Juvenile dermatomyositis and polymyositis: Treatment, complications, and prognosis

INTRODUCTION — Juvenile dermatomyositis (JDM) and juvenile polymyositis (JPM) are autoimmune myopathies of childhood. JDM is primarily a capillary vasculopathy, whereas JPM involves direct T cell invasion of muscle fibers similar to that seen in adult polymyositis [1-3]. However, as the diagnostic tools become more sophisticated (eg, biopsies that demonstrate inclusion body myositis or inflammatory dystrophies, or autoantibodies that are markers of particular types of myositis such as anti-signal recognition particle [SRP] and necrotizing myopathy), fewer patients are diagnosed with JPM, calling into question whether JPM is a specific entity. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

The treatment, complications, natural history, and prognosis of JDM and JPM are reviewed here. The pathogenesis, clinical manifestations, and diagnosis of these disorders are discussed elsewhere. (See "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations" and "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis".)

TREATMENT GOALS — The goals of treatment include control of the underlying inflammatory myositis and prevention and/or treatment of complications (eg, contractures and calcinosis).

INITIAL TREATMENT — The intensity of initial therapy increases with increasing severity of the symptoms [4], which range from mild disease with little muscle weakness and mild cutaneous manifestations to serious, life-threatening weakness, internal organ damage, and ulcerative skin lesions. There are no standardized definitions of disease severity for JDM and JPM. However, most experts would agree that the following constitute severe disease:

●Interstitial lung disease

●Ulcerative disease (skin or gastrointestinal [GI] tract)

●Other GI manifestations that may indicate GI vasculopathy (eg abdominal pain, diarrhea, GI bleeding)

●Myocardial or neurologic involvement (rare in children)

There are few data from randomized, controlled trials to guide management decisions in children with JDM or JPM. Thus, the treatment approach is based mostly upon observational studies and clinical experience. In a 2008 survey of North American pediatric rheumatologists, the majority of respondents used a combination of glucocorticoids and methotrexate to treat children with JDM [5]. However, the dose, route of administration, and the use of adjunctive therapy (eg, intravenous immune globulin [IVIG] and hydroxychloroquine) varied. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) has proposed several treatment strategies for initial therapy for JDM based upon a North American survey of practice [6]. Our approach is consistent with the CARRA treatment strategies.

Mild-to-moderate disease — The initial treatment used for children with mild-to-moderate JDM or JPM is a combination of high-dose oral prednisone (2 mg/kg per day, maximum 80 mg/day, in divided doses given twice daily) and methotrexate (15 mg/m², maximum 25 mg/dose once weekly, administered as a subcutaneous injection). Children who receive methotrexate should also be given folic acid at 1 mg per day to limit methotrexate toxicity. Leucovorin (folinic acid; usual dose 5 mg once a week) is an alternative to folic acid.

The skin findings of amyopathic/hypomyopathic JDM may remit without systemic therapy in some patients [7-9]. However, we feel that children with amyopathic/hypomyopathic JDM with muscle enzyme elevation or other evidence of subclinical muscle inflammation should be treated, regardless of whether or not clinically evident weakness is present, in order to prevent long-term complications such as calcinosis.

Oral prednisone — Daily oral prednisone, in combination with a steroid-sparing agent (preferably methotrexate [10]), has been the mainstay of treatment of JDM and JPM for many years [11,12]. In responsive patients, muscle weakness and rash improve and serum muscle enzymes return to normal levels over six to eight weeks of therapy. Most North American pediatric rheumatologists, including the authors, use a high-dose glucocorticoid regimen to initially treat JDM and JPM [5]. Our standard initial regimen is prednisone at 2 mg/kg per day (maximum 80 mg/day) in divided doses, given twice daily for six weeks, after which it is consolidated into one daily dose (see 'Tapering therapy in responsive patients' below). Others adjust the dose relative to the disease severity, using lower doses in children with milder disease in order to decrease the total cumulative dose and reduce the adverse effects of glucocorticoids. Intravenous methylprednisolone (IVMP) is added for patients who have a poor response or worsening of their disease on oral prednisone therapy. (See 'Intravenous methylprednisolone' below.)

Early evidence demonstrating the efficacy of systemic glucocorticoids was based upon a retrospective review of 47 children with JDM treated at a single center between 1964 and 1982 [13]. Patients who received high-dose prednisone (2 mg/kg per day) within four months of the onset of their symptoms had better functional outcome and less calcinosis compared with those who received smaller doses of prednisone or who were treated later in the course of their disease. Patients who received smaller doses of prednisone generally had a poorer outcome than those who received a high prednisone dose (2 mg/kg per day) [13]. In another study, lower-dose prednisone therapy (1 mg/kg per day) was administered to 36 children with JDM. At a mean follow-up of 4.9 years, 28 had no functional impairment, 5 had persistent disability with inactive disease, and 3 had ongoing active disease [14]. Fifteen children (42 percent) developed dystrophic calcifications. These findings suggest that lower-dose prednisone is not sufficient for all patients.

Prolonged glucocorticoid therapy is associated with significant adverse effects. In children, these include growth retardation, Cushingoid appearance, elevation of blood pressure, hyperglycemia, cataracts, and osteoporosis. (See "Major side effects of systemic glucocorticoids" and "Causes of short stature", section on 'Glucocorticoid therapy'.)

Steroid-sparing agents — A steroid-sparing agent is usually started concomitantly with systemic glucocorticoids to decrease the total dose and duration of glucocorticoids and thereby minimize their side effects. Both methotrexate and cyclosporine are effective, but methotrexate has fewer side effects, and a randomized comparative trial showed greater efficacy [10]. Thus, methotrexate is preferred.

Methotrexate — The addition of methotrexate to the initial therapy shortens the duration of glucocorticoid therapy considerably, reduces the total cumulative glucocorticoid dose, and improves efficacy compared with glucocorticoid therapy alone [10,15,16]. Methotrexate is usually administered at a dose of 15 mg/m² (dose rarely exceeds 25 mg/dose) given once weekly, either by mouth or subcutaneous injection. The CARRA protocols suggest the subcutaneous route, which is our preferred route of administration [6]. Children should be provided folic acid (1 mg/day) in order to limit toxicity. Leucovorin (folinic acid; usual dose 5 mg once a week) is an alternative to folic acid.

In a randomized, unblinded, multicenter trial, 139 children with new-onset JDM with no cutaneous or GI ulcerations were assigned to prednisone alone, prednisone plus methotrexate, or prednisone plus cyclosporine [10]. There was a significant increase in the Pediatric Rheumatology International Trials Organization (PRINTO) 20 level of improvement (20 percent improvement in three of six core set variables) at six months in the two combination-therapy groups compared with prednisone alone (51, 70, and 72 percent improvement for prednisone, prednisone plus cyclosporine, and prednisone plus methotrexate, respectively). Median time to clinical remission for the prednisone plus methotrexate group was 42 months but could not be determined for the other groups due to the low number of events. Median time to treatment failure was 17 months for patients on prednisone alone and 53 months for prednisone plus cyclosporine but could not be calculated for prednisone plus methotrexate due to the low event number. The highest rate of adverse events was seen in patients treated with prednisone plus cyclosporine. Higher rates of infection were seen in both groups of patients treated with a steroid-sparing agent compared with prednisone alone.

Another study compared 31 patients newly diagnosed with JDM who were initially treated with methotrexate (15 mg/m² per week) and prednisone (2 mg/kg per day, maximum dose 75 mg per day) with 22 similar historical controls who received prednisone therapy alone [15]. Patients treated with combination therapy had a shorter average time to discontinuation of prednisone (10 versus 27 months) and a lower average cumulative prednisone dose (7.5 versus 15.1 grams) compared with those treated with only prednisone. Recovery of strength and physical function were similar in both groups. The children who received combination therapy had fewer side effects, greater height velocity, lower weight gain, and decreased risk of developing cataracts compared with controls.

Favorable outcome was reported with the early use of methotrexate in combination with IVMP in newly diagnosed patients with severe JDM characterized by dysphagia and skin ulcerations [16,17]. In particular, the early use of combination therapy appeared to minimize long-term sequelae, including calcinosis [17].

In a small case series, methotrexate and IVIG were successfully as primary therapy without glucocorticoids in select patients with mild-to-moderate disease [18].

Side effects may include nausea and vomiting in the 12 to 24 hours following administration. Other adverse effects include aphthous oral ulcers, liver enzyme elevation, and increased susceptibility to infection.

Cyclosporine — Cyclosporine is used by some as a steroid-sparing agent early in treatment of children with JDM, although it is typically reserved for refractory disease at the authors' institution because of its higher rate of side effects [10]. The dosing regimen for cyclosporine is 3 to 5 mg/kg given once daily or split into two daily doses. The most common adverse effects include skin and subcutaneous tissue disorders (eg, gingival hypertrophy, hypertrichosis/hirsutism), GI symptoms and disorders, neurologic disorders (eg, headache, reversible encephalopathy, seizures), and increased susceptibility to infection. (See 'Refractory or recurrent disease' below and 'Methotrexate' above.)

Severe/life-threatening disease — We use IVMP for patients who have:

●Ulcerative disease

●Respiratory compromise and who are unable to take oral medications

●GI complications that may limit absorption of orally administered medications

●Marked dysphagia/dysphonia with increased risk of aspiration

●A poor response or worsening of their disease on oral prednisone therapy

We treat patients with more severe ulcerative skin disease or life-threatening major organ involvement (eg, interstitial lung disease, GI vasculopathy) with cyclophosphamide, usually in combination with high-dose glucocorticoids. Cyclophosphamide is most often administered intravenously every four weeks at a dose of 500 to 750 mg/m² for a total of seven doses. An alternative to cyclophosphamide in these patients is IVIG. (See 'Intravenous immune globulin' below.)

Intravenous methylprednisolone — IVMP is often used in more severely affected patients because of concerns that these patients, particularly those with GI vasculopathy, may have decreased absorption of orally administered prednisone [19]. However, patients are usually concomitantly treated with daily oral glucocorticoids, starting after the three-day course of IVMP, because response failure and disease relapse are common on IVMP alone [20]. The most frequently used regimen administers IVMP at a dose of 30 mg/kg per day (maximum dose 1 g) for three consecutive days followed by additional weekly or monthly boluses as needed [3]. In some cases, those treated with IVMP alone are transitioned to oral prednisone, without additional IVMP boluses, after a three-day course of IVMP.

A study of 139 newly diagnosed patients with JDM that compared IVMP with high-dose oral prednisone did not find significant differences in outcome at 36 months follow-up after matching patients for disease characteristics [21]. However, in this study, all of the most severely ill patients were excluded from the analysis because they all received IVMP and, therefore, could not be matched. It remains uncertain whether IVMP has a sufficiently greater benefit compared with oral prednisone in patients with only moderate disease to justify its cost and invasiveness [22].

Intravenous cyclophosphamide — In a retrospective review of 12 patients who received intravenous cyclophosphamide for severe and refractory disease, 10 patients demonstrated improvement in muscle disease, extramuscular disease, and skin disease [23]. Two patients who required mechanical ventilation prior to receiving cyclophosphamide died shortly after beginning therapy. Death was attributed to their underlying disease and not to the use of cyclophosphamide. Observed side effects of cyclophosphamide included transient alopecia, lymphocytopenia, and herpes zoster infection, but no severe adverse events were noted.

A subsequent publication looked at 56 patients treated with cyclophosphamide compared with 144 not treated with cyclophosphamide from the UK JDM Cohort and Biomarker Study [24]. A marginal structural models (MSM) approach was used in which like patients were compared with like. Cyclophosphamide was given intravenously, 500 mg/m² every two weeks for three doses and then 750 mg/m² every three or four weeks for a total of six or seven doses. Disease activity (global, skin, and muscle) was reduced in the cyclophosphamide group at 6, 12, and 24 months. Few side effects were seen. The cyclophosphamide-treated patients had more severe muscle and global disease severity (hence the need for the MSM approach), suggesting that cyclophosphamide is indeed effective in more severe disease.

EVALUATION OF RESPONSE TO THERAPY — The response to treatment is assessed based upon the following:

●Normalization of elevated serum muscle enzymes (see "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis", section on 'Measurement of muscle enzymes')

●Increased muscle strength both by history and objective measures, such as the Childhood Myositis Assessment Scale (CMAS) (see "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Diagnosis", section on 'Muscle strength testing')

●Resolution of skin rash (see "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations", section on 'Heliotrope rash' and "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations", section on 'Gottron's papules')

●Improvement in nailfold capillary changes, including an increase in the measured density of capillaries/mm as shown in panel C (picture 1) [25,26]

Muscle strength and skin rash may heal slowly over months. As long as consistent progress is observed, treatment should not be considered a failure.

In one study of 16 patients with JDM, elevations of serum lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) were associated with disease flare [27]. The risk of disease flare within the next four months increased threefold following a 20 percent rise in serum AST levels. However, an association with disease flares was not seen with either an elevation of serum alanine aminotransferase (ALT) or creatine kinase (CK).

Definitions for improvement in adult and juvenile myositis were revised by an international group of myositis experts [28]. These definitions are based upon the weighted absolute change in six core set activity measures, with different cut points for minimal, moderate, and major improvement for each measure.

The core set activity measures include:

●Clinician's global assessment of the patient's overall disease activity, usually measured with a 100 mm visual analog scale

●Patient or parent/caregiver global assessment of the child's overall well-being, usually measured with a 100 mm visual analog scale

●Muscle strength, assessed using the standardized confrontational (manual) muscle strength testing score of eight muscle groups (MMT8) or the CMAS

●Health-related quality-of-life assessment, assessed with the Health Assessment Questionnaire (HAQ) or the Child Health Assessment Questionnaire (CHAQ) [29]

●Muscle inflammation, assessed by either muscle enzyme values or the Childhood Health Questionnaire (CHQPF-50)

●Extramuscular disease activity, assessed by the extramuscular section of the JDM disease activity score (DAS) [30]

A similar group of disease activity core set measures was developed by the International Myositis Assessment and Clinical Studies Group (IMACS) [31].

The Juvenile DermatoMyositis Activity Index (JDMAI) attempts to simplify the assessment of response to therapy using a composite score consisting of four elements, comprising the clinician’s global assessment of overall disease activity, the caregiver's/child's global assessment of the child's well-being, a measurement of muscle strength, and assessment of skin disease activity [32].

Additional biomarkers have been identified for tracking disease activity. Specifically, galectin 9 and C-X-C motif chemokine ligand 10 (CXCL-10; thought to be markers of interferon activity) are better markers of disease activity than muscle enzymes [33].

CHRONIC TREATMENT — Chronic treatment is determined by the response to therapy and the pattern of the disease. (See 'Evaluation of response to therapy' above and 'Natural history' below.)

Tapering therapy in responsive patients — If there is a response to therapy, prednisone is consolidated to a daily dose at approximately six weeks. Prednisone is then weaned slowly in a stepwise fashion [11,13]. At our center, we taper the dose every two weeks by 5 mg decrements until a daily dose of 25 mg is reached; at that point, prednisone is decreased by 2.5 mg every two weeks. The median length of time on prednisone in our clinic is approximately 10 months. Patients on combination therapy with an additional immunosuppressive agent will often tolerate weaning this quickly [15].

Muscle strength, skin rash, and enzymes are monitored for evidence of relapse. Relapses may be managed by increasing the glucocorticoid or methotrexate doses or, more often, by adding additional medications, such as intravenous immune globulin (IVIG). (See 'Evaluation of response to therapy' above and 'Refractory or recurrent disease' below.)

Refractory or recurrent disease — IVIG is added to the regimen to control persistent or recurrent symptoms and to decrease the cumulative dose of glucocorticoids administered in patients who become steroid resistant or dependent during the course of treatment (generally after several months of therapy) despite use of steroid-sparing medications. In the case of persistent or recurrent symptoms despite the use of glucocorticoids, methotrexate, and IVIG, we have added cyclosporine with some success, which has limited the need for increasing cumulative doses of glucocorticoids. Other medications have been used in a limited number of patients with refractory disease.

Intravenous immune globulin — The benefits of IVIG were reported in several observational studies of children with JDM who had previously failed treatment with glucocorticoids and, in most cases, other immunosuppressive agents [34-38]. The majority of reported patients experienced improvement in skin disease and muscle strength, and the use of IVIG also reduced the cumulative glucocorticoid dose in most patients [34-37,39-42].

IVIG, at our center, is given as a dose of 2 g/kg (maximum dose 70 g), administered as a single dose. IVIG is given every two weeks, initially for five doses, and is then generally administered monthly for up to two years. The decision to begin IVIG typically occurs months into treatment, when patients experience persistent or increasing symptoms as glucocorticoids are weaned, indicating steroid resistance or steroid dependence. However, IVIG is often used earlier in very severe cases of JDM.

In children with JDM, IVIG is generally well tolerated, with reported side effects of headache, diarrhea, nausea, and low-grade fever [34,36]. One study reported an increase in adverse events (eg, fever, lethargy, or malaise, nausea, and vomiting) with IVIG preparations that contained a high immunoglobulin A concentration [41]. (See "Overview of intravenous immune globulin (IVIG) therapy".)

Cyclosporine — Cyclosporine, a calcineurin inhibitor, is primarily used in patients with refractory JDM and JPM. Small observational studies have shown that the addition of cyclosporine to patients with an inadequate response to glucocorticoid and other immunosuppressive agents is associated with clinical improvement (eg, recovery of muscle strength), leading to a reduction in prednisone dose [43-46]. In the randomized trial previously discussed, cyclosporine was effective but did not do as well as methotrexate [10]. (See 'Methotrexate' above.)

The starting dose of cyclosporine is 3 to 5 mg/kg per day. The dose is adjusted depending upon the clinical response and the presence of cyclosporine toxicity (often earliest seen as a rising serum creatinine). Reported side effects in patients with JDM include hirsutism, gingival hypertrophy, hypertension, and diarrhea [43-47]. Treatment with cyclosporine generally continues until the disease has remained in stable remission off glucocorticoids for many months.

Investigational therapies — A number of agents have been used in one to a few patients with refractory disease who have failed other immunosuppressive therapies. Further studies are needed to determine whether there is a role for these agents in the treatment of JDM.

Biologic and targeted synthetic DMARDs — Biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) are increasingly used in the treatment of autoimmune diseases. However, the use of these agents is limited in children with JDM and JPM.

●Rituximab – In two small case series, the use of rituximab, a B cell-depleting monoclonal anti-CD20 antibody, was associated with clinical improvement in children with JDM (three of four in one series [48] and three of six in the other [49]), although calcinosis did not improve. However, the fourth patient in the first series had deterioration of her clinical status following rituximab therapy. A randomized trial (that included 152 adults with myositis as well as 48 children with JDM) demonstrated that most patients eventually saw some benefit, although the time that it took to show improvement was long and there was no statistically significant difference between subjects who received rituximab early or after a delay of nine weeks [50,51]. Despite lack of trial evidence of efficacy, up to one-third of surveyed North American pediatric rheumatologists have used rituximab for refractory JDM [52]. (See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Rituximab'.)

●Anti-tumor necrosis factor agents – A report from the Juvenile Dermatomyositis Research Group cohort highlighted 60 children with JDM refractory to other treatments who were treated with infliximab or adalimumab (often in combination with other therapies listed above) [53]. On average, these anti-TNF agents were steroid sparing and led to reductions in skin and muscle disease activity and to reductions in calcinosis. However, case series of adults with resistant dermatomyositis and polymyositis have failed to show a consistent beneficial response to anti-TNF agents.

●Abatacept – Abatacept is a soluble fusion protein containing the extracellular domain of cytotoxic T lymphocyte antigen 4 (CTLA-4) and the Fc portion of immunoglobulin G1 (IgG1). It binds to CD80/CD86, preventing CD28 binding and thereby downregulating T cell activation. A 14-year-old girl with severe refractory JDM with ulcerations and calcinosis was reported to have improvement in disease scores, ulcerations, pain medication and glucocorticoid use, and laboratory values after treatment with abatacept and sodium thiosulfate [54]. (See 'Other agents' below.)

●Janus kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitors – Given the suggestion that JDM is an interferon-driven process, the use of JAK/STAT inhibition is under exploration. Four refractory patients were reported to have a good response to baricitinib, a small-molecule tsDMARD, in one case series [55].

Other agents

●Mycophenolate mofetil – In a small case series of 12 children with JDM and refractory skin disease, improvement of the skin disease was seen in 10 patients within four to eight weeks of treatment with mycophenolate mofetil at doses ranging from 500 mg to 1 g twice a day [56]. A retrospective review of 50 patients with JDM treated with mycophenolate found that skin and muscle disease activity decreased and glucocorticoid doses were lower after 12 months of mycophenolate therapy [57]. Mycophenolate mofetil is one of the therapies mentioned in a consensus treatment plan for hypomyopathic JDM by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) group based upon typical treatment approaches [58].

●Tacrolimus – Tacrolimus, a calcineurin inhibitor, has been reported to improve the clinical status of children with refractory JDM in case reports [59,60]. Topical tacrolimus has been used for refractory skin disease with varied results [61,62].

●Hydroxychloroquine – Hydroxychloroquine, an antimalarial agent, is reported to be effective in patients with JDM and an incomplete response to glucocorticoid therapy [63]. However, in our experience, it has not been a particularly effective agent.

●Sodium thiosulfate – Thiosulfate is an antioxidant and vasodilator that chelates and dissolves calcium deposits and promotes vascularization of peripheral neuronal units, with associated resolution of pain. It was reported effective in one patient with refractory skin disease and calcinosis who was also treated with abatacept [54]. (See 'Biologic and targeted synthetic DMARDs' above.)

ADJUNCTIVE THERAPIES — Adjunctive therapy includes the use of sunscreen to prevent excessive sun exposure, topical glucocorticoids or calcineurin inhibitors for local skin disease, physical therapy (includes range of motion, muscle strengthening, and aerobic exercise), and supplemental calcium (1000 mg/day) and vitamin D (1000 units/day) to prevent osteoporosis. (See 'Osteoporosis' below.)

Sunscreen — The rash of JDM is generally photosensitive and may be exacerbated by exposure to sunlight. For this reason, we recommend that all children with JDM use sunscreen regularly.

Topical agents — Topical agents (glucocorticoids or calcineurin inhibitors such as tacrolimus or pimecrolimus) are often used to treat localized skin disease in patients with JDM [3,61].

Physical therapy — Physical and occupational therapy are important adjunctive measures to pharmacologic therapy because children with JDM and JPM have decreased aerobic exercise capacity and low levels of weight-bearing physical activity, which may worsen functional limitations and contribute to joint contractures [64,65]. Therapy is focused on appropriate range of motion, muscle strengthening, and aerobic exercises. These measures prevent or improve joint contractures and improve aerobic endurance [64,66].

Physical therapy and exercise regimens do not exacerbate clinical disease in patients with JDM. This was illustrated in a study that included groups of patients with both active and inactive JDM and normal controls that showed no evidence of increased muscle inflammation following a physiotherapy-led exercise session [67].

NATURAL HISTORY — There are three patterns of disease in JDM [1,68]:

●Monocyclic course, in which there is one disease episode, lasting up to two or three years, that responds to standard treatment without relapse (approximately one-third of patients)

●Polycyclic course with multiple remissions and relapses (approximately 3 percent)

●Chronic persistent course, sometimes with persistent complications (approximately two-thirds)

Muscle disease typically responds more quickly to treatment than other disease manifestations in children with JDM [69].

In one series of patients, an increased severity of muscle histopathologic features was associated with an increased risk of a chronic persistent course (as judged by the need for a longer course of treatment), whereas presence of anti-Mi-2 autoantibodies was perhaps associated with a decreased risk [70].

Chronic continuous or polycyclic disease is predictive of a poorer outcome [71,72]. These patients are at increased risk for persistent pain, calcinosis, and disability. (See 'Prognosis' below.)

COMPLICATIONS — Complications associated with JDM include osteoporosis, calcinosis, and intestinal perforation.

Osteoporosis — Patients with JDM have low bone mineral density compared with age-matched controls [73] and an increased risk of vertebral fractures [74]. Risk factors for low bone density include low lean body mass, glucocorticoid therapy, and longer duration of untreated disease [73,75,76]. In one study, children with JDM had increased osteoclast activation and bone resorption compared with age-matched controls [75]. (See "Investigational biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Bone-specific markers'.)

Limited observational data suggest that treatment with supplemental calcium and vitamin D increases spinal bone density by approximately 10 percent in children who are on glucocorticoid therapy for rheumatic disease [77]. Based upon available data, it is standard practice in the authors' institution to provide both calcium and vitamin D supplementation to help prevent osteoporosis (approximately 500 to 1000 mg elemental calcium and 1000 int. units vitamin D3 daily, depending upon dietary intake).

Limited data suggest that the oral bisphosphonate, alendronate, may result in increased bone mineral density in children with connective tissue disease [78]. However, bisphosphonate safety and efficacy in childhood have not been clearly established. Thus, they are not routinely used. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Calcinosis — Dystrophic calcification or calcinosis (soft tissue calcification), as shown in panel D (picture 1), is a well-recognized complication that generally develops within a few years of diagnosis and is associated with delay in diagnosis or treatment or inadequate treatment [13,68,79-81]. The primary focus is to prevent calcinosis through adequate treatment of JDM (eg, early use of combination therapy of high-dose glucocorticoids and methotrexate) since there is no established treatment for calcinosis. If a patient develops calcinosis, the approach is to treat the patient until the disease is inactive and allow the patient's body to resorb the calcium on its own. (See 'Initial treatment' above.)

Reports of its prevalence vary from 30 to 50 percent [13,82]. In contrast, one study of 144 patients from the United Kingdom reported a much lower calcinosis rate of 6 percent [81].

Five distinct patterns of calcinosis have been described [13,83]:

●Small, scattered, superficial plaques or nodules, usually on the extremities. These lesions often do not interfere with function but may be painful and may develop spontaneous cellulitis-like inflammation (sometimes with drainage of toothpaste-like calcium soap). Inflamed superficial calcinosis must be differentiated from lesions that have become infected. Superficial calcinosis often regresses spontaneously over a period of years.

●Deep tumoral muscle calcification, often found in the proximal muscle groups, that may interfere with joint motion. These deposits may ulcerate or extrude calcific material through the skin. These may require surgical debridement in order to maximize joint function.

●Diffuse deposits along myofascial planes that may limit joint motion and may be painful.

●Mixed forms of the above three types may be seen.

●Extensive exoskeleton-like calcium deposits that result in serious limitations in function. Patients with this form of calcinosis often have a history of a severe, unremitting disease course that is sometimes associated with ulcerative cutaneous disease.

The following are risk factors for the development of calcinosis:

●Delay in diagnosis or treatment or inadequate treatment [13,80]

●Tumor necrosis factor (TNF) alpha-308A genotype (this allele is associated with increased levels of TNF-alpha) [84]

●Presence of autoantibodies against nuclear matrix protein 2 (NXP2) [85]

●Younger age at disease onset [85,86]

A number of therapies have been reported to be effective in case reports, but none are consistently successful. Thus, we do not use them. These therapies include probenecid [87-89], diltiazem [90,91], aluminum hydroxide [92,93], alendronate [94], pamidronate [95], intralesional glucocorticoids [96], and sodium thiosulfate [54].

Surgical excision is sometimes required for localized calcific deposits that interfere with joint function or are painful [97]. However, surgical intervention is associated with a reasonable frequency of poor wound healing, recurrence of calcinosis, and ongoing problems in children with active disease. Thus, controlling underlying active disease prior to surgical excision is advised.

Intestinal perforation — Intestinal perforation is a rare complication that is seen most often in children with severe vasculopathy and/or cutaneous ulcers. Surgical intervention is required to treat intestinal perforation. This includes perforation closure, drainage, and excision of bowel when necessary and supportive total parenteral nutrition to allow healing [98]. (See "Overview of gastrointestinal tract perforation".)

Cardiovascular and cerebrovascular comorbidities — A study using admission codes has suggested that children with JDM admitted to the hospital have increased rates of hypertension; atherosclerosis; transient ischemic attacks, cerebral infarction, and other cerebrovascular disease; disorders of the pulmonary vasculature; arrhythmia; bradycardia; and hypotension compared with admitted children without JDM [99]. The authors were unable to separate the effects of having JDM from the treatment, such as glucocorticoids, for JDM. Lipodystrophy and associated metabolic syndrome are discussed separately. (See "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations", section on 'Lipodystrophy'.)

Risk of malignancy — Unlike adults, children with JDM or JPM do not have an increased risk of malignancy. Thus, a search for malignancy does not need to be made when children present with idiopathic inflammatory myopathy, unless the presenting features are quite unusual (eg, cytopenias, lack of typical rash, lymphadenopathy). In one Scottish population-based study, for example, cancer was not observed among 35 and 9 children with JDM or JPM, respectively [100]. There are rare case reports of solid tumors or hematologic malignancies in children with JDM. However, there is no evidence that the incidence of these cancers is greater than in the general population. (See "Malignancy in dermatomyositis and polymyositis".)

PROGNOSIS — Advances in the treatment have improved mortality and morbidity rates in children with JDM. Some feel that early treatment may help limit JDM to a monocyclic pattern [101]. (See 'Natural history' above.)

Mortality — The reported mortality rate has declined from greater than 30 percent in the 1960s [102], before routine glucocorticoid therapy was administered, to less than 2 or 3 percent in the 2000s with the advent of early combination immunosuppressive therapy [11,68,71,79].

Morbidity — The long-term outcome of JDM has become increasingly important as the survival rate has improved. Prognosis is poorer in patients with chronic continuous or polycyclic disease and in those with higher initial disease activity scores. Additional risk factors for more severe disease and a worse prognosis include the presence of ulcerative lesions, anasarca, or gastrointestinal (GI) tract involvement. Major morbidities include cumulative organ system damage (including skin, musculoskeletal, endocrine, pulmonary), functional limitations, and persistent pain. (See "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations", section on 'Skin ulcerations' and "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations", section on 'Anasarca' and "Juvenile dermatomyositis and polymyositis: Epidemiology, pathogenesis, and clinical manifestations", section on 'Gastrointestinal vasculopathy'.)

In a retrospective case series that included 6 of 47 children with JDM with extensive ulcerative skin vasculitis present at diagnosis, these six patients continued to have persistent muscle weakness, elevations of muscle enzyme activity, and severe generalized cutaneous vasculopathy despite receiving glucocorticoid therapy [13]. In another study, 10 of 29 patients had a chronic disease course characterized by ulcerative cutaneous and GI lesions [103]. Two of the 10 died due to complications including GI perforation, and five had severe musculoskeletal and cutaneous damage, while three had no residual disease [103].

Although data on long-term morbidity are limited, it appears that patients with JDM treated with combined therapy have a favorable prognosis.

This was illustrated in a retrospective review of 65 of 80 patients from a cohort of patients diagnosed with JDM between 1984 and 1995 at four Canadian tertiary centers [68]. Sixty-two (95 percent) were treated with high-dose glucocorticoids therapy (31 received intravenous methylprednisolone [IVMP]); 41 (63 percent) also received a second-line agent (ie, hydroxychloroquine [n = 10], intravenous immune globulin [IVIG; n = 6], methotrexate [n = 5], and two or more agents [n = 20]); and three patients received no therapy. Patients were surveyed at a median follow-up time of 7.2 years (range 3.2 to 13.9 years) and median age of 13 years (range 7 to 26 years). There was one death in this cohort. The following findings were noted:

●Twenty-four patients (37 percent) had monocyclic disease, and the remaining had chronic continuous or polycyclic disease.

●Physical function was excellent, with only five patients reporting moderate-to-severe disability. Almost 80 percent had no pain.

●Approximately one-third of patients had calcinosis, which was severe in one patient. Approximately 40 percent of patients continued to have a rash, although 22 of the 26 patients indicated that the rash was of little or no consequence.

●Data on growth demonstrated that most patients were within 1 standard deviation (SD) of their predicted height. However, 10 patients (16 percent) were ≥2 SD below their predicted height. Delayed puberty was reported in a large European study [104].

●Approximately one-third of patients continued on medication despite being more than three years from diagnosis.

●Patients with chronic disease were more likely to have functional limitations, persistent pain, and calcinosis.

●All patients had either completed or were attending high school, and, of those who had graduated, all went on to pursue postsecondary education. Three patients needed to repeat a single grade because of missing time from school because of their disease. Of the 14 patients who were working full or part-time (of whom 13 were still attending school), none of the patients felt that their disease interfered with their ability to work.

In a long-term follow-up report of 60 patients from Norway (median duration of follow-up of 16.8 years), most patients had cumulative organ damage [105]. The risk of cumulative organ damage was greater in patients with higher scores of disease activity and organ damage six months after diagnosis. The following areas of injury and their frequency were noted at last follow-up:

●Cutaneous (calcinosis, scarring or atrophy, lipodystrophy) – 75 percent

●Muscle (atrophy, weakness, dysfunction) – 63 percent

●Skeletal (joint contractures, osteoporosis, avascular necrosis, arthropathic deformity) – 48 percent

●Endocrine (growth failure, menstrual abnormalities) – 23 percent

●Pulmonary – 17 percent

●Other organ systems included peripheral vascular, cardiovascular, GI – 8, 7, and 3 percent, respectively

In subsequent publications, the group from Norway has demonstrated mild but persistent damage in a number of patients with JDM when followed into adulthood. Ongoing problems include impaired muscle function [106], reduced aerobic capacity [107], and (subtle) cardiac defects [108]. In another group of highly selected adult patients with JDM, overall function was good, but organ damage was frequent [109].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dermatomyositis and polymyositis".)

SUMMARY AND RECOMMENDATIONS

●Treatment goals – Treatment goals in children with juvenile dermatomyositis (JDM) and polymyositis (JPM) include control of the underlying inflammatory myositis and prevention and/or treatment of complications (eg, contractures and calcinosis). Immunosuppressive therapy is generally used to treat JDM and JPM, based upon limited controlled trial data, observational studies, and clinical experience. (See 'Introduction' above and 'Treatment goals' above.)

●High-dose glucocorticoid therapy in all patients – We recommend high-dose glucocorticoid therapy in all patients with JDM or JPM (Grade 1B). This recommendation is based upon the significant increase in survival rate and clinical outcome with the routine use of high-dose glucocorticoid therapy versus low-dose glucocorticoid or no treatment. In our institution, high-dose oral prednisone (2 mg/kg per day, maximum dose of 80 mg/day) is the preferred glucocorticoid regimen. In other centers, the initial dose of prednisone used is individualized based on the clinical presentation and may be lower than 2 mg/kg per day. We reserve the use of intravenous methylprednisolone (IVMP) for patients who fail to respond to oral prednisone or who have pulmonary or gastrointestinal (GI) complications that limit their ability to either take or absorb oral medications. (See 'Mild-to-moderate disease' above and 'Severe/life-threatening disease' above.)

●Steroid-sparing agent – We suggest adding a steroid-sparing agent to high-dose glucocorticoid therapy versus glucocorticoid therapy alone (Grade 2B); methotrexate is the preferred steroid-sparing agent (approximately 15 mg/m² once weekly, administered as a subcutaneous injection). Cyclosporine is an alternative to methotrexate (starting dose of 3 to 5 mg/kg per day, administered in one or two doses). (See 'Steroid-sparing agents' above.)

●Severe or life-threatening disease – We suggest the use of intravenous cyclophosphamide (500 to 750 mg/m² every four weeks) in combination with high-dose glucocorticoid therapy in patients with severe or life-threatening disease (Grade 2C). (See 'Severe/life-threatening disease' above.)

●Refractory disease – Intravenous immune globulin (IVIG) is added for refractory disease or when there is a poor response to glucocorticoids. (See 'Refractory or recurrent disease' above.)

●Determining response to treatment – Response to treatment is determined by evaluating for improvement in skeletal muscle enzymes, muscle weakness, and rashes. (See 'Evaluation of response to therapy' above.)

●Adjunctive therapies – Adjunctive therapy includes the use of sunscreen, topical agents for localized skin care, physical therapy, and supplementation of calcium (up to 1000 mg/day) and vitamin D (1000 units/day) to prevent osteoporosis. (See 'Adjunctive therapies' above.)

●Natural history – The natural history of JDM and JPM follows one of three disease courses: monocyclic (one disease episode that responds to standard treatment without relapse), polycyclic (multiple remissions and relapses), or chronic persistent that may include persistent complications. (See 'Natural history' above.)

●Complications – Complications include osteoporosis, calcinosis, and intestinal perforation. An increased risk of malignancy is not seen in children with JDM or JPM. (See 'Complications' above.)

●Prognosis – Advances in the treatment of JDM have improved survival mortality and morbidity rates in children with JDM. (See 'Prognosis' above.)