Clinical practice guidance for juvenile dermatomyositis (JDM) 2018-Update

Abstract

Juvenile dermatomyositis is the most common type of juvenile idiopathic inflammatory myopathy mainly affecting the skin and proximal muscles. We have published the Japanese version of ‘Clinical practice guidance for juvenile dermatomyositis (JDM) 2018 ‘consisting of a review of articles in the field and evidence-informed consensus-based experts’ opinion on the treatment strategy in collaboration with The Pediatric Rheumatology Association of Japan and The Japan College of Rheumatology under the financial support by ‘Research on rare and intractable diseases, Health and Labor Sciences Research Grants’. This article is a digest version of the Japanese guidance.

Keywords:

• Diagnosis
• pathophysiology
• management
• interstitial lung disease
• myositis-specific autoantibodies

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1. Introduction

Juvenile idiopathic inflammatory myopathy is an umbrella entity comprising juvenile dermatomyositis (JDM), juvenile polymyositis (JPM), immune-mediated necrotizing myopathy (IMNM), inclusion body myositis (IBM), and connective tissue disease-associated myositis, which develops before the age of 18 [1]. JDM is the most common form of juvenile idiopathic inflammatory myopathies (JIIMs) currently affecting 1.7 per 100,000 children in Japan [2]. Recently, Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) has published consensus-based recommendation for the management of JDM [3]. However, there are several differences in the frequency of complications and drug use between Europe or United States and Japan such as the frequency of anti-melanoma differentiation-association gene 5 (MDA5) antibody-positive rapidly progressive (RP)-interstitial lung disease (ILD) and the available route of methotrexate (MTX) administration, respectively [4–6]. These facts prompted us to develop clinical practice guidance for JDM suitable for patients in Japan. The Scientific Research Group for Pediatric Rheumatic Diseases (SRGPRD) was organized to standardize the diagnosis, evaluation of severity, and management of pediatric rheumatic diseases under the support by the Japanese Ministry of Health, Labor and Welfare. The JDM Research Group of SRGPRD consisting of 13 pediatric rheumatologists, a dermatologist and a pathologist has published the Japanese version of the guidance in collaboration with The Pediatric Rheumatology Association of Japan (PRAJ) and The Japan College of Rheumatology (JCR). Because evidence on the management of JDM is limited, this guidance mainly consists of narrative review of articles in the field and evidence-informed consensus-based experts’ opinion on the treatment strategy. Articles were searched for the consensus-based part in MEDLINE and PubMed in 2017. Articles after the publication of the original Japanese version were hand-searched. Each section was reviewed and approved by all the JDM research group member. Final version of the manuscript was confirmed after public comments and approved by the steering committee of both PRAJ and JCR. The present English version summarizes the Japanese version with an update consisting of several recently published articles.

2. Definition

JDM is a symmetrical inflammatory myositis predominantly affecting proximal muscles with characteristic skin lesions [7]. However, some cases lack muscle weakness despite skin lesions characteristic of JDM and this is currently called juvenile clinically amyopathic dermatomyositis (JCADM) [8]. JCADM comprises juvenile amyopathic dermatomyositis (JADM) and juvenile hypomyopathic dermatomyositis (JHDM). JHDM is defined as cases lacking clinical muscle weakness despite clinicopathologically confirmed classical cutaneous manifestations of JDM and the presence of myositis on laboratory, electrophysiological and/or radiological examinations. JADM patients have no clinical or laboratory evidence of myositis despite clinicopathologically confirmed skin lesions typical of JDM. Gerami et al. originally defined JCADM as cases fulfilling the above conditions for 6 months after onset without systemic treatment [8]. However, early commencement of systemic glucocorticosteroid (GC) and immunosuppressants is often required in the clinical setting. Thus, these terms may be applied to patients who lack obvious muscle weakness despite typical skin rashes regardless of disease duration before initiating systemic treatment.

3. Etiology and pathophysiology

Although the pathogenesis of JDM is not fully clarified, involvement of both genetic and environmental factors has been suggested. In addition to the relationship with human leukocyte antigens (HLA), JDM-related polymorphisms are reported in the genes encoding TNF-α promotor, interleukin-1β, interleukin-1 receptor antagonist intron, interferon regulatory factor 5 (IRF5), mannose-binding lectin (MBL), chemokine (C-C motif) ligand 21 (CCL21), phospholipase C-like protein a (PLCL1) and B lymphoid kinase (BLK) [5,9–11]. Reported environmental factors include infectious agents such as coxsackievirus, influenza virus, parvovirus, hepatitis B virus, group A streptococcus, toxoplasma, and borrelia, as well as vaccines, ultraviolet exposure, and medications [5].

Histopathological studies have revealed ischemic change due to inflammatory or non-inflammatory systemic vasculopathy, and both apoptosis of the muscle cells and amplification of inflammation mediated by type-I interferon (IFN) in JDM [1,5,12]. Pathological roles of macrophages, T cells, plasmacytoid dendritic cells (pDCs), and autoantibodies have been suggested in the development of inflammatory myositis.

4. Diagnosis

Diagnosis of JDM is not difficult for experienced physicians when presented with a typical rash but is often delayed in general clinical settings because of its rarity and the difficulty of objective assessment of muscle weakness in young children. JDM can be misdiagnosed as developmental disorders or muscular dystrophy, which often results in delayed treatment (Table 1).

Table 1. Currently used ‘guidance for diagnosis in research project of specified pediatric chronic diseases’.

Guidance for diagnosis
1) Dermatological symptom
Heliotrope rash: reddish purple edematous erythema in the eyelids, unilateral or bilateral Gottron’s signs: Erythematous or violaceous macules on extensor surface of the finger joints with hyperkeratosis and dermatrophy Erythema of extensor surfaces of the joints of the elbow, knee, etc.^a. Findings of skin biopsy consistent with dermatomyositis^b
2) Muscular symptom
Muscle weakness of proximal muscles in upper or lower extremities^c
3) Imaging
Findings indicating myositis with MRI: High intensity on T2 weighted/fat suppression MRI and normal intensity on T1 weighted MRI
4) Biochemical examination
Elevated serum level of muscle enzymes (creatine kinase or aldolase)
5) Immunological examination
Positive result for myositis-specific autoantibodies^d
6) Pathological examination
Pathological findings indicating myositis with muscle biopsy (degeneration of muscle fibers and cellular infiltration)
Diagnostic criteria Classical JDM: The presence of 1 or more items of (1) dermatological symptoms (a) to (c), (2) muscular symptom and 2 or more items of (3) to (6) during the follow-up. JHDM: The presence of 1 or more items of classical dermatological symptoms (a) to (c), and 1 or more items of findings indicating myositis (3) to (6) without clinical muscle weakness. JADM: The presence of 1 or more items of classical dermatological symptoms (a) to (c) without any evidences of myositis (2) to (6). JPM: The presence of 3 or more items of (2) to (6) without dermatological symptoms (1).
Exclusions
Myositis caused by infections, noninfectious myositis such as eosinophilic myositis, autoinflammatory diseases with rash similar to DM such as Nakajo-Nishimura syndrome, drug-induced myopathy, myopathy due to endocrine abnormality or congenital anomaly, muscle symptoms due to electrolyte abnormality, muscular dystrophy and other congenital muscular diseases, muscle weakness due to central or peripheral neuropathy, psoriasis, eczema, and other related diseases with other causes such as allergy.
Comments
If a patient presents with following symptoms and/or complications, JDM should be considered. Dermatological symptoms: erythema around the nail, erythema in anterior neck of upper chest (V-sign), erythema in shoulder to upper back (shawl sign), skin ulcer, Raynaud’s symptoms Muscular symptoms: muscle pain, and muscle pain caused by pressure Respiratory system: interstitial pneumonia (dry cough and exertional dyspnea in advanced cases), respiratory muscle weakness, and nasal voice Gastrointestinal tract: dysphagia, and gastrointestinal ulcer and bleeding Abnormalities on electrocardiograms (block, extra systole, changes in ST-T segment), myopathy, and pericarditis Non-erosive arthritis Frequent appearance of fever, malaise, weight loss and fatigability, which may rarely be accompanied by systemic edema Dilatation and loop formation or loss of capillary vessels in the nail bed. These symptoms are not specific for JDM but are often found in JDM. Calcinosis (skin, subcutaneous tissue, muscle/fascia, and bone/ joint

^a Ulcerative lesions or secondary infection may modify the appearance of rash.

^b Hyperkeratosis, vacuolation of basal keratinocytes, deposition of melanin, perivascular lymphocyte infiltration, increased dermal edema, mucin deposition and thickening or atrophy of skin are observed, but it is difficult to differentiate JDM from SLE by pathological findings alone. Thus, single symptom is not adopted as a dermatological finding.

^c Muscle weakness ranges from mild ones (e.g. stumbling, new onset of difficulties in exercise) to advanced ones (e.g. difficulties in standing up from sitting position or rolling over in the bed).

^d Although only anti-Jo-1 antibodies could be measured at the time of revision of this guidelines, anti-ARS, anti-MDA5, anti-Mi-2, and anti-TIFI-ɣ antibodies are currently listed on the national health insurance price list. The other antibodies can be measured in some institutions but may be commercially available in the future.

Diagnostic criteria proposed by Bohan and Peter [7] described the disease but do not include modern diagnostic methods. The classification criteria for PM/DM by the Japanese Ministry of Labor, Health and Welfare (1992) had been applied to pediatric cases but had the following problems [13]. First, electromyography is painful and scarcely used for the diagnosis of JDM particularly in young children. Second, the criteria cannot be used for the diagnosis of JADM. On the other hand, magnetic resonance imaging (MRI) is useful for the detection of muscle lesions and is widely available in Japan. Recently established ‘the Guidance for Diagnosis in Research Project of Specified Pediatric Chronic diseases’ has been developed by modification of the previous criteria, which include both MRI and myositis-specific autoantibodies (MSAs) instead of electromyography and anti-Jo-1 antibodies, respectively. The criteria are used for both epidemiological surveys and financial support by action for intractable disease, and specific chronic diseases in childhood (http://www.shouman.jp/instructions/6_1_3/). There are several differences between the criteria for JDM and the current criteria for adult DM/PM; neither MRI nor MSAs are included in the criteria for adult DM, whereas Gottron’s sign and Gottron’s papules were not separated in the criteria for JDM. Recently developed ACR/EULAR classification criteria for IIM [14] are also specific and sensitive in Japanese patients with JIIM (unpublished) and may be applied in Japan in the near-future.

5. Skin lesions

Heliotrope rash, Gottron’s papules, and Gottron’s sign are pathognomonic and tend to associate with disease activity, although Gottron’s sign may persist after achieving remission. The color of the heliotrope rash is rather dark reddish than purple in Japanese patients compared with Caucasians. Butterfly erythema which spreads over the cheeks on both sides of the root of the nose and often over the entire face is frequently an initial dermatological symptom of JDM. Inverse Gottron’s papules are frequently observed in adult patients with DM complicated with RP-ILD, whereas the correlation is not evident in JDM [15]. Periungual erythema is not specific but often observed as an initial symptom of JDM [16]. Elongation of the nail epithelium and dilated nail-fold capillaries are characteristic to both (J)DM and scleroderma. Poikiloderma is an intermix of pigmentation, depigmentation, dilatation of capillary vessels and skin atrophy in the same area, indicating chronic disease. Calcinosis is a characteristic cutaneous sign in JDM compared with DM [17]. Undermining ulcer is a possibly vasculitis-associated ulcerative lesion expanding from the dermis into subcutaneous tissues and associated with anti-MDA5 autoantibodies.

Other dermatological symptoms include V-sign, holster sign, and shawl sign; these are dark reddish purple-colored erythema on the upper chest, buttock to the outside of the thigh, and bilateral shoulders, respectively. Mechanic’s hands are associated with anti-aminoacyl-tRNA synthetase (ARS) antibodies in DM, but these skin signs are rare in patients with JDM [18,19].

6. Myopathy

Symmetrical muscle weakness, predominantly proximal, is a major sign of JDM. Functional disability varies from a mild one (e.g. stumbling) to a severe one such as difficulty in rolling over, standing up from lying, or maintaining a sitting position. Involvement of the laryngopharynx muscles causes dysphagia, aspiration, and dysphonia. Weakness often progresses gradually and insidiously [1,5,7]. Deep tendon reflexes are preserved despite apparent muscle atrophy.

7. Laboratory examination

All patients with suspected JDM should be assessed by laboratory tests focusing on the differential diagnosis and assessment of both myositis and vascular endothelial damage in addition to routine hematological, biochemical and immunological investigations (Table 2). Although measurement of muscle-derived enzymes is useful for the diagnosis and the assessment of disease activity of myositis, the results should be carefully interpreted particularly in the cases with liver dysfunction [20–25]. Von Willebrand factor and fibrin degradation product reflect activation and damage of vascular endothelial cells [26–28]. Serum levels of ferritin, neopterin and soluble interleukin-2 receptor also correlate with disease activity but are not specific to JDM [29–33]. Myositis-specific antibodies are mentioned in the next section. Once the diagnosis of JDM is made, complications such as interstitial lung disease should be serially assessed [34].

Table 2. Laboratory tests.

Purpose	Laboratory tests
Diagnosis and differential diagnosis	Antinuclear antibody Myositis-specific autoantibodies: anti-Jo-1, anti-ARS, anti-MDA5, anti-TIF1-γ, and anti-Mi-2 antibodies） Myositis-associated autoantibodies: anti-U1-RNP, anti-Pm-Scl, anti-SS-A/Ro, anti-SS-B/La, anti-Sm antibodies (Anti-NXP-2, anti-SAE, anti-Ku antibodies are not supported by National Health Insurance) Serum levels of complements (C3, C4, CH50) Matrix metaloroteinase-3 Serological tests for viruses such as Epstein-Barr virus, cytomegalovirus, hepatitis B and C virus Urinalysis Bacterial culture
Assessment of myopathy	CK, LDH, AST, ALT, aldolase, and serum and urine myoglobin
Assessment of endothelial damage	FDP-E, D-dimer, and von-Willebrand factor
Assessment of inflammation	Complete blood cell count, C-reactive protein, erythrocyte sedimentation rate, immunoglobulins, serum ferritin, neopterin. Soluble interleukin-2 receptor is not supported by National Health Insurance.
Assessment of complications	KL-6, SP-D, cholesterol, triglyceride, and blood glucose

ARS: aminoacyl-tRNA synthetase; MDA5: melanoma differentiation-association gene 5; TIF1-γ: transcriptional intermediary factor-1ɣ; NXP-2: nuclear matrix protein-2; SRP: anti-signal recognition particle; CK: creatine phosphokinase; LDH: lactate dehydrogenase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; FDP: fibrin degradation product; KL-6: Krebs von Lugen-6; SP-D: surfactant protein-D.

8. Myositis-specific autoantibodies

Although recent reports have demonstrated association of clinical features with MSAs, there are several differences in clinical features between races or age groups even with the same antibody. In the US and European cohorts, autoantibodies are identified in about 70% of patients with JDM, and many of them showed positive response for anti-transcriptional intermediary factor-1ɣ (TIF-1ɣ) or anti-MJ/nuclear matrix protein (NXP) 2 antibodies [4,5,23]. After the Japanese version of the guidance had been published, two Japanese groups have reported the frequency of MSAs [6,35]. Both reports show higher frequencies of anti-MDA5 antibodies (20-30%) than those in the UK registry (7.4%) [4]. The presence of anti-Mi-2, anti-signal recognition particle (SRP), and anti-ARS antibodies are quite rare in JIIMs [4–6,23]. Anti-MDA5 antibodies are related to ILD and arthritis but not necessarily to JCADM [6,30]. This is in contrast to JDM in Western countries where the complication of ILD is rare and to adult DM in Japan where the antibody is related to clinically amyopathic cases [4,5,23,36–40]. Anti-TIF-1ɣ antibodies are, similar to JDM patients in Western countries, associated with a chronic course, typical rashes and mild myositis [4–6,35,41]. However, in contrast to adult DM, there is no association of the autoantibody with malignancies in JDM [4–6,23,41,42]. Anti-MJ/NXP2 antibodies are associated with severe muscle weakness and calcinosis [43,44]. Both anti-SRP and anti-HMGCR antibodies are very rare but associated with JIMNM in both Japan and Western countries [4–6]. Anti-small ubiquitin-like modifier activating enzyme (SAE) antibodies are positive in 8% of DM patients in the USA and Europe and 2% in Asian countries but are quite rare in JDM [4–6].

9. Imaging

MRI is widely available in Japan and easy for children because of its non-invasiveness [20,45]. Acute phase inflammatory edema of the muscles is reflected by high intensity signal on fat suppression/T2-weighted image or short tau inversion recovery (STIR) image with a high sensitivity, although these findings are not specific to myositis [20,45–47]. Similar findings in the fascia and subcutaneous tissues can be seen in an early phase of severe myositis and can be associated with the development of lipodystrophy [48,49]. MRI is also used for the assessment of disease progression, prediction of severity, and decision of site of muscle biopsy [50–53].

10. Muscle pathology

Muscle tissues are usually biopsied from biceps brachii or rectus femoris muscle but may be taken from other involved muscles. Fresh freeze fixation using isopentane/liquid nitrogen technique and, if possible, glutaraldehyde fixation is recommended for histochemistry/immunohistochemistry and electron microscopic studies, respectively [54]. Biopsy and tissue fixation should be performed by an experienced physician.

Perifascicular atrophy and microinfarction are specific to (J)DM [55]. The other JDM-specific findings include expression of type I interferon-induced molecules such as myxoma resistance protein (MxA), and deposition of membrane attack complex (MAC) associated with or without immunoglobulin on immunohistochemical studies [56,57]. Tubulointerstitial inclusions are found in endothelium on electron microscopy [58]. Variability in muscle fiber size, necrotic and regenerating fibers and infiltration of inflammatory cells around perivascular and perimysial regions are observed in a large number of patients but are not specific to (J)DM [7,55]. Fibrosis of endomysium is often observed. Infiltrating cells are mainly CD4-positive cells, B cells, macrophages and plasmacytoid dendritic cells (pDCs) [59,60]. CD4⁺CD123⁺ CD11⁺ pDCs account for approximately a half of CD4⁺ cells [61].

In contrast to JDM, infiltration of lymphocytes into endomysium, surrounding non-necrotic fibers and invasion into non-necrotic fibers are seen in patients with PM. Infiltrating cells are mainly CD8-positive T cells [59,60]. MHC-class I molecules are expressed on the muscle fibers. In IMNM, fiber size variability, necrosis, and regeneration of muscle fibers are observed. Cellular infiltration is absent or mild [62].

Muscle biopsy from anti-ARS syndrome shows necrotizing and regenerating fibers in the perifascicular region but lack expression of MxA in the fibers [63]. Thus, the syndrome is pathogenetically distinct from (J)DM.

11. Electrophysiological examination

Electromyography (EMG) is a useful examination for differential diagnosis of muscular diseases even in the cases without abnormal findings on MRI. The biceps brachii muscle or quadriceps muscles are usually used for the examination. Myositis is suggested by the following observations; increased insertional activity at time of needle insertion, fibrillations and positive sharp waves at resting condition, and decreased amplitude and short duration of motor unit potential by voluntary movement [64]. It is noted that the findings can vary by insertion site, disease stage, and treatments. EMG examination should be assessed by experts in neuro-muscular disorders.

12. Assessment of severity

Although Gowers’ test and Trendelenburg test are simple methods to detect weakness, all patients should be assessed for muscle weakness by validated methods such as manual muscle testing (MMT)-8 or Childhood Myositis Assessment Scale (CMAS) [65–67]. However, younger children tend to have a lower total score and are more difficult to assess. [68]. Childhood Health Assessment Questionnaire (CHAQ) is used for the assessment of functional ability [65]. These assessment methods, together with various indices related to disease activity, myopathy, and patient-reported outcomes, are included in the Myositis Core Set Measures established by the International Myositis Assessment and Clinical Study Group (IMACS) [69] and core set of measures for disease activity in JDM proposed by Pediatric Rheumatology International Trials Organization (PRINTO) [70]. Myositis Disease Activity Assessment Tool (MDAAT) is used for assessment of overall disease activity including both muscular and extramuscular diseases [71]. These were proposed for clinical trials but not for routine clinical practice.

PRINTO has defined inactive disease in JDM as fulfillment of three of four criteria: (1) serum CK activity ≤150 IU/L, (2) CMAS ≥48, (3) MMT score ≥78 and (4) physician global assessment (PGA) score of overall disease activity ≤0.2 [72]. A large cohort study from United Kingdom has suggested to incorporate PGA score of overall disease activity as an essential criterion, because skin disease is underestimated by the PRINTO criteria [73].

13. Differential diagnoses

Diagnosis of JDM is often difficult in cases without characteristic rashes or typical symptoms such as muscle weakness of proximal muscles and muscle pain. Measurement of MSA, electromyography, and muscle biopsy may be helpful in such cases [74]. Differential diagnosis includes muscular dystrophy, metabolic myopathy (glycogen storage disease type II and V, carnitine cycle disorders, and mitochondrial diseases), and endocrine disease (hypo- and hyper-thyroidism, hypo- and hyper-calcemia, and hypokalemia), other immunological diseases (X-linked agammaglobulinemia, Nakajo–Nishimura syndrome, and mixed connective tissue disease), and infectious myositis [75–79].

14. Treatment

14.1. Principle of treatment

All patients with suspected JDM should be referred to pediatric rheumatologists. Early and aggressive therapy is recommended to reduce inflammation, because prolonged disease activity is associated with increased morbidity such as calcinosis.

Glucocorticosteroid (GC) therapy has reduced the mortality of JDM and is still a mainstay of treatment [80]. Early and aggressive treatment with high-dose GC in combination with MTX or other immunosuppressants may reduce calcinosis and is particularly recommended for severe/fulminant cases and cases with ILD [81–86]. These immunosuppressive drugs have additive and/or steroid-sparing effect and are recommended even in mild cases to minimize adverse effects of long-term GC therapy such as growth failure, obesity, osteoporosis and cataract [87–89]. On the basis of evidence-informed consensus-based experts’ opinion, we propose a treatment algorithm that conforms to the present status in Japan (Figure 1).

Figure 1. Algorithm of treatment for JDM. ADM: amyopathic dermatomyositis; AZA: azathioprine; CNI: calcineurin inhibitor; GC: glucocorticoid; HRCT: high-resolution computed tomography; ILD: interstitial lung disease; IVCYC: intravenous cyclophosphamide; IVIG: intravenous immunoglobulin; MMF: mycophenolate mofetil; mPSL: methylprednisolone; PE: plasma exchange; RTX: rituximab.

At diagnosis of JDM all patients should be screened for complication of ILD by high-resolution computed tomography (HRCT) scan of the chest and biomarkers such as serum levels of Krebs von den Lungen-6 (KL-6) [34]. Patients with dysphagia, dyspnea, skin ulcer, generalized edema or gastrointestinal bleeding are classified as severe or fulminant cases. The other cases are classified as mild/moderate.

Before starting therapy, screening for infection should be performed. This should include hepatitis B virus (HBs antigens, anti-HBs antibodies, and anti-HBc antibodies), hepatitis C virus (anti-HCV antibodies), mycobacterium tuberculosis (tuberculosis-specific interferon-gamma release assay), fungus (β-D-glucan), Epstein–Barr virus, and cytomegalovirus. Vaccination to measles, rubella, and varicella may be indicated in non-immune patients if possible. Vaccination before and during treatment should adhere to the recommendations for vaccination in pediatric rheumatic diseases by PRAJ [90]. Non-pharmacological management includes physiotherapy and avoidance of ultraviolet exposure using sunscreen (SPF 30 or higher).

14.2. Induction therapy

In JADM, topical GC and/or tacrolimus (TAC) is indicated, although systemic use of GC in combination with weekly MTX may be used in refractory cases [3,91,92].

Mild/moderate JDM including JHDM needs high-dose oral GC or methylprednisolone (mPSL) pulse therapy as an induction therapy [82–89], although the efficacy of lower dose of GC is reported [93]. Japanese pediatric rheumatologists tend to start with 1-3 courses of mPSL pulse therapy followed by oral PSL at 0.7–1.5 mg/kg/day. Weekly MTX is used as a concomitant medication [87–89]. Although intramuscular MTX is recommended as first line treatment with GC as it has fewer side effects and similar effectiveness to cyclosporine A [94], only oral administration of MTX is supported by National Health Insurance in Japan and often causes intolerance due to abdominal discomfort. Azathioprine, mycophenolate mofetil or calcineurin inhibitors such as CyA and TAC can be used in patients who are intolerant or resistant to MTX [94–102]. Because of nephrotoxicity, trough levels of CyA and TAC should be monitored (CyA 100–200 ng/ml and TAC 5–10 ng/ml in acute phase, and lower in a long-term use). High-dose intravenous immunoglobulin (IVIG) therapy is recommended for refractory cases [103–105]. In severe/fulminant JDM, mPSL pulse therapy in combination with intravenous cyclophosphamide (IVCYC) therapy is recommended [3,106]. The efficacy of IVCYC has recently been confirmed by marginal structural modeling approach [107]. Special attention should be paid to bone marrow suppression, hemorrhagic cystitis, and nausea. The period of treatment depends on the response in each case but should not exceed the cumulative dose related to infertility. Male appear to be more sensitive to infertility secondary to CYC than female. In malignancy, cumulative dose of CYC over 7.5 g/m² is a risk factor for infertility in both sexes (http://www.j-sfp.org/public_patient/fertility_treatment.html), whereas 89% of male patients who received less than 4 g/m² of CYC are normospermic [108]. Although a randomized control study has failed to show short-term efficacy of rituximab (RTX), 83% of patients receiving RTX met the definition of improvement [109]. Thus, RTX reduces disease activity allowing the dose of GC to be tapered, and should be considered in refractory cases [109,110]. The use of plasma exchange (PE) has not been established in JDM but may be considered in combination with immunosuppressive drugs for refractory cases such as anti-SRP antibody-positive IMNM [111,112].

14.3. Maintenance therapy

Following achievement of improvement with induction therapy, the dose of GC is gradually reduced. Empirically in cases with long term remission for 1–2 years on maintenance dose of PSL (0.15–0.2 mg/kg/day), PSL is slowly tapered out in Japan. However, steroid tapering plans over 1 year have recently been proposed by Childhood Arthritis and Rheumatology Research Alliance (CARRA) and PRINTO, and may be applied to Japanese patients with JDM [113,114]. Withdrawal of MTX or immunosuppressive drugs is considered in patients who have been in steroid-free remission for at least 1 year.

If myopathy or skin lesions relapse, which can be accompanied by elevation of muscle-derived enzymes, sIL-2R or FDP, adherence to medication should be assessed. Escalation of GC dose or alteration of adjunctive immunosuppressants should be considered in cases of relapse.

14.4. Management of infectious diseases

JDM itself is a risk factor for infection. In addition to opportunistic infections due to immunosuppressive therapy, aspiration pneumonia and infection of calcinotic sites or skin ulcers are observed in JDM and often need antibiotic therapy [115]. Although evidence is absent in JDM, prophylactic administration of trimethoprim/sulfamethoxazole for pneumocystis jiroveci can be considered in cases taking a high dose GC or aggressive immunosuppressive therapy [116].

14.5. Osteoporosis

Consensus has not been obtained on the treatment of osteoporosis in patients with JDM. Combination of vitamin D3 and calcium is used to minimize osteoporosis and prevent bone fracture, although it is not associated with full recovery of bone mass [117–120]. Bisphosphonate is reported to be effective for osteoporosis in childhood connective diseases [120]. However, bisphosphonate is currently not supported by National Health Insurance for children and is considered as off-label use for this age-group.

15. Special conditions in JDM

15.1. Interstitial lung diseases

ILD is a major cause of JDM-associated death in Japan. Although the incidence of ILD in JDM is not clear, a nationwide survey in Japan reported 13 deaths with JDM in 5 years, six of which were attributed to RP-ILD [121]. Anti-MDA5 autoantibodies are positive in one-third of Japanese patients with JDM in Japan (seen more frequently than in Western countries) and related to both DM- and JDM-associated ILD [4–6,30,35–39,122,123]. Particularly high titers of the autoantibody are associated with RP-ILD in children [30,36]. On the other hand, anti-ARS antibodies which are related to chronic and recurrent ILD in adult DM are quite rare in children [4–6,35].

ILD can develop at an early disease stage or with disease relapse and is initially often asymptomatic or presents with only a mild cough, ILD needs to be looked for in every patient with JDM particularly those with positive anti-MDA5 autoantibodies regardless of ILD-related symptoms [27,36,99]. Screening of ILD includes high-resolution chest CT (HRCT) and serum levels of KL-6, SP-D, lactate dehydrogenase (LDH), and in older children pulmonary function tests and carbon monoxide diffusion capacity, all of which are also used for assessment of disease activity of ILD during therapy.

Differential diagnosis includes pneumonia caused by pneumocystis, cytomegalovirus, mycoplasma, chlamydia, mycobacterium tuberculosis, and mycoplasma. However, they often complicate JDM-associated ILD and need specific treatments such as antibiotics, antifungals or antiviral agents in addition to the treatment for ILD.

Poor prognosis is associated with consolidation and ground glass opacity in the lower lung field and multiple subpleural ground glass opacity on chest HRCT in adult DM [124]. However, because RP-ILD may not be differentiated from chronic ILD by HRCT at an early phase [30,99], it is critical to start aggressive treatment as early as possible. Anti-MDA5 antibody-positive JDM-associated ILD is usually refractory to mPSL pulse therapy alone [99], although there is no randomized control study on the efficacy of immunosuppressant. Based on the studies in adult DM and case series in JDM, we recommend the combination of mPSL pulse therapy with immunosuppressive drugs such as calcineurin inhibitor and/or IVCYC. CyA is usually started with 3–5 mg/kg/day and is adjusted to maintain the trough levels at 150–200 ng/ml for the treatment of ILD [99]. To date, evidences of the efficacy of TAC in ILD are limited to adult cases [125]. Combination therapy with mPSL pulse therapy, calcineurin inhibitor and IVCYC reduced the mortality of adult DM-associated RP-ILD [126] and should be considered in patients with respiratory symptoms at diagnosis of JDM or refractory to the above-mentioned treatments. Efficacy of IVIG therapy, RTX, MMF, PE, and plasma purification therapy using polymyxin B has been reported in adult cases [127–146].

After the commencement of therapy for ILD, disease activity of ILD should be serially assessed by the methods as described above. Serum levels of KL-6 may remain high even after improvement of HRCT findings and pulmonary function when treated with CyA [99]. Sudden respiratory deterioration suggests pneumothorax or pneumomediastinum [147]. In cases requiring artificial ventilation, high frequency oscillation (HFO) should be considered.

15.2. Calcinosis

Calcinosis is observed in 30–70% of patients with JDM and associated with prolonged disease activity due to delay in diagnosis or commencement of treatment, cardiac involvement, and anti-NXP2 autoantibodies [17,43,83,148]. Calcinosis usually develops 1 year or more after the onset of disease prevalently in the extremities [149,150]. Four distinct patterns of soft-tissue calcification have been described; deep calcareal masses, superficial calcareal masses, deep linear deposits, and a lacy, reticular, subcutaneous deposition of calcium encasing the torso [151]. Calcinosis consists of hydroxyapatite and various calcium salts and contains inflammatory cells such as macrophages and proinflammatory cytokines [150,152]. Plain X-ray is useful for the detection of calcinosis [153]

Although case reports and case series have suggested efficacy of diltiazem, aluminum hydroxide, IVIG, thalidomide, probenecid, intralesional corticosteroid injection, bisphosphonates, infliximab, and abatacept, there is no definitive treatment of severe calcinosis [154–164]. Surgical treatment is often necessary but should not be performed when disease is active [165,166].

15.3. Other complications

Thrombocytopenia with or without cytopenia of other lineages has been reported. Autoantibody formation, bone marrow suppression and hemophagocytosis have all been postulated as pathogenetic causes [167]. Effectiveness of GC, immunosuppressants, and IVIG has been reported for these complications.

Although generalized edema complicates 6% of adult DM, the frequency is not known in JDM [168]. Generalized edema is non-pitting and associated with severe muscle weakness, dysphagia, and skin or gastrointestinal ulcer [168,169]. Although the mechanism of generalized edema has not been clarified, vasculitis associated with hyperpermeability and microinfarction may be involved [170]. Cases with generalized edema are usually resistant to oral monotherapy with PSL and require combination therapy of intravenous GC with immunosuppressant and/or IVIG [168,169].

Lipodystrophy is often accompanied by acanthosis nigricans and complicates 8–40% of JDM [171–173]. Calcinosis, muscle atrophy, contracture of joints, butterfly rashes, and chronic disease course are risk factors for lipodystrophy [173]. Lipodystrophy is accompanied by hypertriglyceridemia, insulin-resistance, nonalcoholic fatty liver, and decreased levels of HDL-cholesterol, and associated with anti-TIF-1γ autoantibodies [41,171–174]. In addition to the treatment of hypertriglyceridemia and insulin-resistant diabetes, the clinical effectiveness of metreleptin has been reported in 3 cases [175].

Although the complication of arrhythmias or myocarditis/cardiomyopathy is rare [176–179], recent studies have demonstrated subclinical cardiac dysfunction in late disease which is associated with sustained early skin disease rather than myopathy [180,181]. Accordingly, all patients with JDM should be tested for cardiac complications by echocardiogram and electrocardiogram. High-dose GC, mPSL pulse therapy and/or IVIG should be considered in cases with myocarditis/cardiomyopathy [182].

Gastrointestinal ulcer or perforation reflects severe vasculopathy and require aggressive treatment with both mPSL pulse and IVCYC therapy, and in some cases, surgical therapy [183–187].

Non-erosive arthritis develops in 40–60% of JDM patients and is often accompanied by synovitis which is similar to active JIA by imaging. The most frequently affected joint is reported to be the knee followed by wrists and finger joints [148,188]. The presence of anti-MDA5 autoantibodies is associated with arthritis [4–6,189]. Arthritis usually responds to standard treatment for JDM but can flare during reduction of GC.

Although membranous nephropathy and nephrotic syndrome were also reported in patients with JDM, complication of chronic kidney disease is very rare [190–193]. Renal tubular necrosis due to myoglobinuria is rare but can be associated with severe myositis and dehydration [194].

16. Prognosis

A 2010 international multicenter study reported a mortality rate of 3.1% and major functional impairment of 6.5% [83]. Forty percent of the patients followed a monophasic course, whereas polyphasic course was observed in 60%. However, most of the patients with JDM finally achieve a drug-free remission [6]. Major sequelae of JDM include muscle atrophy often accompanying joint contracture, subcutaneous calcinosis, and related functional impairment [195].

Conflict of interest

Masaaki Mori: Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K. K., Japan Blood Products Organization, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Towa Pharmaceutical Co., Ltd., UCB Japan Co. Ltd., with TMDU paid the salary of Masaaki Mori. All other authors have declared no conflicts of interest.

Additional information

Funding

Research on rare and intractable diseases, Health and Labor Sciences Research Grants for ‘Study about the standardization of diagnostic criteria and disease severity classification and the development of evidence-based treatment guidelines for pediatric rheumatic diseases such as mainly juvenile idiopathic arthritis’ (H27-nanchitou(nan)-ippan-029).