation of type I interferon genes is correlated with clinical improvement in dermatomyositis.[40]

Noninfectious agents implicated in the onset of JDM include D-penicillamine, vaccinations, and bone marrow transplants.[42, 43, 44]

Certain factors that have been associated with adult-onset myositis have not been described in children. These include the following[3] :

• Agents related to occupational exposures

• Silica

• Silicone implants

• Lipid-lowering medicines

Patients with human leukocyte antigen DQA1*0501 (HLA-DQA1*0501) have an increased susceptibility to JDM, in a strong linkage disequilibrium to HLA-DR3, compared with age-matched controls in white, black, and Hispanic children.[45, 46] The HLA-DQA1*0301 and HLA-DRB*0301 alleles confer an increased risk in whites compared with race-matched controls.[47]

Maternally derived chimeric cells have been identified in patients with JDM, suggesting a role in pathogenesis. Chimeric cells from mothers with HLA-DQA1*0501 may interact with hosts’ immune responses.[48] Microchimerism has been found in 70-100% of muscle tissue and peripheral blood mononuclear cells in patients with JDM.[49, 50]

Cytokine polymorphisms (eg, the substitution of A to G in the promoter region of tumor necrosis factor [TNF]–alpha-308 allele) is associated with a prolonged, refractory course. The course may be related to an increased production of TNF-alpha in peripheral blood mononuclear cells and muscle fibers of untreated patients with JDM.[51, 52] Polymorphisms in the variable number tandem repeat (VNTR) of the interleukin (IL)-1 receptor antagonist have also been implicated as a risk factor in JDM.[53]

A study that investigated the association between ultraviolet radiation (UVR) exposure and the clinical and autoantibody expression of juvenile idiopathic inflammatory myopathies (IIM) found that short-term UVR exposure prior to illness onset may have a role in the clinical and serologic expression of juvenile myositis. Further research examining the mechanisms of action of UVR in the pathogenesis of juvenile IIM is needed.[54, 55]

In the United States, the annual incidence of JDM ranges from 2.5-4.1 cases per million population.[56] In the United Kingdom, the incidence is lower at 1.9 cases per million children younger than 16 years.[31]

Racial, sexual, and age-related differences in incidence

Racial differences are observed in the incidence of JDM in the United States. The estimated annual incidence in Whites is 3.4 cases per million children; the annual incidence in Blacks is 3.3 cases per million children; and the incidence in Hispanics is 2.7 cases per million children.[56]

JDM affects females more often than males, with a ratio of 2.3:1 in the United States.[56] In the United Kingdom, the ratio is even higher at 5:1.[31]

The median age of onset of JDM is 6.8 years in girls and 7.3 years in boys, with a median delay to diagnosis of 3-4 months.[31, 32, 57] One fourth of patients are aged 4 years or younger at diagnosis.[57]

Prior to the widespread use of corticosteroids, the prognosis was poor. One third of patients died from JDM and another third suffered from significant long-term disability.[58, 59] Mortality has been related to complications from the vasculopathy, chronic infections, and septicemia.[59] Mortality has now declined to 2-3% with improvement in functional outcomes.[59, 60, 61, 62]

The average disease duration has varied widely, from 1.5 years to throughout the life span. In general, children with JDM are able to lead normal lives with full recovery, compared with adults.[63, 7] Delayed or inadequate treatment with corticosteroids is a predictor of poor outcome and a prolonged disease course.[32, 64]

Calcinosis cutis develops in one third of patients and is a major cause of morbidity.[60, 64] Calcinosis cutis leads to pain, cosmetic disfigurement, and decreased physical function and quality of life. It may lead to skin atrophy, contractures, nerve entrapment, and ulceration with secondary skin infections.[60, 65, 66] Calcinosis has been associated with a delay in diagnosis, lack of aggressive treatment, and cardiac involvement; progression may occur with inadequately treated disease.[32, 67]

In a retrospective cohort study of 58 patients with JDM, the most common long-term complication was calcinosis, which occurred in 36% of the patients. Calcinosis was associated with the onset of JDM at age 6 years or younger, higher muscle biopsy scores, and positivity for the autoantibody MDA5.[68]

Over one half of patients with JDM develop a chronic disease 24 months after diagnosis; the disease manifests as rash, muscle weakness, or both.[60] In severe disease, impairments in physical function may lead to limb contractures.

Constitutional, respiratory, and GI symptoms may occur within 3 months of onset of juvenile dermatomyositis (JDM).[57] With eruption of skin lesions, pruritus may be present in 38% of children.[69] Photosensitive rashes may occur.[2] Muscle involvement can be insidious, with development of functional limitations such as difficulty getting out of bed or tiring easily from sporting events.[32]

Other common symptoms include fever, dysphagia, dysphonia or hoarseness, myalgias, arthralgias, abdominal pain, and melena from GI involvement as a consequence of vasculopathy.[32, 69]

Rarely, pneumatosis intestinalis or colonic perforation may occur.[70, 71]

JDM primarily affects the skin and muscles. The eyelids and face may be swollen with a heliotrope rash (the color of a garden perennial), a purple or dusky mauve color in the periorbital region, and an overlying scale. Periorbital edema is sometimes present. See image below.

A characteristic, violaceous rash is present over the eyelids with periorbital edema in a child with juvenile dermatomyositis.

A malar rash in a photosensitive distribution with sparing of the nasolabial folds may occur, making the diagnosis of JDM difficult to distinguish from systemic lupus erythematosus.[72]

Gottron papules are shiny, elevated, violaceous papules and plaques present over the bony prominences such the metacarpophalangeal joints, the proximal interphalangeal joints, the distal interphalangeal joints, the elbows, the knees, and the ankles. Sparing of the interphalangeal spaces is observed. See image below.

Gottron papules are present over the metacarpophalangeal joints and proximal interphalangeal joints in a child with juvenile dermatomyositis.

Erythematous, violaceous scaly plaques may occur on the extensor surfaces of the extremities (see the image below).

An erythematous, violaceous, scaly rash is present over extensor surfaces in a child with juvenile dermatomyositis.

Nailfold telangiectasias, periungual erythema, poikiloderma, lichenification, and psoriasiform dermatitis may be seen. Hypertrophic, ragged cuticles may accompany periungual erythema.[69] Inadequately treated children have persistent nailfold abnormalities reflective of skin disease activity but not muscle involvement.[73]

Diffuse vasculopathy may be associated with vasomotor instability, such as Raynaud phenomenon, livedo reticularis, or vascular infarctions on the medial canthus of the eyelids.

Mechanic's hands may occur, with hyperkeratosis and peeling of the skin over the lateral and palmar aspects of the fingers. Mechanic’s hands are usually seen in the setting of myositis-specific autoantibodies and interstitial lung disease.[74]

Less common findings related to complement deposition and associated with a more severe disease course include cutaneous and mucosal ulcerations.[7, 14, 69]

Symmetrical proximal muscle weakness involving the deltoids, quadriceps, or both is a prominent clinical finding in JDM.[69] These children may demonstrate a Gower maneuver (ie, needing to use their arms to raise themselves from the floor to a standing position).

Calcinosis cutis

Although calcinosis (a manifestation of dystrophic calcification with normal serum calcium and phosphorus levels) is rare in adults with dermatomyositis, it occurs in 20-40% of patients with JDM.[64] The deposits are firm, white or flesh-colored nodules over bony prominences that have a high mineral content of calcium hydroxyapatite, as well as osteopontin, osteonectin, and bone sialoprotein (see the image below).[75]

Calcinosis cutis over the left elbow in a patient with juvenile dermatomyositis for 16 years.

The sites most commonly affected with calcinosis cutis include the elbows, knees, and extremities. Onset is within 3 years of diagnosis but may occur as long as 20 years later.[76, 64]

Calcinosis is divided into the following 4 subtypes[77] :

• Superficial calcareal masses

• Deep calcareal masses

• Linear deposits

• Subcutaneous deposition of calcium that encase the torso

Laboratory studies in the workup of juvenile dermatomyositis (JDM) include an erythrocyte sedimentation rate (ESR); muscle enzyme levels; lupus profile (ie, antinuclear antibody [ANA], extractable nuclear antigens [ENA]); and myositis-specific antibody assays such as antibodies against the aminoacyl t-RNA synthetases (ie, anti-Jo-1 antibody), antisignal recognition particle (anti-SRP antibody), and nuclear helicase (anti-Mi-2 antibody).[9]

Nailfold capillary microscopy may show end-row loop capillary loss and formation of bushy loops representing capillary dilatation and branching.[78]

A muscle biopsy is not usually performed to confirm the diagnosis of JDM, as it is for adult myositis. However, it is needed in the workup of juvenile polymyositis.

Magnetic resonance imaging (MRI) with T2-weighted fat suppression and short tau inversion recovery (STIR) is useful in the diagnostic workup because it reveals edema, a marker of muscle inflammation.

Muscle ultrasonography reveals increased muscle echogenicity, attenuation, and reduced bone surface echo. These changes are not specific for JDM, however, and this technique is not widely used.[79]

Electromyography (EMG) reveals a reduction of the motor unit action potentials in the proximal muscles and fibrillation potentials suggestive of fiber splitting, necrosis, and vacuolization. However, the EMG findings may be normal in approximately 19% of children.[32]

The ESR is commonly elevated in patients with JDM, but this finding is nonspecific.

Levels of muscle enzymes such as aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and aldolase may be elevated early in the disease course. Creatine kinase levels may initially be within the reference range in approximately 10-40% of patients and may return to normal within a few months of disease onset.[32, 69]

An elevated ANA level may be seen in approximately half of patients with JDM.[69] Generally, the extractable nuclear antigens (SSA, SSB, Sm, RNP, DNA) are negative.

Approximately 10% of patients have myositis-specific autoantibodies that define clinical subsets and serve as prognostic indicators of disease severity.[2, 80] These subsets are associated with different sets of signs and symptoms and, in some cases, onset at different times of year.

Rarely, the aminoacyl-transfer RNA (tRNA) synthetases such as Jo-1 (histidyl-tRNA synthetase), PL-12 (alanyl-tRNA synthetase), and PL-7 (threonyl-tRNA synthetase) have been associated with a spring onset of myositis, with the following clinical manifestations[81, 82] :

• Nonerosive arthritis

• Interstitial lung disease

• Fever

• Raynaud phenomenon

• Mechanic’s hands.

The anti–signal recognition particle (SRP) autoantibodies are associated with an autumn onset and a severe, refractory myositis in less than 5% of JDM cases; in adults, the prognosis is poor, with a high mortality rate and cardiac involvement.[80, 83, 82] The anti-Mi-2 autoantibody may be seen in 5% of patients with mild to moderate JDM.[82]

The p155/140 kDa doublet protein, a myositis-associated autoantibody, has been identified in 29% of patients with JDM and may correlate with more extensive cutaneous involvement, including ulcerations and edema.[84, 85]

MRI with T2-weighted fat suppression and short tau inversion recovery (STIR) is useful in the diagnostic workup because it reveals edema, which is a marker of muscle inflammation. STIR findings must be interpreted cautiously, however, because patients with muscle dystrophies may have inflammation as well.[86]

The signal intensity from STIR may correlate with disease activity.[87] Areas of calcinosis or intramuscular fluid collections may be revealed. T1-weighted images reveal atrophy and fatty replacement from chronic damage.[88] MRI also helps in localizing an area for a potential muscle biopsy.[86]

A muscle biopsy is not usually performed to confirm the diagnosis of JDM, as it is for adult myositis; however, it is needed in the workup of juvenile polymyositis. Emerging data has suggested that muscle biopsy findings may be useful in predicting the clinical course and prognosis of JDM based on extensive active myopathic and arteriopathic changes.[89, 90]

If muscle biopsy is performed, a moderately weak muscle should be selected with specimens frozen for cryostat sections to perform histologic and enzyme histochemical stains and immunocytochemistry for major histocompatibility complex (MHC) antigens, immunophenotyping of T cells, and detection of cytokines and complement.[20]

Characteristic findings include perifascicular atrophy and a perivascular, mononuclear cell infiltrate with membrane attack complexes; swelling and occlusion of the capillary lumen; muscle degeneration; muscle regeneration; and infarcts. Necrosis of muscle fibers can occur in the fascicle periphery or in the center of the fascicle.[14, 20] CD4+ positive cells and B cells are seen in the perimysial and perivascular areas.

In contrast, in polymyositis, typical findings are invasion of non-necrotic fibers by CD8+ cytotoxic cells, activated macrophages with expression of major histocompatibility complex I, and inflammatory infiltrates in an endomysial distribution.[20]

An international consensus group has developed a scoring system for muscle biopsy findings in JDM. The system is based on 4 domains of change (inflammatory, vascular, muscle fiber, and connective tissue) and includes the following[90] :

• CD3+ and CD 68+ endomysial, perimysial, and perivascular inflammation

• Vascular changes, including capillary dropout, arterial findings, and infarction

• Muscle fiber changes, such as MHC I overexpression, perifascicular atrophy, neonatal myosin, muscle degeneration, muscle regeneration, and necrosis

• Endomysial and perimysial fibrosis

The consensus group suggests that if validated, the scoring system could be used in prospective studies to test which features of muscle pathology are prognostic of disease course or outcome.[90]

Assessment of muscle strength, physical endurance, and function is the primary means for determining clinical status and predicting outcomes in JDM. Several clinical outcome measures in JDM patients have been developed over the last decade to facilitate assessment of clinical response to treatment.

Physical function is measured by the Childhood Health Assessment Questionnaire (CHAQ), a reliable and validated instrument that correlates well with disease activity and functional outcomes. The CHAQ is a 30-item questionnaire that measures proximal muscle strength by assessing 8 areas of physical function, including dressing, grooming, eating, walking, hygiene, and the use of assistive devices.[91]

The Childhood Myositis Assessment Scale (CMAS) is a measure assessing muscle strength, functional capacity, and muscle endurance that has been developed and validated for JDM patients The 14-point scale measures activities such as timed neck flexion and sit-ups.[63]

The Disease Activity Scale assesses skin and muscle involvement.[92]

The cutaneous assessment tool (CAT), a 21-item test used to assess cutaneous manifestations in JDM, has been validated and correlated with skin disease damage scores.[93]

A multidisciplinary approach is required to prevent and reduce long-term morbidity in juvenile dermatomyositis (JDM). Various therapies are used to treat skin manifestations of JDM. For active muscle disease, oral corticosteroids are the mainstay of treatment. Second-line agents are routinely added for steroid-sparing effects and for recalcitrant or refractory disease.

Cyclophosphamide at a dose of 0.5-1 g/m2 may be given with bladder protection on a monthly basis and adjusted for leukopenia for patients with significant morbidity such as skin or GI ulcerations, respiratory disease, or both.[94]

For patients with dysphonia, a referral to a speech therapist is appropriate. Children with dysphagia should meet with an occupational therapist for instruction on food consistency and proper positioning of the head, chin, and tongue.[2]

Because of the rarity of the disease, patients with JDM should be transferred to a tertiary care center for experienced clinical care in the initial course of the disease and for periodic follow-up. Patients should be followed on a regular basis, with monitoring of muscle enzymes and muscle strength every 3-6 months. Remission occurs when stable improvement or normalization of muscle strength and muscle enzymes is observed over 6 months.

Consultations

Consultations may be indicated with the following:

• Pediatric rheumatologist

• Dermatologist

• Pediatric neurologist

• Physical therapist

• Occupational therapist

• Speech therapist

• Orthopedic surgeon

• Pediatric endocrinologist

Photosensitive rashes in patients with JDM may be exacerbated by sunlight exposure; sun avoidance, and judicious use of sunscreens that protect against ultraviolet A and B rays. U

Topical corticosteroids are used to treat skin manifestations of JDM. Hydroxychloroquine at a dose no greater than 5-7 mg/kg/day may be beneficial. Topical tacrolimus (0.1%) has been used to treat cutaneous disease,[95] but this use is falling out of favor. Methotrexate, which is an established second-line agent for muscle involvement in JDM, may also be effective for cutaneous manifestations.[96]

Calcinosis cutis

Medical therapy for calcinosis in JDM has been controversial due to inconsistent responses. Diltiazem at doses of 240-480 mg (3-6 mg/kg/day) has been used with varying success rates.[2, 97, 98] Other agents used with little success include bisphosphonates, aluminum hydroxide, probenecid, and local corticosteroid injections.[98] Calcinosis cutis may regress over time.

Areas of calcinosis that cause significant disfigurement, pain, or compromised physical function may be resected surgically. Resection is not usually recommended, however, as areas of resection may be complicated by draining sinuses, infections, and ulcerations; the calcinosis may recur.

For active muscle disease, oral corticosteroids are the mainstay of treatment. High doses (1-2 mg/kg/day) are initially used until improvement or for 4-6 weeks, with a slow taper to avoid relapse. Weaning of steroids often occurs over 1-2 years. For refractory or severe disease, pulse therapy with intravenous methylprednisolone is used at a dose of 30 mg/kg, with a maximum dose of 1 g daily for 3 days with efficacy.[99] Calcium and vitamin D supplementation is recommended for patients on long-term corticosteroid therapy.

Second-line agents are routinely added for steroid-sparing effects and for recalcitrant or refractory disease. Methotrexate has been the most widely accepted agent and is used at doses of 10-20 mg/m2 per week orally or subcutaneously with 1 mg/d of folic acid supplementation.

Methotrexate administration may be started at the outset of severe disease (eg, moderate to severe weakness, manifestations of vasculopathy) or started if patients fail to respond to high-dose corticosteroids within 6 weeks. The use of methotrexate in conjunction with a tapering course of prednisone may be effective in reducing the long-term cumulative dose of corticosteroids.[100, 98]

Cyclosporin A has been used as an alternative, effective, steroid-sparing agent in JDM.[101] Preliminary data also suggest that the use of cyclosporine A in combination with methotrexate may be associated with further improvement in clinical outcome.

Intravenous immunoglobulin (IVIG) may also be used in patients with JDM who are steroid-resistant or steroid-dependent at a dose of 1 g/kg on 2 consecutive days, or 2 g/kg in one day, then every month thereafter, generally for a 6-month course. Other second-line agents include azathioprine and mycophenolate mofetil.[98]

Biologic agents such as the anti–tumor necrosis factor agents have had mixed results. More recently, infliximab has shown major clinical benefit in 5 patients with refractory JDM.[102] Another promising agent for JDM is the anti-CD20 monoclonal antibody rituximab.[103] In one trial of adults with refractory polymyositis and adults and children with refractory dermatomyositis, 200 patients were randomized to either rituximab early or rituximab late. Glucocorticoid and immunosuppressive therapy were allowed at entry. While no significant differences in outcomes between treatment groups were observed, 83% of refractory adult and juvenile myositis patients met the International Myositis Assessment and Clinical Studies Group definition of improvement.[104]

Rehabilitation

Rehabilitation plays an active role in the first-line management of myositis to restore and maintain muscle strength and endurance and to prevent contractures. If the myositis is active, then passive range of motion exercises are recommended; pool therapy may also be helpful.

When the disease is stabilized, isometric and isotonic exercises have been recommended.[2] However, one study indicated that an intensive muscular training program involving resistance training may be beneficial and safe without worsening of muscle inflammation.[105]

For patients with severe contractures, physical and occupational therapy with assistive devices is recommended.

No special diet is advised for most patients with JDM, although calcium and vitamin D supplementation are usually recommended for those using corticosteroids. Patients who have dysphagia may have a consistency-limited diet as recommended by a physical therapist.

Vigorous physical activity should be avoided if the child has instabilities, severe fatigue, or concerns of falling or aspiration. Bed rest is not indicated. Protective measures against sun exposure are recommended.

Guidelines on the management of juvenile dermatomyositis were made by an expert panel using the European League Against Rheumatism standard operating procedures. The guidelines included the following recommendations[106] :

In every patient with a possible diagnosis of JDM, the following should be considered:

• Muscle enzymes—including creatinine phosphokinase (CPK), LDH, AST (SGOT), ALT (SGPT), adolase (if available)

• Full blood count and blood film

• ESR (or plasma viscosity) and CRP

• Myositis-specific and myositis-associated antibodies

• Renal function and liver function tests

• Infection screen (for differential diagnosis)

• Investigations for alternative systemic causes of myopathy, including endocrine disorders (especially thyroid function), electrolyte disturbances, and vitamin D deficiency

• Further tests for metabolic/mitochondrial myopathies (especially in the absence of rash/atypical presentation)

• Urine dipstick (with further evaluation if positive for protein)

• Nailfold capillaroscopy

• Echocardiogram and ECG

• Pulmonary function tests (chest x-ray and HRCT if concern)

• MRI of muscles (+quantitative ultrasound)

• EMG (particularly if suspicion of neuropathy/disorder of neuromuscular junction)

• Muscle biopsy (especially in the absence of rash/atypical presentation)

• MRI brain if neurologic involvement suspected

• Abdominal ultrasound scan

High-risk patients are defined by the following:

• Disability defined by inability to get off the bed

• CMAS (Childhood Myositis Assessment Scale) score < 15 or MMT8 (Manual Muscle Test) score < 30

• Presence of aspiration or dysphagia

• Gastrointestinal vasculitis

• Myocarditis

• Parenchymal lung disease

• CNS disease (decreased level of consciousness or seizures)

• Skin ulceration

• Requirements for ICU management

• Age < 1yr

Treatment recommendations:

• High-dose corticosteroids should be administered orally or by IV in moderate to severe JDM.

• For new-onset JDM, high-dose corticosteroids by oral or IV route with methotrexate (MTX).

• MTX should be started at a dose of 15–20 mg/m2/wk (max absolute dose of 40 mg /wk) preferably administered subcutaneously at disease onset.

• Ongoing skin disease reflects ongoing systemic disease and therefore should be treated by increasing systemic immunosuppression. Topical tacrolimus (0.1%)/topical steroids may help localized skin disease, particularly for symptomatic redness or itching.

• For patients with severe disease (such as major organ involvement/extensive ulcerative skin disease), addition of intravenous cyclophosphamide should be considered.

Systemic corticosteroids are the mainstay of treatment for juvenile dermatomyositis (JDM). Other immunosuppressive and immunomodulatory agents are used as steroid-sparing agents, to lower the risk of steroid-related complications.

Long-term use of corticosteroids is associated with toxicities such as cataracts, hypertension, a cushingoid appearance, growth failure, menstrual irregularities, avascular necrosis, and metabolic complications.[2] The risk of osteopenia and osteoporosis is also increased with long-term corticosteroid use,[107, 108] as are the risks of insulin resistance, lipodystrophy, and hypertriglyceridemia. Screening for metabolic disorders is recommended during routine follow-up visits.[109]

Class Summary

Corticosteroids are the mainstay of therapy. These agents have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Prednisone

Prednisone is a first-line therapy for JDM. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity. Administration in IV pulses may be beneficial and may be associated with lower frequency of calcinosis.

Methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol)

Methylprednisolone is used as an anti-inflammatory or immunosuppressant agent in the treatment of a variety of diseases.

Prednisolone (Orapred ODT, Prelone, Pred Forte, Omnipred)

Prednisolone decreases autoimmune reactions, possibly by suppressing key components of the immune system. This agent does not need to undergo hepatic metabolism.

Class Summary

These agents inhibit immune reactions that result from diverse stimuli.

Methotrexate (Rheumatrex, Trexall)

Methotrexate has benefits in both muscle and skin disease. Its mechanism of action in treatment of inflammatory reactions is unknown. It may affect immune function. Methotrexate ameliorates symptoms of inflammation (eg, pain, swelling, stiffness).

This agent is an antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells. It may suppress the immune system. A satisfactory response may be seen 3-6 wk following initiation of treatment. Gradually adjust dose to attain satisfactory response.

It is used early in the course as a steroid-sparing agent to lower the risk of steroid-related complications.

Cyclosporine (Neoral, Sandimmune, Gengraf)

An 11-amino acid cyclic peptide and natural product of fungi, cyclosporine acts on T-cell replication and activity. It is a specific modulator of T-cell function and depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in G0 or G1 phase of cell cycle has been suggested.

Cyclosporine binds to cyclophilin, an intracellular protein, which, in turn, prevents formation of interleukin 2 and the subsequent recruitment of activated T cells. It has about 30% bioavailability but this widely varies. Cyclosporine specifically inhibits T-lymphocyte function, with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that drug be present during first 24 h of antigenic exposure.

Cyclosporine suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for various organs.

Mycophenolate (CellCept, Myfortic)

Mycophenolate is useful for both skin and muscle disease. It inhibits purine synthesis and proliferation of human lymphocytes.

Infliximab (Remicade)

Infliximab is a tumor necrosis factor (TNF) antagonist that is a chimeric human-murine monoclonal antibody. It blocks the effects of TNF-alpha by inhibiting receptor binding.

Immune globulin intravenous (Carimune, Gammagard S/D, Gamunex, Octagam, Gammaplex)

Intravenous immune globulin (IVIg) is used for patients in whom corticosteroids and immunosuppressive agents have failed. IVIg downregulates proinflammatory cytokines, including interferon-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).

Hydroxychloroquine (Plaquenil)

Hydroxychloroquine may allow partial or complete control of the skin manifestations in JDM. Anecdotal reports suggest that morbilliform drug reactions are more common in patients with JDM than in other collagen vascular diseases. This agent inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions.

Cyclophosphamide

Cyclophosphamide is an alkylating agent of the nitrogen mustard family that exerts cytotoxic effects by binding to nucleic acids and crosslinking DNA and RNA strands and inhibiting protein synthesis.

Azathioprine (Imuran)

Azathioprine is an imidazolyl derivative of 6-mercaptopurine. Many of its biological effects are similar to those of the parent compound. Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver. No azathioprine or mercaptopurine is detectable in urine 8 h after ingestion.

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. The mechanism whereby azathioprine affects autoimmune diseases is unknown.

This agent works primarily on T cells. It suppresses cell-mediated hypersensitivities and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity are suppressed to a greater degree than antibody responses.

Azathioprine works very slowly; a 6-12 mo trial may be needed before the drug takes effect. Up to 10% of patients may have an idiosyncratic reaction that disallows use of this agent. Do not allow WBC count to drop below 3000/mL or the lymphocyte count to drop below 1000/mL.

Azathioprine is available in tablet form for oral administration and in 100-mg vials for IV injection.

Class Summary

Consider using these agents for calcinosis cutis.

Diltiazem (Cardizem, Cardizem CD, Tiazac, Dilacor XR, Cartia XT)

During depolarization, diltiazem inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. The resultant decrease in intracellular calcium inhibits the contractile processes of myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.

Diltiazem decreases conduction velocity in the AV node. It also increases the refractory period via blockade of calcium influx. This, in turn, stops reentrant phenomena.

This agent decreases myocardial oxygen demand by reducing peripheral vascular resistance, reducing heart rate by slowing conduction through SA and AV nodes, and reducing LV inotropy. It slows AV nodal conduction time and prolongs the AV nodal refractory period, which may convert supraventricular tachycardia or slow the rate in atrial fibrillation. It also has vasodilator activity but may be less potent than other agents. Total peripheral resistance, systemic blood pressure, and afterload are decreased.

Calcium channel blockers provide control of hypertension associated with less impairment of function of the ischemic kidney. Calcium channel blockers may have beneficial long-term effects, but this remains uncertain.