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REVIEW ARTICLE
Ahead of print publication  

Juvenile dermatomyositis: Controversies and recent developments in management


1 Advanced Pediatrics Centre, Allergy Immunology Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pediatrics and Chief, Advanced Pediatrics Center, Allergy Immunology Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission24-Apr-2020
Date of Acceptance07-Jun-2020

Correspondence Address:
Surjit Singh,
Department of Pediatrics and Chief, Advanced Pediatrics Center, Allergy Immunology Unit, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_107_20

  Abstract 


Juvenile dermatomyositis (JDM) is an autoimmune disorder of childhood that mainly affects the skin and muscles. As compared to adults, children are more likely to suffer from disease relapses and long-term complications such as lipodystrophy, insulin resistance, calcinosis, and systemic vasculopathy. There have been significant advancements in our understanding of the pathophysiology, disease course and complications of JDM in the last two decades. Due to scarcity of clinical trials in JDM, therapeutic decisions in every patient with JDM remain a challenge. This review aims to provide a comprehensive overview of the controversies, challenges in clinical management and latest advances in treatment regimens of JDM.

Keywords: Calcinosis, clinically amyopathic dermatomyositis, inflammatory myositis, lipodystrophy, myositis autoantibodies



How to cite this URL:
Chaudhary H, Loganathan SK, Singh S. Juvenile dermatomyositis: Controversies and recent developments in management. Indian J Rheumatol [Epub ahead of print] [cited 2020 Aug 9]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=290256




  Introduction Top


Juvenile dermatomyositis (JDM) is the most common type of juvenile idiopathic inflammatory myositis (JIIMs). It represents more than three quarters of all JIIMs, with an incidence of approximately 2.5 per million per year.[1] Typical clinical features include a characteristic skin rash and proximal muscle weakness. A wide spectrum of systemic involvement is also described in JDM, particularly involving the gastrointestinal and cardio-pulmonary systems. JDM is frequently complicated by relapses, small-vessel vasculopathy, and 'difficult-to-treat' skin and metabolic abnormalities. Evidence from registry studies has expanded our knowledge about the spectrum of phenotypes, etiopathogenesis, outcome, and long-term complications associated with JDM. The optimal treatment of the disease is limited by scarcity of clinical trials and long-term follow-up data of patients with JDM.[2] In this review, we have discussed the controversies in the management of JDM and summarized the latest developments in clinical evaluation, therapeutic management, and management of long-term complications of JDM.


  Classification of Juvenile Dermatomyositis: Journey Beyond the Bohan and Peter Criteria Top


The earliest classification criteria for idiopathic inflammatory myositis (IIMs) were given by Bohan and Peter in 1975.[3],[4] IIMs were classified into 5 groups based on common phenotypic features. These were used as diagnostic as well as classification criteria and remained in use for more than 40 years for both clinical and research purposes. Although beset with several limitations [Table 1], these criteria are user friendly and provide a good understanding of the clinical features of JDM and polymyositis and continue to be used even in the modern era. A series of classification criteria of IIMs have since been proposed by various authorities. These are based on clinical variables, histopathology, autoantibodies, and response to therapy. Later studies focused on myositis-specific autoantibodies (MSAs) and their unique clinical associations with different categories of IIMs.
Table 1: Comparison of various classification criteria for inflammatory myositis

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The latest classification criteria for adult and juvenile IIMs have been published by the Consensus Group of European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) in 2017.[5] Two models have been developed for disease classification, utilizing 16 variables, with and without a muscle biopsy. Each variable is given a predecided weightage and a web-based calculator gives a score that determines the probability of IIMs in a patient. The criteria are data-driven, have high sensitivity and specificity, and permit flexibility in variables that are to be included in the classification of IIMs.[5] However, the classification criteria of IIMs need to be continually updated to reflect the ongoing pathological and molecular advances in the field of IIMs.


  Juvenile Dermatomyositis and Dermatomyositis: Two Different Diseases? Top


JDM and DM share common clinical characteristic like rash, muscle weakness, systemic manifestations and MSAs. However, the disease course, clinical outcomes, and disease-related complications differ significantly between the two groups [Table 2]. Tansley et al. have described a host of clinical, serological, and genetic differences between the two groups.[6] Shinjo et al. analyzed muscle biopsies of juvenile and adult DM patients and found differences in inflammatory cell phenotyping of muscle biopsies in both groups.[7] The spectrum of MSAs is also unique in the two groups. JDM may have an early progression, higher disease-related complications, and substantial morbidity. However, once remission is achieved, children regain muscle strength and function more frequently than their adult counterparts.[8] JDM tends to have a better prognosis than adult DM if the condition is diagnosed in time and treated appropriately.
Table 2: Comparison of clinical characteristic of juvenile dermatomyositis and dermatomyositis

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  Muscle Biopsy in Juvenile Dermatomyositis: Is it the Standard of Care Today? Top


Muscle biopsy has traditionally been the gold standard for characterizing IIMs. It was also one of the classification criteria in Bohan and Peter classification for the diagnosis of DM/PM. Although all IIMs have muscle fiber necrosis and inflammatory cell infiltrates, a constellation of histopathologic alterations can help differentiate DM from other subtypes of IIMs. The pathologic hallmark of JDM is myonecrosis, myophagocytosis, and perifascicular atrophy involving both Type 1 and Type 2 muscle fibers and it is almost pathognomonic of JDM even in absence of inflammatory cells. JDM also has a component of vasculopathy which is characterized by microvascular endothelial damage that causes endothelial swelling and narrowing of small vessels. Vascular changes are most apparent in earlier stages of the disease and muscle atrophy is usually a feature of late disease. Immunohistochemical demonstration of Class I major histocompatibility complex expression, deposition of complements, and immunoglobulin on muscle fibers are more sensitive markers of JDM.[9]

Wedderburn et al. published a report of the UK JDM Research Group, which generated a scoring system for measuring the severity of histopathological damage in JDM muscle biopsy.[9] The histological scoring tool was later validated by the same research group in a cohort of 55 patients with JDM.[10] The most reliable items of the score were changes in the inflammatory and muscle fiber domain, which correlated with measures of clinical disease activity. The score also had a good correlation with clinical disease activity. In a recent study by the same group, Deakin et al. have shown that muscle pathology predicts long-term treatment status of patients with JDM and that this effect is influenced by MSAs.[11]

However, the following factors should be taken into consideration while evaluating a patient with JDM for muscle biopsy.[12]

  1. Site of biopsy: It is crucial that the biopsy be taken from affected group of muscles. As clinical evaluation may be imprecise, imaging of muscles on magnetic resonance imaging (MRI) is advocated to select the best site for a biopsy. Usual sites for a muscle biopsy are quadriceps femoris and biceps humerii
  2. Type of biopsy: An open biopsy is preferred to a needle biopsy as a larger sample can be obtained. This allows proper orientation of muscle tissue and is more suited for immunocytochemical and ultrastructural studies
  3. Interpretation of muscle biopsy requires an experienced pathologist with expertise in myopathology and immunoenzyme histochemistry
  4. Muscle involvement is usually patchy in JDM. Focal inflammatory infiltrates and muscle fiber atrophy can be easily missed while evaluating a specimen. Serial sections need to be examined to avoid false-negative results. Preoperative hook wire localization using MRI has also been tried for tissue localization before the muscle biopsy.[13]


Over the last 2 decades, muscle biopsy has been mostly abandoned as an obligatory investigation in patients with JDM, especially in the presence of supportive clinical, radiological and immunological (MSAs) evidence. However, some centers still prefer to do a muscle biopsy as it can help predict disease outcome and response to therapy.[10] A muscle biopsy is indicated in all cases of atypical presentation of JDM, where the diagnosis is in doubt or where response to therapy is poor, to rule out other variants of IIMs.[14] Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) expert group advocate performing muscle biopsy in patients with atypical presentation or unclear diagnosis.[15]


  Nailfold Video Capillaroscopy in Juvenile Dermatomyositis Top


Nailfold capillaroscopy (NFC) is a highly sensitive and non-invasive tool for morphological evaluation of nail fold capillaries. The earliest studies on NFC visualization described the abnormal nail fold patterns seen in patients with scleroderma and JDM as scleroderma-JDM pattern.[16] Like scleroderma, JDM also has prominent microvasculopathy which can be appreciated on NFC as giant capillaries, abnormal capillary morphology, avascular areas, and capillary hemorrhage. The disease duration and severity have an impact on the capillaroscopic changes.[17] Pizzorni et al. did a longitudinal study on patients with DM and systemic sclerosis and found that capillaroscopic changes of DM may persist even after therapy has been completed.[18] Selva-O'Callaghan et al. showed that NFC abnormalities were more common in DM than PM and correlated significantly with disease severity and poor prognosis. It can also predict development of cardiopulmonary complications such as pulmonary hypertension and interstitial lung disease (ILD) in JDM.[19] SHARE guidelines recommend performing an NFC in every patient with JDM at the time of presentation and during disease flares.[15]


  Myositis-Spectrum Disease Autoantibodies: Road to Personalized Medicine? Top


With advances in research on IIMs, several autoantibodies have been identified in patients with JDM. These can be classified into two major subgroups:

  1. MSAs: These are found exclusively in patients with myositis
  2. Myositis-associated antibodies (MAAs): These may also be seen in other connective tissue disorders where myositis can occur.


MSAs have been detected in up to 54% of children with JDM in the United States[20] and 51% of patients with JDM in the United Kingdom.[6] Each individual is known to generate only one type of MSAs and each MSA is associated with a distinctive set of clinical manifestations. The common MSAs, MAAs, and their clinical associations are enumerated in [Table 3]. Common MSAs associated with JDM are anti-TIF-1 Ab)/p155/140, anti-NXP-2, anti-melanoma differentiation-associated gene 5 (MDA-5)/CADM-140 and anti-Mi-2 antibodies. A variety of commercial assays (single and multiplex) have been developed for detection of these MSAs. These include enzyme-linked immunosorbent assay, immunoblotting techniques, and laser bead immunoassay. MSAs have emerged as potential biomarkers of IIMs and can provide useful prognostic information. Their presence in a patient can predict future development of certain complications such as calcinosis in a patient with anti-NXP2 antibodies and ILD in a patient with anti-MDA5 antibodies. [Figure 1] shows distinct clinicoimmunological associations of different MSAs. These have provided key insights into potential immunopathogenic mechanisms and can predict disease activity and response to therapy. Consequently, MSAs can provide a mechanism for personalized management for every patient with JDM.
Table 3: Clinical association of myositis-specific autoantibodies and myositis-associated autoantibodies in juvenile dermatomyositis

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Figure 1: Clinicoimmunological associations of MSAs (original)

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  Clinically Amyopathic Dermatomyositis Top


CADM is characterized by classical cutaneous manifestations of JDM in absence of clinical evidence of muscle weakness. It includes the category of amyopathic DM (ADM) and hypomyopathic DM.[21] Sontheimer reviewed the cutaneous manifestations of JDM in great detail and published the first criteria for ADM.[22] The latest EULAR/ACR classification also gives a provision of classifying the patients into the category of ADM in presence of two skin related items and without muscle involvement.[5] Some patients with CADM can develop significant muscle disease and progress into classic DM several months after initial presentation-they are labeled as having “premyopathic DM”.[21] El-Azhary andPakzad recorded 2 patients with ADM in their cohort who developed clinical signs of muscle weakness within 5 years of diagnosis.[23] Certain MSAs are known to be associated with ADM (e.g., anti-CADM/anti-MDA5),[24] anti-TIF-1 gamma,[25] and antiaminoacyl-tRNA synthetase antibodies.[26] CADM has also been occasionally described in children. It is associated with a milder disease with less risk of vasculopathy, ILD, and internal malignancy[27] as compared to adults with ADM.


  Is Juvenile Dermatomyositis a Type-1 Interferonopathy? Top


Type 1 interferon (IFN) signature is upregulated in several autoimmune diseases like systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis. Initial gene profiling studies on JDM had pointed toward elevated expression of type 1 IFN-stimulated genes (ISG) in muscle biopsy of four children with JDM.[28] Further studies have shown elevated type 1 ISG such as MXA, ISG15, and DDX58 in blood and skin cells of patients with DM and JDM. These patients also have high levels of IFN-1 cytokines such as IFN-b and IFN-a in circulation. ISG transcripts and IFN cytokine score have shown significant correlations with degree of vasculopathy, muscle inflammation, cutaneous manifestations, constitutional symptoms, and muscle activity scores in DM. They are proposed as potential biomarkers for assessing disease activity in patients with DM.[29] The type 1 IFN signaling pathway involves signal transduction through Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. JAK/STAT pathway inhibitors such as ruxolitinib have been tried as potential targeted therapy in patients with refractory DM and have shown encouraging results.[30]


  Controversies in the Management of Juvenile Dermatomyositis Top


The goals of therapy in JDM include control of disease activity, preventing systemic damage, and improving quality of life of patients. Early therapy can help in attaining remission in up to 30%–50% of patients with JDM within 2–3 years of disease onset and limit long term disease-related complications. Majority of patients with JDMS, however, will have relapses or persistent disease activity. Mortality rates due to JDM in the developed countries are now <4%.[31] However, we reported mortality rates of 11.1% in our cohort of children with JDMS at Chandigarh. Reasons for high mortality included delays in diagnosis and initiation of therapy, poor compliance to medications and increased rates of infections in our cohort.[32]

The optimum therapeutic strategy in JDM remains undetermined, largely because of dearth of adequate clinical trials. Corticosteroids form the backbone of therapy. Evidence for other anti-inflammatory therapy comes from two clinical trials in JDM: (1) Pediatric Rheumatology International Trials Organization trial which recommended combination of steroids and methotrexate over steroids alone in the initial therapy of JDM,[33] (2) Rituximab in Myositis trial, which showed good response of the disease to rituximab along with ability to taper steroids in JDM,[34] and a number of case-control studies.

Children's Arthritis and Rheumatology Research Alliance (CARRA) developed clinical treatment plans (CTP) for the treatment of patients with moderately severe JDM based on expert opinions.[35] They suggested 3 treatment plans for initiation of therapy in patients with moderately severe JDM (Plan A: 3 days of intravenous high-dose methylprednisolone + methotrexate + oral steroids; Plan B: 3 days of intravenous high-dose methylprednisolone + methotrexate + oral steroids + intravenous immunoglobulins (IVIg); Plan C: methotrexate + oral steroids). They also gave detailed guidelines on initiation, tapering and stopping steroids. Recently, SHARE provided recommendations for the diagnosis and treatment of JDM based on expert opinion.[15] Some of the therapeutic challenges are discussed below:

Therapy for refractory disease

CARRA CTP recommend re-evaluation of patients based on physician judgment after 4 weeks of initiation of therapy. If the disease remains unchanged, therapy with corticosteroids and methotrexate should be extended for 4 more weeks. If the condition worsens after 4 weeks of therapy or remains unchanged after 8 weeks of therapy, additional therapy in the form of high-dose intravenous methylprednisolone, immunomodulatory agents (e.g. IVIg) and immunosuppressants (e.g. cyclosporine, mycophenolate mofetil (MMF), azathioprine) and biologic agents (e.g. infliximab, rituximab) are recommended.[36] SHARE guidelines also recommend aggressive immunomodulatory and immunosuppressive therapy. Autologous stem cell transplantation has also been recommended in patients with refractory disease.[15] CARRA JDM biologic workgroup published a survey and consensus on use of biologics in refractory JDM. They recommend considering use of four biologics (rituximab, abatacept, tocilizumab, and infliximab) for management of refractory JDM.[37]

Therapy for skin only disease

Management of skin rash is also as important as management of muscle weakness in patients with JDM. A persistent rash may be associated with pain, functional impairment, and psychosocial issues in patients with JDM. Rash in JDM can be associated with calcinosis and lipoatrophy. It is considered by some to be a pointer toward ongoing systemic immune activity.[38] A persistent rash or relapse of cutaneous manifestations in a patient with JDM is often an indication to consider more aggressive therapy.[39] The cutaneous assessment tool is recommended as a part of initial evaluation and follow-up for assessment of JDM skin activity. CARRA has published another set of CTP for patients with JDM who have persistent skin rash even after complete resolution of muscle weakness. They have recommended 3 plans of therapy (Plan A: IVIg, Plan B: MMF and Plan C: cyclosporine) along with continuation of oral corticosteroids in all groups and continuation of methotrexate and IVIg in plans B and C.[38] SHARE guidelines also recommend JDM skin activity assessment periodically. Ongoing skin disease warrants hiking up of systemic immunosuppression. Topical tacrolimus/topical steroids are recommended in localized skin disease. Photoprotection is also recommended in all patients with JDM.

Therapy for severe disease

Disease severity in JDM was defined at the CARRA consensus conference in 2010 [Table 4].[35] Early and aggressive therapy of JDM results in fewer disease related complications. SHARE guidelines recommend assessment of lung involvement with pulmonary function tests (PFT) at diagnosis and further frequent monitoring with PFT and high-resolution computed tomography for detection of ILD in children with JDM. For cardiac evaluation, electrocardiography and echocardiography is recommended for all patients with JDM at diagnosis and may be repeated periodically in children with risk factors. It recommends addition of monthly pulse cyclophosphamide for 3–6 months to the baseline regimen. In absence of improvement, it recommends intensification of therapy by addition of rituximab or changing to anti-tumor necrosis factor therapy (infliximab/adalimumab) or using a combination of high-dose methotrexate, cyclosporine, and IVIg. A similar strategy has been recommended by JDM working group in Germany and Austria.[40]
Table 4: Definition of disease severity in children with juvenile dermatomyositis

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  Long-Term Complications of Juvenile Dermatomyositis: Calcinosis, Lipodystrophy, Insulin Resistance Top


Patients with JDM may experience long term complications like persistent muscle weakness and atrophy, joint contractures, calcinosis, lipodystrophy (LD), and insulin resistance even after effective therapy. Calcinosis refers to the deposition of calcium carbonate apatite in the skin and soft tissues. It is one of the late complications of JDM and often correlates with prolonged disease activity. It has been seen in 30%–70% of JDM as compared to 20% in adult DM.[41] Almost one-fourth of patients with JDM have calcinosis at time of the first presentation.[22] Six different patterns of calcinosis have been described in DM:[42]

  1. Superficial calcifications: small and hard plaques/nodules under the skin surface
  2. Subcutaneous calcifications: popcorn like appearance on X-ray due to large, tumor like deposits of calcium in the subcutaneous plane
  3. Intermuscular calcification: Calcium deposition in the intermuscular fascia which can lead to limitation of movement in the involved muscle
  4. Dystrophic calcification: looks like an exoskeleton, usually in severe forms of calcification
  5. Mixed form
  6. Calcinosis universalis.


The exact mechanism of calcinosis in JDM is uncertain. Reports have suggested that calcinosis occurs due to intracellular calcium accumulation at a site of chronic inflammation or trauma. Several studies have demonstrated the accumulation of proinflammatory cytokines, inflammatory cells and mineralization proteins like osteopontin at the site of calcinosis.[43] Fisler et al. showed an association of calcinosis in JDM with prolonged disease activity, delay in diagnosis and/or the initiation of treatment and elevated muscle enzymes.[44] Subcutaneous calcifications present as extrusions from the skin and can result in ulcerations, secondary infections and pain especially at the site of pressure or compression. Extreme calcium laden fluid structures can be seen in rare cases of calcinosis which is termed as “milk of calcium.”[45] Calcification of the muscles is usually asymptomatic. Treatment of calcinosis remains challenging as no standard therapy has been found effective in halting the progression or decreasing the calcification.[46] Several therapeutic agents have been tried for treatment of recalcitrant calcinosis [Table 5].
Table 5: Treatment strategies for calcinosis in juvenile dermatomyositis

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LD is another well-established complication of JDM with an estimated prevalence of 10%–40%.[47] It is accompanied by a host of metabolic abnormalities like insulin resistance, dyslipidemia, and diabetes. The pathogenesis remains unclear, but cytokines like interleukin-1 and TNF-α seem to have a role in the development of LD in JDM. A study also suggests the role of MSAs in the development of LD. MSAs interfere with adipocyte function and decrease fat uptake by adipocytes. The anti-TIF-1 γ antibody is more prevalent in patients with generalized LD. Three patterns of LD have been seen in JDM:

  1. Focal LD
  2. Partial LD
  3. Generalized LD.


These 3 patterns suggest a gradient of severity in the affected individuals. Patients with generalized LD have more severe disease features such as loss of buccal pad of fat, acanthosis nigricans, hypertrichosis, hyperpigmentation, hyperandrogenism, and dyslipidemia. Verma et al. objectively quantified the pattern of fat distribution in children with JDM using standard anthropometric measurements and skinfold thickness.[48] They showed that patients with JDM had lower mean anthropometric measures like height, weight and mid-upper-arm circumference in comparison with controls. Gross LD was evident in 40% of patients and almost 50% had objective evidence of subcutaneous fat loss at various sites. Regional fat loss can also be evaluated through a Dual-energy X-ray absorptiometry[49] and MRI. Childhood Myositis Heterogeneity Study Group published a comprehensive review of LD in JDM.[50] They reported an association between calcinosis, muscle atrophy, joint contractures, facial rash, and development of LD. Metabolic studies revealed elevated testosterone, dyslipidemia, and evidence of insulin resistance in patients with partial and generalized LD. Risk factors associated with LD include severe, prolonged disease course, and occurrence of calcinosis.

In conclusion, LD is a poorly understood long term sequelae of JDM. Patients should be closely monitored for evolving LD and the associated metabolic abnormalities, especially in high-risk disease.


  Monitoring of Disease Activity Top


Tools for monitoring of ongoing disease activity are needed to assess response to medication and need for timely intensification of immunosuppressive therapy. Most important is clinical assessment by an experienced clinician using various tools such as Manual Muscle Testing of 8 muscle groups (MMT-8), Childhood Myositis Assessment Scale, Physician's and Patient's Global Assessment on a visual analog scale. Clinical measures have limited capacity to assess low grade muscle inflammation which may contribute to long term tissue damage. Laboratory biomarkers include muscle enzymes, autoantibodies, Type 1 IFN gene transcripts and cytokines, inflammatory mediators like TLR4 ligand myeloid related protein 8/14 (MRP8/14) and inflammatory cells T helper cells.[51] Biomarkers for disease activity in other organ systems have also been studied in patients with DM [Table 6].
Table 6: Biomarkers to assess disease activity in juvenile dermatomyositis

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  Conclusion Top


JDM is a chronic, heterogeneous inflammatory myopathy that can have a wide spectrum of systemic manifestations and can be associated with protean long-term complications. Developments over the last 2 decades have resulted in significant improvement in prognosis and outcomes. Early and aggressive immunosuppression remains the cornerstone of management. Collaborative international trials are essential to facilitate research on various aspects of JDM and provide evidence-based treatment strategy for JDM.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Classification o...
Juvenile Dermato...
Muscle Biopsy in...
Nailfold Video C...
Myositis-Spectru...
Clinically Amyop...
Is Juvenile Derm...
Controversies in...
Long-Term Compli...
Monitoring of Di...
Conclusion
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