Review Article

Pediatric Idiopathic Inflammatory Myopathies: An Update on Diagnostic and Treatment Strategies Wolfgang Muller-Felber1

Julia Wanschitz2

Katharina Vill1

1 Dr. von Hauner Children’s Hospital, Ludwig-Maximilian University of

Munich, Munich, Germany 2 Neurological Department, Innsbruck Medical University, Innsbruck, Austria 3 Department of Paediatrics I, Paediatric Neurology, Innsbruck Medical University, Innsbruck, Austria

Matthias Baumann3

Address for correspondence Prof. Dr. Wolfgang Muller-Felber, MD, Dr. von Hauner Children’s Hospital, Lindwurmstr. 4, 80337 Munich, Germany (e-mail: [email protected]).

Neuropediatrics 2013;44:314–323.

Abstract Keywords

► inflammatory myopathies ► juvenile dermatomyositis ► children ► muscle biopsy

Diagnostic approach and treatment of idiopathic inflammatory myopathies have changed considerably during the past decades. In this review, new insights in the pathogenesis, the role of muscle biopsy, and magnetic resonance imaging in the diagnostic process in children with suspected myositis are discussed. Current treatment strategies and complication management is described in detail.

Introduction Idiopathic inflammatory myopathies (IIM) in childhood are rare, potentially life-threatening diseases. Because of the advances in therapy, the prognosis has improved markedly during the last decades. It is still important however, how quick and consequent therapy is started. IIM are a group of inflammatory muscle conditions with varying additional organ involvement. In children, juvenile dermatomyositis (JDM) is the most prevalent IIM and accounts for approximately 85% of the cases.1,2 Other diseases are juvenile polymyositis and myositis associated with another autoimmune disease (overlap myositis). Adult dermatomyositis (DM) and JDM are characterized clinically by proximal muscle weakness and characteristic rashes including a periorbital heliotrope rash, Gottron papules over the extensor surfaces of the joints, and generalized photosensitive erythema.3 DM is a systemic vasculopathy and evidence of small-vessel inflammation can be seen in nail folds, eyelids, and gums as telangiectasias of the capillary loops.4,5 Diagnostic criteria for DM include additional signs of muscle

received July 2, 2013 accepted after revision August 21, 2013 published online November 7, 2013

Issue Theme Neuroinflammation Update: New Insights and Future Directions; Guest Editor, Kevin Rostasy, MD.

involvement such as raised serum levels of muscle enzymes, electromyographical changes consistent with myositis, and evidence of inflammation in muscle biopsy.6,7

Epidemiology The incidence of inflammatory myopathies varies considerably between the different countries. In the United Kingdom, an incidence of 2 per million children and in the United States, an incidence of 3.2 per million is estimated.8,9 The disease can begin at any age, the average age is 7 years. In 25% of the children, the onset is before the fifth year. Although some epidemiological studies reported a seasonal clustering, there is no clear seasonal increase in the incidence. Girls are about three times more frequently affected than boys. In contrast to adults, there is no clear increase in malignant tumors in children with dermatomyositis. In a literature review, over a period of 45 years only 12 cases of JDM with a concomitant malignancy have been found indicating that pediatric/JDM is not a paraneoplastic syndrome.10 Registry data showed a prevalence of 1% tumor diseases associated with JDM.11

© 2013 Georg Thieme Verlag KG Stuttgart · New York

DOI http://dx.doi.org/ 10.1055/s-0033-1358600. ISSN 0174-304X.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

314

The most common subtype IIM is dermatomyositis with a relative frequency of 82–85%.12 Significantly less frequent are polymyositis with 7% and myositis in the context of a mixed connective tissue disease with 11%.13,14 Inclusion body myositis does not appear in childhood.

Pathogenesis Both environmental and genetic risk factors seem to determine susceptibility to JDM.1 JDM is characterized pathologically by varying degrees of perivascular cell infiltrates (composed of CD4þ T-cells, plasmacytoid dendritic cells [pDCs], B cells, and macrophages), deposition of C5b-9 complement membrane attack complex on muscle capillaries, tubuloreticular inclusion bodies within endothelial cells, upregulation of major histocompatibility complex (MHC) class I on muscle fibers, muscle fiber degeneration and regeneration, and perifascicular atrophy.15–17 There is increasing evidence that not only the adaptive but also the innate immune system and nonimmune mechanisms are involved in the disease process, suggested by the fact that the response to glucocorticoid treatment varies and patients can continue to experience muscle fiber degeneration even after successful suppression of autoreactive lymphocytes.18,19 Timely, seasonal20 or geographic clusters of new cases of JDM have been observed and different environmental factors have been analyzed. Studies suggest that JDM might follow exposure to infectious agents, mainly with respiratory or gastrointestinal symptoms within 3 months before onset of rash or weakness.21,22 Infectious agents associated with the onset of JDM among others are coxsackievirus B23 and group A-β hemolytic streptococci, possibly playing a role for molecular mimicry,24 but no specific agents have been consistently identified. Some association of birth seasonality has been observed,20 and also ultraviolet radiation exposure prior to illness onset may have a role in the clinical and serologic expression of juvenile myositis.14 Genetic risk factors are polygenic and might be associated with the patient’s ethnic origin. Certain HLA alleles have been associated with JDM, in particular B08, DRB10301, DQA10501, and DQA10301.25–27 Also, cytokine gene polymorphisms of tumor necrosis factor-α (TNF-α) and interleukin 1 (IL-1)28,29 as well as polymorphisms of the lymphocyte signaling gene PTPN2230 contribute to the risk and disease severity of JDM. Maternal chimerism may also play a role in susceptibility to JDM. A higher frequency of maternal chimerism can be found in peripheral blood mononuclear cells and muscle biopsies of boys with JDM.31–33 Humoral and cellular components of the adaptive immune system contribute to the pathogenesis. Mononuclear cell infiltrates consisting B cells, CD4þ T-cells and pDCs are present in perivascular and perifascicular areas.16 B cells produce immunoglobulin and participate in complement fixation and deposition in vessels and perivascular muscle. Beside myositis-associated antibodies which can be present in other autoimmune conditions, myositis-specific

Muller-Felber et al.

autoantibodies, directed against intracellular proteins, have been identified and characterized.18,34 In JDM patients with anti-p155/140 autoantibodies had significantly more cutaneous involvement and anti-p140 autoantibodies were associated with calcinosis.35,36 CD4þ T-cells are primary cellular components of the lymphocytic infiltrates in perivascular and perimysial areas in JDM. In these areas, immature and mature CD4þ T-cells are associated with B cells, pDCs, and macrophages, suggesting local maturation of the T cells.37 T cells are activated when antigen-presenting cells (APCs), particularly B cells, macrophages, and dendritic cells (DCs), express antigen in the context of MHC antigen. Adhesion molecules such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 promote lymphocyte migration through the vascular space and expression is increased in muscle biopsy samples from children with early JDM.38,39 DCs bridge the innate and adaptive immune system and are present in inflamed muscle of the patients with JDM.16 They are professional APCs and maturation of DCs to mature pDCs results in a strong type 1 interferon response.40 Not only foreign invaders such as microbes but also damage-associated self-proteins or injury-associated selfproteins can be rapidly and efficiently recognized via germline-encoded pattern recognition receptors of the innate immune system: the Toll-like receptors (TLRs). TLRs are upregulated in muscle tissue from the patients with IIM41–43 and TLR3 is particularly upregulated in JDM and mainly localized on vascular endothelial cells in areas of perifascicular atrophy.43 TLRs can stimulate production of type 1 interferon by pDCs and recognition of damage-associated molecular pattern by TLRs initiates a signaling cascade, leading to the activation of type 1 interferons, IL-6, and other proinflammatory cytokines.42,43 Type 1 interferon induces several cytokines, which activate antigen-specific and nonspecific effector mechanisms.1,43–45 Among the cytokines which might be important for the pathogenesis of JDM are IL-1, interferon inducible protein 10 (IP-10 or CXCL10), monocyte chemoattractant protein (MCP-½), myxovirus resistance protein (MxA), IL-15 and monokine, inducible by interferon gamma. The expression of MxA in peripheral blood mononuclear cells is associated with disease activity and might serve besides other cytokines as a novel biomarker for JDM.46 Interferons also enhance MHC I expression and promote activation and survival of T cells. MHC class I proteins are essential for immune surveillance and are expressed on nearly all cells with only a few exceptions. Under normal conditions, skeletal muscle cells usually express very few MHC class I molecules, although transient expression can be observed following injury or viral infections. Type 1 interferon-inducible genes and TNFα might promote the inappropriate expression of MHC class I molecules in affected myofibers in JDM. There is emerging evidence that, in myositis, overexpression of the MHC class I molecules in skeletal muscle can induce endoplasmic reticulum stress which contributes to pathology in IIM. 47,48 Neuropediatrics

Vol. 44

No. 6/2013

315

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Pediatric Idiopathic Inflammatory Myopathies

Pediatric Idiopathic Inflammatory Myopathies

Muller-Felber et al.

Clinical Symptoms Patients with dermatomyositis usually show an acute to subacute onset of their symptoms. The mean interval between onset of the disease and diagnosis is 4 months. Polymyositis can show a more insidious course of the disease. The characteristic symptomatology of dermatomyositis is the combination of muscle weakness, severely disturbed general condition, and skin lesions. Constitutional signs such as fever are found in 39% of the patients.14 Malaise is one of the leading signs especially in younger children. Proximal weakness is found in 95% of the patients.11 There is an early involvement of the neck flexors and hip flexors. The trunk muscles are frequently involved too. At more advanced stages of the disease, there may be a severe proximal weakness with difficulties to raise the arms and to get up from the floor. At the beginning of the disease, nonovert paresis can be easily overlooked. Sometimes, the children are only reluctant to move around. Muscle pain which can be provoked by muscle exercise is present in most patients. Typical dermatological features of the disease are Gottron papules on extensor surfaces, periungual capillary abnormalities, malar rash, and heliotrope discoloration over the eyelids. Sometimes dermatological features are so discreetly pronounced that they easily can be missed. Raynaud phenomenon is rarely found in dermatomyositis (9%), but it is more common in mixed connective tissue disease (40.8%) and in polymyositis (24.2%).14 Some of the dermatological features can be used as prognostic markers. Persistence of capillary changes and Gottron papules after 6 months of treatment seems to indicate a prolonged course of the disease.49 Ulcerations are also associated with a severe disease.50 In polymyositis, which is very rarely seen in childhood, there is a slowly progressive proximal muscle weakness without skin changes. Frequently, there is a weakness of the neck extensors which can be very severe. In some patients, the proximal arms are more severely affected than the legs. Myositis can occur as part of an overlap syndrome. In these cases, muscle weakness is combined with features of scleroderma or systemic lupus erythematodes (SLE). Immune-mediated orbital myositis with pain and decreased motility of the orbital muscles has been described in few children. In childhood, this has to be distinguished carefully from infectious or malignant processes in the orbita.51,52

Complications Calcinosis In contrast to adult patients with dermatomyositis calcinosis cutis is a frequent complication of pediatric/JDM: it occurs in 10 to 70% of the patients.53,54 A couple of risk factors for the development of calcinosis have been discussed but still there is no consent about the exact risk profile. According to some studies, delayed onset of treatment,55,56 poor adherence to treatment, and refractory disease are major risk factors for the development of calcinosis. Other reports could not conNeuropediatrics

Vol. 44

No. 6/2013

Fig. 1 (A) Extensive calcinosis in patient with full remission of dermatomyositis. (B) Abscess-like milky calcium deposits in dermatomyositis. (MRI of the thigh, STIR-sequence).

firm such correlation.54,57 In the author’s experience, calcinosis is often associated with the risk factors mentioned above. Nevertheless, it can occur even in stages where myositis and dermatitis seem to be in full remission (►Fig. 1A). In some cases, liquefied calcium deposits can mimic an abscess58,59 (►Fig. 1B).

Lung Disease Only rarely inflammatory myopathies can lead to respiratory failure which requires mechanical ventilation, fatality was reported in a few single cases. In contrast, subclinical involvement of the respiratory muscles is rather frequent with a reduced total lung capacity in 26 to 78% of the patients.14,60,61 Dyspnea at exertion is found in up to 40% of the patients14 and is more frequent in patients with polymyositis than in dermatomyositis or overlap syndromes. Restriction can be caused either by muscle weakness or by reduced motility of the thoracic wall. Interstitial lung disease is a rare complication with a negative impact on prognosis which is seen in between 15 and 50% of the patients.14,62–64 Involvement of the respiratory system as a whole including weakness of the respiratory muscles is found in up to 75% of the patients.63

Cardiomyopathy Clinical signs of cardiac involvement are rarely seen in dermatomyositis and are much more frequent in overlap syndromes.

Other Vascular Complications Vasculopathy of the gastrointestinal tract is a rare albeit lifethreatening complication of the disease, which can lead to ulcerations or perforation.65,66 Central nervous system vasculopathy is a rare complication.67 In our own group, one of 52 patients showed seizures and a second one presented with infarction of the middle cerebral artery (W.M.-F., unpublished data, 2001).

Differential Diagnosis IIM has to be distinguished from quite several neuromuscular disorders. Although nearly every neuromuscular disorder can mimic an inflammatory myopathy, the clinical course with a

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

316

Pediatric Idiopathic Inflammatory Myopathies

Muller-Felber et al.

317

Major subgroups

Specific characteristics

Disturbance of general condition

Viral myositis

Enterovirus, influenza, coxsackievirus, echovirus, parvovirus, poliovirus, hepatitis B, HTLV-1

Acute or subacute onset short duration CK-elevation Other signs of viral infection

þþþ

Metabolic disorders

Lipid-/glycogen-metabolism respiratory chain vascular disease

Exercise induced myalgia rhabdomyolysis with rapid (near) normalization of CK-levels muscle cramps

0

Muscle dystrophy

Dystrophinopathy, LGMD

Slowly progressive disease

0

Rheumatic disorders

SLE, arthritis

Arthritis Exanthema Other organ involvement (kidney, heart, lung, etc.)

þþ

Endocrine myopathy

Hypothyroidism/ hyperthyroidism, Cushing syndrome

þ

Abbreviations: HTLV-1, human T-lymphotropic virus type I; LGMD, limb-girdle muscular dystrophy; SLE, systemic lupus erythematosus.

subacute onset, a rapid progression in most patients, and some additional features help to narrow the differential diagnosis. Whereas worldwide parasitic myositis plays a major role, in Europe and North America viral myositis is one of the most important differential diagnosis. ►Table 1 shows the most relevant differential diagnosis and the main clinical clues.

Investigations Myositis-Associated Antibodies The role of autoantibodies for diagnosis and management of JDM is still under discussion. Myositis-specific antibodies are found in 15 to 34% of affected children.14,68 In contrast to adult patients, antisynthetase antibodies (e.g., jo-1) are only rarely found in children (0–3.7%).68,69 Mi2-Antibodies occur in 6 to 17% of the children, similar to adult patients.68,70 In recent years, new antibodies have been identified. Anti-p155/ 140 autoantibodies can be detected in 22–29% of juvenile patients.35,71 In contrast to adult patients, in whom the presence of these antibodies is highly correlated with malignancies, in children there is no such correlation but an increased frequency of calcinosis. Currently, antibody testing is mainly available in scientific laboratories. Anti-MJ (NXP-2) is another antibody with 140 kDa molecular weight which was detected in 18 to 25% of juvenile patients with a high incidence of calcinosis and a severe course of the disease.72 Anti–signal recognition particle antibodies which are associated with a severe necrotizing myopathy, dysphagia, and interstitial lung disease were only found in 3% of the JDM patients of African American origin.73

Magnetic Resonance Images T2-weighted images and short-tau-Inversion recovery sequences are able to detect muscle edema in inflammatory myopathies. In dermatomyositis, edema can be found in both the muscle and the subcutaneous fat tissue. Data from an

European myositis registry suggest that 78% of the patients show abnormal magnetic resonance images (MRI).12 Using whole body MRI, radiographic disease activity in whole body MRI correlates well with clinical disease activity represented by clinical severity scales.74 Nevertheless, there are some limitations of MRI. MRI findings are nonspecific. In a considerable number of the patients, changes in benign parainfectious myositis, rhabdomyolysis, or even dystrophic myopathies cannot be differentiated from autoimmune myositis.75 In young children, the diagnostic value of MRI has to be balanced against the possible risks of anesthesia. In elder children, MRI is useful to give further albeit nonspecific information if the clinical picture is not clear. There is still discussion about the role of MRI for the monitoring of the disease. At the beginning of the disease, prognostic clues cannot be drawn from the severity or distribution of MRI changes.76 Only abnormal reticulated signal intensity in the subcutaneous fat seems to be associated with a worse outcome. In the course of the disease, normalization of clinical symptoms and laboratory findings can precede the normalization of MRI findings by 2 months.77

Muscle Biopsy Muscle biopsies from patients with JDM display distinctive features including microvascular changes and perifascicular muscle fiber atrophy as the main histological findings. The capillary endothelium is considered as the primary target of immune-mediated damage,78 indicated by swelling of endothelial cells and deposition of immunoglobulin or complement components on the surface of capillaries.15 At an electron microscopic level, tubuloreticular inclusions can be demonstrated within endothelial cells. The extent of inflammation is variable. Inflammatory infiltrates are composed by monocytes, B and T-lymphocytes that accumulate perivascularly around intermediate-sized vessels in the Neuropediatrics

Vol. 44

No. 6/2013

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Table 1 Differential diagnosis of idiopathic inflammatory myopathy

Pediatric Idiopathic Inflammatory Myopathies

Muller-Felber et al.

endomysial and perimysium which may result in vascular occlusion and microinfarction of muscle.1 Reduction of endothelial cells and capillaries is particularly pronounced in perifascicular regions associated with degeneration/regeneration and finally atrophy of muscle fibers in these areas. Affected muscle fibers in inflammatory myopathies demonstrate increased expression of MHC-class I antigens on their surface (also with perifascicular accentuation in dermatomyositis) which significantly enhances the diagnostic value of a muscle biopsy even when pathological changes or cellular infiltrates are sparse or absent.79 Conversely, fibrosis of the endomysial and perimysial connective tissue may accompany atrophy of muscle fibers at advanced stages of the disease. An International Consensus Group recently proposed a scoring system on the basis of the four pathological domains of change: inflammatory, vascular, muscle fiber, and connective tissue to ensure standardized evaluation of muscle biopsies in JDM.15 It has to be considered that inflammatory changes in muscle biopsy can also occur in some dystrophic myopathies such as facioscapulohumeral muscular dystrophy or limbgirdle muscular dystrophy type 2i. On contrary, an unremarkable muscle biopsy does not exclude an inflammatory myopathy. Thus, the interpretation of the biopsy has to be done in close correlation to clinical findings. If there is a typical clinical picture of JDM or mixed connective tissue disease a muscle biopsy is not mandatory.

Monitoring of the Disease Clinical Rating Scales To monitor disease activity, several rating scales have been developed. A very concise review about available scales has been written by Rider et al.80 A consensus of American rheumatologists suggested that the following scales should be used on a routine basis81: Physician and Patient/Parent Global Activity Health scale is based on a visual analog scale filled out by the physician as well as by the patient (or the parents). The physician has to take clinical as well as laboratory findings into account. Childhood Myositis Assessment Scale , myositis disease activity assessment tool, disease activity score, physician global damage, myositis damage index, quantitative muscle testing, myositis functional index-2 (FI-2).

Laboratory Investigation There is consensus that creatine phosphokinase, lactate dehydrogenase, aldolase, ALAT/GPT (alanine aminotransferase), ASAT/GOT (aspartate aminotransferase) should be monitored in each patient. It is still unclear whether measurement of cytokine levels makes a contribution to monitoring of the patients. Potentially, IL-6–levels correlate with prognosis and disease activity.44

Treatment Currently, there is no generally accepted treatment algorithm for children with inflammatory myopathies. Until now, consensus conferences did not lead to a protocol which is Neuropediatrics

Vol. 44

No. 6/2013

applicable in daily practice.82 There are still considerable differences in the way IIM is treated in different continents and regions.83 Although there is no doubt amongst experts that immunosuppressive treatment is successful in IIM no statistical evidence is available.61

Basic Treatment Corticosteroids Corticosteroids are still the essential treatment for inflammatory myopathies. Since the 1960s, the use of corticosteroids has dramatically reduced mortality in pediatric myositis. The exact way how patients with myositis are treated is still based on the personal experience of the physician. There is no controlled therapeutic data comparing the different treatment modalities. Because of the very variable course of the disease the chances to come to an evidence-based treatment in the future are low. A consensus conference of the American Childhood Arthritis and Rheumatology Research Alliance agreed that reduction of steroid treatment should be based on clinical and laboratory findings.82 Before dose reduction, patients should be treated at least for 4 weeks. There is consensus that early and consistent treatment has a significant impact on the outcome of the disease. Unfortunately, there is no consensus about the initial dosage of corticosteroid treatment and about the exact way of tapering the medication. Corticosteroid treatment is started either with 2 mg prednisone/kg bodyweight given orally or by pulsed therapy with 10 to 30 mg methylprednisolone/kg bodyweight administered intravenously in 3 to 5 days. Until now, there are no prospective data to decide about the preferable therapy. Some retrospective data showed that early aggressive treatment resulted in a better functional outcome and less subcutaneous calcinosis.84 However, this finding could not be confirmed in another retrospective study.85

Methotrexate Most of the patients with DM are treated with a combination of corticosteroids and Methotrexate (Mtx). Although there exists no prospective study, retrospective data indicate that Mtx has a corticosteroid sparing effect with less corticosteroid-associated side effects.56 For this reason, Mtx treatment should be initiated early in the course of the disease. In the author’s personal experience, a limited trial of a corticosteroid monotherapy over a period of some weeks can be done. In few cases, there is an immediate excellent response to corticosteroid monotherapy, which can be easily tapered without reactivation of the disease. Nevertheless, it should be taken in mind that Mtx takes a considerable time until it is efficient. Therefore, it may be preferable to start Mtx early to prevent severe morbidity from corticosteroid treatment and to consider later to stop it again.

Azathioprine Azathioprine (AZT) can be used as an alternative to Mtx in the patients who do not tolerate Mtx treatment. Currently, it is

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

318

Pediatric Idiopathic Inflammatory Myopathies

Muller-Felber et al.

less frequently used than Mtx.83 There is no difference in efficacy between Mtx and AZT.

because of statistical power was not significant in the juvenile patients.93 There is still need for further evaluation.

Treatment of Refractory Disease

Anti-TNFα Antibodies It is known that TNFα is upregulated in myositis. Studies in adult patients with infliximab could not prove a beneficial effect in myositis.94,95 Etanercept has been shown to have a steroid sparing effect. Until now, no studies on children have been performed.

In recent years, a considerable number of new treatment options have been developed. Most of them have not been tested in a controlled clinical trial. The evidence is based on expert views, case studies, and small case series.

319

Intravenous Immunoglobulins

Mycophenolate Mofetile Currently, mycophenolate mofetile (MMF) is mainly used in Lupus erythematodes. Because of similarities in the immune response between SLE and JDM retrospective data of eight JDM patients treated with MMF as an add-on therapy to various other treatments have been analyzed. An effect on strength or skin changes was described in six of eight patients.

Cyclophosphamide Cyclophosphamide (CYP) is rarely used in severe refractory cases of dermatomyositis. In a series of patients with very severe manifestations of JDM, 10 of 12 patients showed significant improvement. Death in two patients was attributed to the disease and not to side effects of the treatment.88

Tacrolimus Tacrolimus has been tested in a small series of adult patients who did not respond to previous treatment. It is mainly used in the patients with concomitant lung disease. Overall, nine pediatric patients with very refractory disease despite numerous treatments including IVIG, rituximab, and others have been described.89,90 In a small series of three patients, tacrolimus was shown to have an effect mainly on skin manifestations.91 Another six patients responded respecting both, skin and muscle symptoms.

Monoclonal Antibodies Rituximab The use of Rituximab has been described in some retrospective studies dealing with small series of refractory patients showing positive effects in some cases.92 However, a large study which examined adult and 48 juvenile patients could not show a clear effect of this therapy in the study group as a whole. Nevertheless, there was a probable effect which

Management of Calcinosis Cutis Calcinosis Cutis There are no controlled studies concerning a standardized treatment of calcinosis. In pediatrics, treatment is based on single case reports, only. Individual response to treatment is very variable and hardly predictable. Unfortunately, treatment of severe calcinosis is often a strenuous and timeconsuming task. Treatment is based on five principles: • Influencing the inflammatory pathway by intensifying the immunosuppression or by the use of IVIG, which leads to a decreased activity of macrophages thus reducing cytokine activity. IVIG treatment was successful in single adult patients with CREST syndrome. • Lowering of phosphorus level. As ectopic calcium masses in dermatomyositis are composed of hydroxyapatite and amorphous calcium phosphate, reduction of phosphorus seems to be a suitable approach. This can be done either by reducing intestinal absorption or by increasing renal phosphate clearance. Aluminum hydroxide has been successfully tried in a 9-year-old boy and in a 13-year-old girl.96 Probenecid was successfully tried in a young man who had not responded to aluminum hydroxide treatment before.97 • Blocking the calcium influx into the cell. Diltiazem, which is a blocker of the calcium channel, has been used successfully in a 3-year-old child98 and in a young adult with dermatomyositis. Dosage was between 2 mg/kg and 4 mg/ kg bodyweight. After 1 and 2.5 years of treatment calcium masses significantly disappeared. Lower doses of diltiazem have been tried in adult patients without success. In another series, two of four patients showed a reduction of calcium deposits following treatment with 6 mg/kg diltiazem.99 • Surgical removal of calcium masses can be done if few calcium deposits exist. In our experience, there is a high risk of recurrence of calcium deposits even after successful removal. • Bisphosphonates seem to have two different modes of action. One is an influence on macrophages thus reducing cytokine secretion. The other is a direct effect on the calcium turnover. Nevertheless, the exact mechanism how bisphosphonates remove calcium deposits is still unknown.100

Physiotherapy During the acute phase of the disease, most of the physicians do not advocate active training programs. In milder forms of Neuropediatrics

Vol. 44

No. 6/2013

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Intravenous Immunoglobulins (IVIG) treatment has been shown to be efficient in adults with refractory dermatomyositis.86 In children, IVIG treatment has been suggested as second line treatment. In a retrospective study, 78 children with severe and refractory disease receiving IVIG have been matched to a control group with less disease activity at the beginning. After up to 4 years, disease activity in the IVIG group was lower as compared with the controls.87 A survey amongst pediatric rheumatologists showed that in clinical practice the use of IVIG is restricted to more severe cases of dermatomyositis.83

Pediatric Idiopathic Inflammatory Myopathies

Muller-Felber et al.

the disease, physical therapy has been shown to be safe and useful.101 It has been hypothesized that physical therapy may add to a better vascularization of the muscle.

8 Symmons DP, Sills JA, Davis SM. The incidence of juvenile

9

Prognosis Mortality has significantly decreased since the beginning of corticosteroid treatment. At the moment, it is less than 5% in the pediatric population.102 Lethality is mainly related to cardiac or pulmonary involvement or in rare cases to other vascular complications such as intestinal perforation. It is higher in the group of overlap syndromes than in dermatomyositis. With regard to functional outcome a cross-sectional multicenter study showed that 41.2 to 52.8% of the patients had reduced muscle strength or endurance, but less than 10% had severe impairment. A total of 40.7% of the patients had decreased functional ability, but only 6.5% of the patients had major impairment.103

10

11

12

13 14

Conclusions Pediatric inflammatory myopathies are multisystem disorders which must be treated consequently to avoid severe complications. As there is a highly variable course of the disease standardized treatment protocols are not available. Therefore, it is mandatory that physicians with special knowledge in this field should be involved from the beginning.

Acknowledgment We thank Dr. T. Geis from Regensburg for providing the magnetic resonance images (Fig. 1).

1 Feldman BM, Rider LG, Reed AM, Pachman LM. Juvenile derma-

3

4

5

6 7

tomyositis and other idiopathic inflammatory myopathies of childhood. Lancet 2008;371(9631):2201–2212 Martin N, Krol P, Smith S, et al; Juvenile Dermatomyositis Research Group. A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years’ experience; the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies. Rheumatology (Oxford) 2011; 50(1):137–145 Robinson AB, Reed AM. Clinical features, pathogenesis and treatment of juvenile and adult dermatomyositis. Nat Rev Rheumatol 2011;7(11):664–675 Kissel JT, Mendell JR, Rammohan KW. Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986;314(6):329–334 Ostrowski RA, Sullivan CL, Seshadri R, Morgan GA, Pachman LM. Association of normal nailfold end row loop numbers with a shorter duration of untreated disease in children with juvenile dermatomyositis. Arthritis Rheum 2010;62(5):1533–1538 Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med 1975;292(8):403–407 Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292(7):344–347

Neuropediatrics

16

17

18

References

2

15

Vol. 44

No. 6/2013

19

20

21

22

23

24

dermatomyositis: results from a nation-wide study. Br J Rheumatol 1995;34(8):732–736 Mendez EP, Lipton R, Ramsey-Goldman R, et al; NIAMS Juvenile DM Registry Physician Referral Group. US incidence of juvenile dermatomyositis, 1995-1998: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Registry. Arthritis Rheum 2003;49(3):300–305 Morris P, Dare J. Juvenile dermatomyositis as a paraneoplastic phenomenon: an update. J Pediatr Hematol Oncol 2010;32(3): 189–191 Sato JO, Sallum AM, Ferriani VP, et al; Rheumatology Committee of the São Paulo Paediatrics Society. A Brazilian registry of juvenile dermatomyositis: onset features and classification of 189 cases. Clin Exp Rheumatol 2009;27(6):1031–1038 McCann LJ, Juggins AD, Maillard SM, et al; Juvenile Dermatomyositis Research Group. The Juvenile Dermatomyositis National Registry and Repository (UK and Ireland)—clinical characteristics of children recruited within the first 5 yr. Rheumatology (Oxford) 2006;45(10):1255–1260 Rider LG. The heterogeneity of juvenile myositis. Autoimmun Rev 2007;6(4):241–247 Shah M, Mamyrova G, Targoff IN, et al; Childhood Myositis Heterogeneity Collaborative Study Group. The clinical phenotypes of the juvenile idiopathic inflammatory myopathies. Medicine (Baltimore) 2013;92(1):25–41 Wedderburn LR, Varsani H, Li CK, et al; UK Juvenile Dermatomyositis Research Group. International consensus on a proposed score system for muscle biopsy evaluation in patients with juvenile dermatomyositis: a tool for potential use in clinical trials. Arthritis Rheum 2007;57(7):1192–1201 López de Padilla CM, Vallejo AN, McNallan KT, et al. Plasmacytoid dendritic cells in inflamed muscle of patients with juvenile dermatomyositis. Arthritis Rheum 2007;56(5): 1658–1668 Rostasy KM, Schmidt J, Bahn E, et al. Distinct inflammatory properties of late-activated macrophages in inflammatory myopathies. Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology/ed the Gaetano Conte Academy for the study of striated muscle diseases 2008;27:49–53 Khanna S, Reed AM. Immunopathogenesis of juvenile dermatomyositis. Muscle Nerve 2010;41(5):581–592 Coley W, Rayavarapu S, Nagaraju K. Role of non-immune mechanisms of muscle damage in idiopathic inflammatory myopathies. Arthritis Res Ther 2012;14(2):209 Vegosen LJ, Weinberg CR, O’Hanlon TP, Targoff IN, Miller FW, Rider LG. Seasonal birth patterns in myositis subgroups suggest an etiologic role of early environmental exposures. Arthritis Rheum 2007;56(8):2719–2728 Pachman LM, Lipton R, Ramsey-Goldman R, et al. History of infection before the onset of juvenile dermatomyositis: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Research Registry. Arthritis Rheum 2005;53(2): 166–172 Manlhiot C, Liang L, Tran D, Bitnun A, Tyrrell PN, Feldman BM. Assessment of an infectious disease history preceding juvenile dermatomyositis symptom onset. Rheumatology (Oxford) 2008; 47(4):526–529 Christensen ML, Pachman LM, Schneiderman R, Patel DC, Friedman JM. Prevalence of Coxsackie B virus antibodies in patients with juvenile dermatomyositis. Arthritis Rheum 1986;29(11): 1365–1370 Massa M, Costouros N, Mazzoli F, et al. Self-epitopes shared between human skeletal myosin and Streptococcus pyogenes M5 protein are targets of immune responses in active juvenile dermatomyositis. Arthritis Rheum 2002;46(11):3015–3025

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

320



Muller-Felber et al.

25 Reed AM, Stirling JD. Association of the HLA-DQA1 0501 allele in

41 Brunn A, Zornbach K, Hans VH, Haupt WF, Deckert M. Toll-like

multiple racial groups with juvenile dermatomyositis. Hum Immunol 1995;44(3):131–135 Mamyrova G, O’Hanlon TP, Monroe JB, et al; Childhood Myositis Heterogeneity Collaborative Study Group. Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians. Arthritis Rheum 2006;54(12):3979–3987 Sanner H, Kirkhus E, Merckoll E, et al. Long-term muscular outcome and predisposing and prognostic factors in juvenile dermatomyositis: A case-control study. Arthritis Care Res (Hoboken) 2010;62(8):1103–1111 Mamyrova G, O’Hanlon TP, Sillers L, et al; Childhood Myositis Heterogeneity Collaborative Study Group. Cytokine gene polymorphisms as risk and severity factors for juvenile dermatomyositis. Arthritis Rheum 2008;58(12):3941–3950 Pachman LM, Liotta-Davis MR, Hong DK, et al. TNFalpha-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications. Arthritis Rheum 2000;43(10): 2368–2377 Chinoy H, Platt H, Lamb JA, et al; UK Adult Onset Myositis Immunogenetic Collaboration and the Juvenile Dermatomyositis Research Group. The protein tyrosine phosphatase N22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients. Arthritis Rheum 2008;58(10):3247–3254 Reed AM, Picornell YJ, Harwood A, Kredich DW. Chimerism in children with juvenile dermatomyositis. Lancet 2000;356(9248): 2156–2157 Artlett CM, Ramos R, Jiminez SA, Patterson K, Miller FW, Rider LG; Childhood Myositis Heterogeneity Collaborative Group. Chimeric cells of maternal origin in juvenile idiopathic inflammatory myopathies. Lancet 2000;356(9248):2155–2156 Ye Y, van Zyl B, Varsani H, Wedderburn LR, Ramanan A, Gillespie KM; Juvenile Dermatomyositis Research Group. Maternal microchimerism in muscle biopsies from children with juvenile dermatomyositis. Rheumatology (Oxford) 2012;51(6):987–991 Tansley SL, McHugh NJ, Wedderburn LR. Adult and juvenile dermatomyositis: are the distinct clinical features explained by our current understanding of serological subgroups and pathogenic mechanisms? Arthritis Res Ther 2013;15(2):211 Gunawardena H, Wedderburn LR, Chinoy H, et al; Juvenile Dermatomyositis Research Group, UK and Ireland. Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheum 2009;60(6):1807–1814 Gunawardena H, Wedderburn LR, North J, et al; Juvenile Dermatomyositis Research Group UK. Clinical associations of autoantibodies to a p155/140 kDa doublet protein in juvenile dermatomyositis. Rheumatology (Oxford) 2008;47(3):324–328 López De Padilla CM, Vallejo AN, Lacomis D, McNallan K, Reed AM. Extranodal lymphoid microstructures in inflamed muscle and disease severity of new-onset juvenile dermatomyositis. Arthritis Rheum 2009;60(4):1160–1172 Kim E, Cook-Mills J, Morgan G, Sredni ST, Pachman LM. Increased expression of vascular cell adhesion molecule 1 in muscle biopsy samples from juvenile dermatomyositis patients with short duration of untreated disease is regulated by miR-126. Arthritis Rheum 2012;64(11):3809–3817 Sallum AM, Marie SK, Wakamatsu A, et al. Immunohistochemical analysis of adhesion molecule expression on muscle biopsy specimens from patients with juvenile dermatomyositis. J Rheumatol 2004;31(4):801–807 Niewold TB, Kariuki SN, Morgan GA, Shrestha S, Pachman LM. Elevated serum interferon-alpha activity in juvenile dermatomyositis: associations with disease activity at diagnosis and after thirty-six months of therapy. Arthritis Rheum 2009;60(6): 1815–1824

receptors promote inflammation in idiopathic inflammatory myopathies. J Neuropathol Exp Neurol 2012;71(10):855–867 Tournadre A, Lenief V, Miossec P. Expression of Toll-like receptor 3 and Toll-like receptor 7 in muscle is characteristic of inflammatory myopathy and is differentially regulated by Th1 and Th17 cytokines. Arthritis Rheum 2010;62(7):2144–2151 Cappelletti C, Baggi F, Zolezzi F, et al. Type I interferon and Toll-like receptor expression characterizes inflammatory myopathies. Neurology 2011;76(24):2079–2088 Bilgic H, Ytterberg SR, Amin S, et al. Interleukin-6 and type I interferon-regulated genes and chemokines mark disease activity in dermatomyositis. Arthritis Rheum 2009;60(11):3436–3446 Baechler EC, Bilgic H, Reed AM. Type I interferon pathway in adult and juvenile dermatomyositis. Arthritis Res Ther 2011;13(6):249 Reed AM, Peterson E, Bilgic H, et al. Changes in novel biomarkers of disease activity in juvenile and adult dermatomyositis are sensitive biomarkers of disease course. Arthritis Rheum 2012; 64(12):4078–4086 Nagaraju K, Casciola-Rosen L, Lundberg I, et al. Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum 2005;52(6):1824–1835 Li CK, Knopp P, Moncrieffe H, et al. Overexpression of MHC class I heavy chain protein in young skeletal muscle leads to severe myositis: implications for juvenile myositis. Am J Pathol 2009; 175(3):1030–1040 Stringer E, Singh-Grewal D, Feldman BM. Predicting the course of juvenile dermatomyositis: significance of early clinical and laboratory features. Arthritis Rheum 2008;58(11):3585–3592 Rider LG, Lachenbruch PA, Monroe JB, et al; IMACS Group. Damage extent and predictors in adult and juvenile dermatomyositis and polymyositis as determined with the myositis damage index. Arthritis Rheum 2009;60(11):3425–3435 Grouteau E, Chaix Y, Armbruster V, et al. [Acute orbital myositis and idiopathic inflammatory pseudotumor in children: three cases]. Arch Pediatr 1998;5(2):153–158 Bakan S, Bakan AA, Cingu AK, et al. Myositic type of idiopathic orbital pseudotumor in a 4-year-old child: a case report. Case Rep Med 2012;2012:473856 Sallum AM, Pivato FC, Doria-Filho U, et al. Risk factors associated with calcinosis of juvenile dermatomyositis. J Pediatr (Rio J) 2008; 84(1):68–74 Clemente G, Piotto DG, Barbosa C, et al. High frequency of calcinosis in juvenile dermatomyositis: a risk factor study. Rev Bras Reumatol 2012;52(4):549–553 Bowyer SL, Blane CE, Sullivan DB, Cassidy JT. Childhood dermatomyositis: factors predicting functional outcome and development of dystrophic calcification. J Pediatr 1983;103(6): 882–888 Ramanan AV, Campbell-Webster N, Ota S, et al. The effectiveness of treating juvenile dermatomyositis with methotrexate and aggressively tapered corticosteroids. Arthritis Rheum 2005; 52(11):3570–3578 Ramanan AV, Feldman BM. Clinical features and outcomes of juvenile dermatomyositis and other childhood onset myositis syndromes. Rheum Dis Clin North Am 2002;28(4):833–857 Hesla RB, Karlson LK, McCauley RG. Milk of calcium fluid collection in dermatomyositis: ultrasound findings. Pediatr Radiol 1990;20(5):344–346 Samson C, Soulen RL, Gursel E. Milk of calcium fluid collections in juvenile dermatomyositis: MR characteristics. Pediatr Radiol 2000;30(1):28–29 Prestridge A, Morgan G, Ferguson L, Huang CC, Pachman LM. Pulmonary function tests in idiopathic inflammatory myopathy: association with clinical parameters in children. Arthritis Care Res (Hoboken) 2013;65(9):1424–1431

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

42

43

44

45 46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

Neuropediatrics

Vol. 44

No. 6/2013

321

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Pediatric Idiopathic Inflammatory Myopathies

Pediatric Idiopathic Inflammatory Myopathies

Muller-Felber et al.

61 Gordon PA, Winer JB, Hoogendijk JE, Choy EH. Immunosuppres-

62

63

64

65 66 67

68

69

70

71

72

73

74

75

76

77

78 79

80

sant and immunomodulatory treatment for dermatomyositis and polymyositis. Cochrane Database Syst Rev 2012;8:CD003643 Morinishi Y, Oh-Ishi T, Kabuki T, Joh K. Juvenile dermatomyositis: clinical characteristics and the relatively high risk of interstitial lung disease. Mod Rheumatol 2007;17(5):413–417 Pouessel G, Deschildre A, Le Bourgeois M, et al. The lung is involved in juvenile dermatomyositis. Pediatr Pulmonol 2013; 48(10):1016–1025 Kobayashi I, Yamada M, Takahashi Y, et al. Interstitial lung disease associated with juvenile dermatomyositis: clinical features and efficacy of cyclosporin A. Rheumatology (Oxford) 2003;42(2): 371–374 Stefanski JC, Shetty AK. Abdominal pain in a girl with juvenile dermatomyositis. Clin Pediatr (Phila) 1998;37(9):561–563 Braunstein EM, White SJ. Pneumatosis intestinalis in dermatomyositis. Br J Radiol 1980;53(634):1011–1012 Ramanan AV, Sawhney S, Murray KJ. Central nervous system complications in two cases of juvenile onset dermatomyositis. Rheumatology (Oxford) 2001;40(11):1293–1298 Rider LG, Miller FW, Targoff IN, et al. A broadened spectrum of juvenile myositis. Myositis-specific autoantibodies in children. Arthritis Rheum 1994;37(10):1534–1538 Wedderburn LR, McHugh NJ, Chinoy H, et al; Juvenile Dermatomyositis Research Group (JDRG). HLA class II haplotype and autoantibody associations in children with juvenile dermatomyositis and juvenile dermatomyositis-scleroderma overlap. Rheumatology (Oxford) 2007;46(12):1786–1791 Feldman BM, Reichlin M, Laxer RM, Targoff IN, Stein LD, Silverman ED. Clinical significance of specific autoantibodies in juvenile dermatomyositis. J Rheumatol 1996;23(10): 1794–1797 Targoff IN, Mamyrova G, Trieu EP, et al; Childhood Myositis Heterogeneity Study Group; International Myositis Collaborative Study Group. A novel autoantibody to a 155-kd protein is associated with dermatomyositis. Arthritis Rheum 2006; 54(11):3682–3689 Espada G, Maldonado Cocco JA, Fertig N, Oddis CV. Clinical and serologic characterization of an Argentine pediatric myositis cohort: identification of a novel autoantibody (anti-MJ) to a 142-kDa protein. J Rheumatol 2009;36(11):2547–2551 Rouster-Stevens KA, Pachman LM. Autoantibody to signal recognition particle in African American girls with juvenile polymyositis. J Rheumatol 2008;35(5):927–929 Malattia C, Damasio MB, Madeo A, et al. Whole-body MRI in the assessment of disease activity in juvenile dermatomyositis. Ann Rheum Dis 2013 (e-pub ahead of print). doi: 10.1136/annrheumdis-2012-202915 May DA, Disler DG, Jones EA, Balkissoon AA, Manaster BJ. Abnormal signal intensity in skeletal muscle at MR imaging: patterns, pearls, and pitfalls. Radiographics 2000;20( Spec No): S295–S315 Ladd PE, Emery KH, Salisbury SR, Laor T, Lovell DJ, Bove KE. Juvenile dermatomyositis: correlation of MRI at presentation with clinical outcome. AJR Am J Roentgenol 2011;197(1): W153–W158 Huppertz HI, Kaiser WA. Serial magnetic resonance imaging in juvenile dermatomyositis—delayed normalization. Rheumatol Int 1994;14(3):127–129 Banker BQ, Victor M. Dermatomyositis (systemic angiopathy) of childhood. Medicine (Baltimore) 1966;45(4):261–289 Danielsson O, Lindvall B, Gati I, Ernerudh J. Classification and diagnostic investigation in inflammatory myopathies: a study of 99 patients. J Rheumatol 2013;40(7):1173–1182 Rider LG, Werth VP, Huber AM, et al. Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire

Neuropediatrics

Vol. 44

No. 6/2013

81

82

83

84

85

86

87

88

89

90

91

92

93

(HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI). Arthritis Care Res (Hoboken) 2011;63(Suppl 11): S118–S157 Ruperto N, Ravelli A, Murray KJ, et al; Paediatric Rheumatology International Trials Organization (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG). Preliminary core sets of measures for disease activity and damage assessment in juvenile systemic lupus erythematosus and juvenile dermatomyositis. Rheumatology (Oxford) 2003;42(12):1452–1459 Huber AM, Robinson AB, Reed AM, et al; Juvenile Dermatomyositis Subcommittee of the Childhood Arthritis and Rheumatology Research Alliance. Consensus treatments for moderate juvenile dermatomyositis: beyond the first two months. Results of the second Childhood Arthritis and Rheumatology Research Alliance consensus conference. Arthritis Care Res (Hoboken) 2012;64(4): 546–553 Stringer E, Bohnsack J, Bowyer SL, et al. Treatment approaches to juvenile dermatomyositis (JDM) across North America: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Treatment Survey. J Rheumatol 2010;37(9): 1953–1961 Fisler RE, Liang MG, Fuhlbrigge RC, Yalcindag A, Sundel RP. Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. J Am Acad Dermatol 2002;47(4):505–511 Seshadri R, Feldman BM, Ilowite N, Cawkwell G, Pachman LM. The role of aggressive corticosteroid therapy in patients with juvenile dermatomyositis: a propensity score analysis. Arthritis Rheum 2008;59(7):989–995 Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329(27): 1993–2000 Lam CG, Manlhiot C, Pullenayegum EM, Feldman BM. Efficacy of intravenous Ig therapy in juvenile dermatomyositis. Ann Rheum Dis 2011;70(12):2089–2094 Riley P, Maillard SM, Wedderburn LR, Woo P, Murray KJ, Pilkington CA. Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety. Rheumatology (Oxford) 2004;43(4):491–496 Yamada A, Ohshima Y, Omata N, Yasutomi M, Mayumi M. Steroidsparing effect of tacrolimus in a patient with juvenile dermatomyositis presenting poor bioavailability of cyclosporine A. Eur J Pediatr 2004;163(9):561–562 Mitsui T, Kuroda Y, Kunishige M, Matsumoto T. Successful treatment with tacrolimus in a case of refractory dermatomyositis. Intern Med 2005;44(11):1197–1199 Hassan J, van der Net JJ, van Royen-Kerkhof A. Treatment of refractory juvenile dermatomyositis with tacrolimus. Clin Rheumatol 2008;27(11):1469–1471 Cooper MA, Willingham DL, Brown DE, French AR, Shih FF, White AJ. Rituximab for the treatment of juvenile dermatomyositis: a report of four pediatric patients. Arthritis Rheum 2007;56(9): 3107–3111 Oddis CV, Reed AM, Aggarwal R, et al; RIM Study group. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: A randomized, placebo-phase trial. Arthritis Rheum 2013;65(2):314–324

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

322

Pediatric Idiopathic Inflammatory Myopathies

Muller-Felber et al.

99 Bertorini TE, Sebes JI, Palmieri GM, Igarashi M, Horner LH.

incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies. Ann Rheum Dis 2008;67(12):1670–1677 Hengstman GJ, De Bleecker JL, Feist E, et al. Open-label trial of anti-TNF-alpha in dermato- and polymyositis treated concomitantly with methotrexate. Eur Neurol 2008;59(3-4):159–163 Nassim JR, Connolly CK. Treatment of calcinosis universalis with aluminium hydroxide. Arch Dis Child 1970;45(239):118–121 Eddy MC, Leelawattana R, McAlister WH, Whyte MP. Calcinosis universalis complicating juvenile dermatomyositis: resolution during probenecid therapy. J Clin Endocrinol Metab 1997; 82(11):3536–3542 Ichiki Y, Akiyama T, Shimozawa N, Suzuki Y, Kondo N, Kitajima Y. An extremely severe case of cutaneous calcinosis with juvenile dermatomyositis, and successful treatment with diltiazem. Br J Dermatol 2001;144(4):894–897

Diltiazem in the treatment of calcinosis in juvenile dermatomyositis. J Clin Neuromuscul Dis 2001;2(4):191–193 Mukamel M, Horev G, Mimouni M. New insight into calcinosis of juvenile dermatomyositis: a study of composition and treatment. J Pediatr 2001;138(5):763–766 Omori CH, Silva CA, Sallum AM, et al. Exercise training in juvenile dermatomyositis. Arthritis Care Res (Hoboken) 2012;64(8): 1186–1194 Huber A, Feldman BM. Long-term outcomes in juvenile dermatomyositis: how did we get here and where are we going? Curr Rheumatol Rep 2005;7(6):441–446 Ravelli A, Trail L, Ferrari C, et al. Long-term outcome and prognostic factors of juvenile dermatomyositis: a multinational, multicenter study of 490 patients. Arthritis Care Res (Hoboken) 2010;62(1):63–72

95

96 97

98

100

101

102

103

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

94 Dastmalchi M, Grundtman C, Alexanderson H, et al. A high

323

Neuropediatrics

Vol. 44

No. 6/2013

Copyright of Neuropediatrics is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.