Juvenile Dermatomyositis

Juvenile DermatomyositisRecognition and Treatment

Ann M. Reed1 and Maricarmen Lopez2 1 Division of Rheumatology, Mayo Clinic, Rochester, Minnesota, USA2 Duke University Medical Center and the University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3151. Treatment of Juvenile Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

1.1 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3161.2 Hydroxychloroquine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3171.3 Intravenous Immunoglobulins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

2. Immunosuppressive Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3182.1 Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3182.2 Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3182.3 Cyclosporine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3182.4 Cyclophosphamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3182.5 Combination Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

3. Additional Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3194. Other Supportive Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

4.1 Vitamin D, Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3195. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

Abstract Juvenile dermatomyositis (JDM) is a multisystem disease characterized by acute and chronic lymphocyticinflammation of the skeletal muscle and skin. The disease is marked early in its course by the presence of avasculopathy or vasculitis, and later by the development of calcinosis. Research has focused on the epidemiol-ogy, etiology, and pathogenesis of the disease with, until more recently, limited therapeutic interventions.

This article highlights treatment regimens, both traditional and more recent interventions. Traditional treat-ment for JDM includes high dose corticosteroid treatment with additional agents used in resistant disease orchildren with unwarranted adverse effects. Traditional therapy begins with daily oral corticosteroids, withintravenous corticosteroids utilized in severe disease; however, recent data suggests that short-term use of intra-venous cortcosteroids will allow a short-term improvement in strength, with no long-term change in outcome.More recent investigations suggest that early intervention with additional immunomodulatory agents will allowfor a faster recovery, with less medication and disease sequelae.

Use of methotrexate as an agent early in the disease course is becoming common place. Methotrexate, inconjunction with oral corticosteroids, allows a rapid improvement in symptoms, and allows for a more rapidreduction in corticosteroid dose. Methotrexate is considered as a steroid sparing agent, whether oral or intrave-nous corticosteroids are used. Additional immunomodulatory agents include the use of cyclosporine with orwithout methotrexate. Intravenous immunoglobulin has been reported to have benefit in resistant disease.

There are exciting new agents which have great potential in treating JDM. Many of these agents are termedbiologics and are being tested in adult myositis and juvenile arthritis. These include tumor necrosis factor(TNF)-α inhibitors, such as a chimeric monoclonal antibody to TNF-α, and a recombinant soluble human TNFreceptor (p75)-Fc fusion protein. Many other new biological agents are also being tested in myositis.

REVIEW ARTICLE Pediatr Drugs 2002; 4 (5): 315-3211174-5878/02/0005-0315/$25.00/0

© Adis International Limited. All rights reserved.

The etiology of juvenile dermatomyositis (JDM) is unknown,but it is thought to occur after an environmental trigger in a gene-tically susceptible individual. It is a rare disease, the incidence ofwhich varies by geographical and genetic background. There havebeen epidemiologic studies that report varying incidences of JDMfrom 0.5/100 000 in Finland, 14/1 million in Sweden, 1/250 000in the UK, and from 8 to 1/200 000 in varying regions within theUS.[1-3] A strong human leucocyte antigen (HLA) association ex-ists with the HLA-DQA1*0501 allele in Caucasian, AfricanAmerican, and Hispanic American children.[4] Evidence that in-fectious agents are involved in the disease is, for the most part,indirect. We know that acute muscle inflammation can occur asa result of a viral infection, but there has been no clear data linkinga viral etiology or trigger to the onset of disease. The diagnosisof JDM requires the presence of a pathognomonic rash and threeof the following criteria: proximal muscle weakness, elevation ofmuscle enzymes, electromyographic changes of myopathy, ormuscle biopsy changes demonstrating vasculitis, necrosis, or in-flammation on histopathologic evaluation

Studies suggest that JDM is an autoimmune disease that re-sults in vasculitis, inflammation, and fibrosis. Both cell-mediatedimmunity to muscle antigens and immune complex disease mayplay a role in the pathogenesis. An increased responsiveness invitro of lymphocytes to allogeneic or autologous muscle extractshas been described in a patient with JDM.[5] Additional studieshave shown a cytotoxic effect on muscle monolayers in cultureby lymphocytes from children with JDM. Immune complex medi-ated vasculitis may also be important in the initiating or perpetu-ating event, with immunoglobulin and complement deposition inthe vessel wall of muscles in children and adults with dermato-myositis. CD4 positive T-cells, B-cells, and macrophages sur-round the areas of immune complex modified cells.[6] The C5b-9membrane attack complex has also been localized in the intramus-cular microvasculature in early lesions in JDM.[7] The inflamma-tory infiltrate in JDM is focal, and includes perivascular and peri-fascicular lymphocyte infiltrate in the skeletal muscle on the skin.

Children with myositis have also been demonstrated to havemyositis-specific autoantibodies, although at much less frequen-cy than in adults.[3]

1. Treatment of Juvenile Dermatomyositis

Overall, the two goals of therapy are to reduce muscle inflam-mation and complications of the disease, while maintaining mus-cle function. Few reports address treatment of other manifesta-tions, including cutaneous disease. It has long been thought thatthe treatment has to be for at least two years in this disease, even

though treatment can be minimal after the acute inflammatorysymptoms have been controlled.

1.1 Corticosteroids

Since their introduction into the treatment of JDM, cortico-steroids have been the primary medication for this disease. Thefirst patient known to have effective treatment from corticoster-oids was in 1949 using corticotropin (ACTH).[8] Shortly after, avariety of corticosteroids were utilized in JDM and found to beeffective in 80% of children.[9,10] Prior to the use of corticoster-oids, 40% of patients achieved sustained improvement, 20% wereleft with a disability, and there was 40% mortality. Causes ofmortality included cardiopulmonary complications, gastrointes-tinal hemorrhage, ulcerations, and sepsis. Also, before the use ofcorticosteroids, the frequency of calcinosis in dermatomyositisranged from 27 to 42%. This has now been reduced dramaticallyand is now 8 to 20%. Currently, the mortality in JDM is 3%.Corticosteroid therapy has reduced mortality and morbidity bydecreasing disability and calcinosis. At present, the treatment rec-ommendations are to use prednisone 2 mg/kg/day up to a 60mgoral dose (see table I), usually started as a once daily dose. Formore severe disease, it can be administered in multiple dailydoses. The use of intravenous methylprednisolone early in thedisease has recently been proposed to help reduce muscle inflam-mation more acutely, and reduce the oral corticosteroid dose andaccumulative adverse effects.[11-15] All studies demonstrated im-proved muscle strength and improved skin disease over oral corti-costeroids alone. This was demonstrated early in the disease, butin two studies the long-term outcome did not change, and in onestudy the disease flared in all patients when the medication wasstopped.[11] Calcinosis was reported in one study to be greatlydecreased; however, in two other studies it was just as high aswith oral corticosteroids. Nevertheless, in severe, life-threateningdisease, intravenous corticosteroids are thought to assist with theimprovement of severe dysphagia, myocarditis, and in individu-als who have rapidly worsening muscle weakness. The hope isthat long-term disabilities and sequelae resulting from oral corti-costeroid therapy can be reduced.

There are also studies using intravenous methylprednisoloneas well as methotrexate in early disease, and those will be dis-cussed in section 2.1. Reports of adverse events with methylpred-nisolone use are varied, but overall it is thought that methylpred-nisolone reduces the requirement for oral prednisone, and thusreduces toxicity. Toxicities have included hypertension, cushin-goid effects, psychological effects, compression fractures, cata-racts, diabetes, and secondary immunodeficiency.

316 Reed & Lopez

© Adis International Limited. All rights reserved. Pediatr Drugs 2002; 4 (5)

1.2 Hydroxychloroquine

Hydroxychloroquine has been used for many years in thetreatment of skin manifestations of autoimmune disease. In JDM,hydroxychloroquine is effective at a dose of 5 to 6 mg/kg/dayorally once daily. Also, it has been suggested that hydroxychloro-quine is corticosteroid sparing. One study showed improvementof cutaneous lesions in all of seven patients treated withhydroxychloroquine; three of these seven patients were able todecrease their corticosteroid dose. Another study showed improve-ment in both skin disease and muscle weakness with a hydroxy-chloroquine dose of 2 to 5 mg/kg/day.[16] This study is limited,with minimal additional published data supporting the use ofhydroxychloroquine for muscle disease. Monitoring is needed forpotential retinal toxicity. Prior to initiation of treatment, glucose-6-phosphate dehydrogenase (G6PD) levels need to be measuredin at-risk individuals.

1.3 Intravenous Immunoglobulins

There have been multiple reports showing the use of intrave-nous immunoglobulin (IVIG) in JDM, both at the onset of diseaseand for corticosteroid resistance or treatment intolerance. IVIGhas become a commonly used treatment, based on a double-blindcontrolled trial in adults, and smaller trials in children. The usualdosage recommendation is 2 g/kg/dose, and this would be per-formed on a monthly basis for at least 3 to 6 months. The mech-anism by which IVIG modulates autoimmune disease response isunknown. Speculation includes decreasing inflammatory cyto-kines, blocking immunoglobulin Fc receptors, and neutralizingcirculating autoantibodies.[37] Recent evidence suggests that IVIGinduces surface expression of FcR11B receptor on macrophages,and has a therapeutic strategy for altering autoantibody-mediatedinflammatory disease.[29]

The largest reported group of patients with JDM treated withIVIG was from a retrospective chart review in which 18 patientswith JDM were treated with IVIG 1 to 2 g/kg/month.[30] Cortico-steroid failure was the main indication for starting IVIG. Tenpatients were taking medications other than corticosteroids fortheir JDM. Twelve patients showed clinical improvement onIVIG. Additional studies included between 5 and 9 patients whoeither did not response to conventional treatment or had severeadverse effects.[3,31-36,38] Patients had previous treatment withprednisone, azathioprine, and cyclosporine. All showed some clin-ical improvement with IVIG, with corticosteroids being reducedor discontinued in 60 to 100%. Treatment with IVIG ranged from1 month to 7 years, with significant improvement in skin condition/rash and muscle weakness in most patients.

((Insert Table I here))

Juvenile Dermatomyositis 317


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Table I. Common drugs used in the treatment of juvenile dermatomyositis

Drug Dose Benefits Adverse effects Advantage over other drugs References

PrednisoneOral 2 mg/kg up to 60mg taper

over 2 yearsControl muscle inflammation,prevents calcinosis, dysphagia,myocarditis

Stunted growth, bodyweight gain,hypertension, avascular necrosis,cataracts, osteoporosis, myopathy

Decrease in calcinosis, with oralprednisone and decreased duration of rash with intravenous prednisone

8-12,14,15

IV 10-30 mg/kg up to 1gHydroxychloroquine 5-7 mg/kg/day Good for skin disease,

photoprotective, some effect onmuscle disease

Retinal toxicity – needs an eye examevery 6 months, and before startingneeds a G6PD level

Improves skin disease 16

MethotrexatePO 0.4-1 mg/kg, given once

weeklyDecrease muscle inflammation Liver toxicity, lung, mouth ulcers,

minimum chance of malignancyCorticosteroid sparing agent 17-20

SubcutaneousAzathioprine 1-2 mg/kg/day, maximum

of 3-5 mg/kg/dayUseful in patients with corticosteroid-dependent disease

Gastrointestinal, need to follow upcomplete blood count, liver function

19,20

CyclophosphamideOral 50-75 mg/m2 Useful in refractory disease Hemorrhagic cystitis, ovarian failure,

varicella zoster virusUsed in severe disease andinterstitial lung disease

21IV ≥500 mg/m2

Cyclosporine 2.5-7.5 mg/kg/day, in two divided doses

Useful in refractory disease, catch up growth in one patient

Decrease glomerular filtration rate,hypertension, hirsutism

Improved disease in case reportswhen other cytotoxic agents werenot beneficial

22-28

IVIG 2 mg/kg/dose monthly Control of muscle inflammation,corticosteroid sparing

Infusion adverse effects, asepticmeningitis, risk of infection, allergicreaction

Improvement in muscle strengthand skin rash

29-36

G6PD = glucose-6-phosphate dehydrogenase; IVIG = intravenous immunoglobulin.

A review has been conducted of patients who had been diag-nosed with JDM,[19] polymyositis,[2] and one overlap disease, andwho had corticosteroid resistant disease. Patients were placed on2 mg/kg/month of IVIG for 3 to 9 months. 30% of patients achievednormalized strength, and over 60% improved strength. Therewere mixed results in two reports[3] concerning attempts to useIVIG as first-line therapy for JDM without concurrent oral corti-costeroids. Severe adverse effects in IVIG are not uncommon.Infusion related toxicities include headache, fever, nausea, andhypertension, which can usually be modulated by change in in-fusion rate, premedication with diphenhydramine, paracetamol(acetaminophen), or methylprednisolone, or by switching to an-other formulation.[3] Other potential adverse effects include asep-tic meningitis, thromboembolic events, and anaphylaxis. The po-tential for transmission of infectious diseases, which in the pasthas been thought to be of concern, is at present thought to bealmost eliminated because of recent changes in the production ofIVIG.

2. Immunosuppressive Agents

2.1 Methotrexate

Methotrexate has been used in combination with corticoste-roids and seems to be beneficial in reducing inflammation andallowing the daily corticosteroid dose to be reduced. Methotrex-ate and intravenous methylprednisolone have been studied incombination, comparing initiation of methotrexate early versuslate in the disease course of JDM.[17] Six patients were treatedearly within 6 weeks of their diagnosis, while another six patientswere treated later with methotrexate, anywhere from 5 to 72 monthsafter diagnosis. Their primary measures were the resolution ofclinical indications for treatment, such as decreased activity ofdisease manifestations and tapering of the corticosteroid dose toa minimal dose, or discontinuation without clinical or biochemi-cal flares. The main indications for starting intravenous methyl-prednisolone and methotrexate were dysphagia and severe cuta-neous vasculitis. All patients received methotrexate orally for atleast 8 months, as well as intravenous methylprednisolone at adose of 30 mg/kg/dose. The six patients who received early metho-trexate showed a significant clinical improvement; the corticoste-roid dose was reduced to <5 mg/day in five out of the six. Noneof them developed calcinosis. In contrast, two of the six patientswho received late methotrexate therapy did develop calcinosis. Areport of methotrexate and prednisone used to treat recalcitrantJDM demonstrated that all 12 patients who used methotrexateregained normal muscle strength; however, five patients had todiscontinue the methotrexate due to adverse effects, and 5 had

disease recurrence once the methotrexate was discontinued.[18] Inanother reported study,[17] patients who received methotrexateearly in therapy were generally shown to have a 21% improve-ment in symptoms, or a 53% remission rate. There does appearto be an increased rate of disease flare during methotrexate reduc-tion. Methotrexate doses varied between studies, ranging from0.4 to 1 mg/kg, with weekly oral, subcutaneous, or intravenousadministration.[19] The initial response usually occurs between 4and 8 weeks after starting therapy, once the dose is optimized.Potential adverse effects include photosensitization, oral ulcers,risk of opportunistic infections, and possible risk of lymphoma.

2.2 Azathioprine

Azathioprine, which is commonly used in adult myositis, hasbeen trialled in JDM (10 children) at a daily dose of 50 to 200mg.Approximately 20% of children had disease improvement, with60% achieving remission.[19,20] Adverse effects with azathioprineinclude gastrointestinal intolerance, myelosuppression, hepato-toxicity, risk of opportunistic infections, hypersensitivity reac-tions, and potential for secondary malignancies. The azathioprinedose is 1 to 2 mg/kg/day PO, increasing to a maximum of 3 to 5mg/kg/day while monitoring the white blood cell count.

2.3 Cyclosporine

Reported experience with cyclosporine in the treatment ofJDM is limited. From multiple reports, of 29 patients with JDM,most of whom had disease refractory to corticosteroids and cyto-toxic therapies, all had improvement of their muscle strength ina mean follow up of 6 to 12 months.[19,20,22-28] The prednisonedose was reduced in most patients (96%) and discontinued in50%. One study reported catch up growth in children treated withoral cyclosporine 2.5 to 7.5 mg/kg/day, divided in two doses tomaintain a trough level of <300 μg/L.[21] Adverse effects fromthe cyclosporine therapy have included a decrease in glomerularinfiltration rate, development of hypertension, and hirsutism.Cyclosporine, as well as corticosteroids, can also induce a myo-pathy and contribute to the development of osteoporosis.[3]

2.4 Cyclophosphamide

The use of daily oral cyclophosphamide has been reported infour patients with therapy resistant JDM disease. All four improvedon a regimen of 50 to 75 mg/m2, with remission in three.[19,39,40]

Adverse effects included hemorrhagic cystitis and herpes zoster.There are reports of pulse intravenous cyclophosphamide,

FK506, and chlorambucil, but these have been limited.[3] Re-cently the use of tacrolimus has also been shown to be of benefit

318 Reed & Lopez


in the treatment of JDM when refractory to corticosteroids andcyclosporine.[41,42]

2.5 Combination Therapies

The use of combination therapy has now become more com-mon, and case reports have indicated that combinations of metho-trexate and azathioprine, as well as combinations with cyclospor-ine and IVIG, have been beneficial in patients who are resistantto standard treatment.[3]

3. Additional Treatments

Plasmapheresis has been used in life-threatening JDM dis-ease. Plasmapheresis was a traditional therapy prior to the use ofimmunosuppressive agents in resistant and severe dermatomyo-sitis disease.[43,44] In adult myositis, a controlled trial did not findimprovement. There have been reports of improvement in chil-dren with JDM, with both plasmapheresis and apheresis. Use ofanti-tumor necrosis factor-α therapies are under investigation, theresults of which are unavailable at present. One study uses Enbreltherapy for new onset disease, and another uses Remicade fordisease resistant to corticosteroid and immune suppressive treat-ment. Case reports in abstract form report varying success.[45]

Autologous stem-cell transplantation has been proposed inJDM, but experience is very limited.[46] Standard treatment pro-tocols have not been established and results are mixed.

4. Other Supportive Measures

As in any chronic illness, supportive measures such as ade-quate rest and nutrition are important.

Sun screens, protective of both ultra violet (UV)-A and UV-Blight, have been strongly recommended, and it has been hypothe-sized that exposure to the sun can not only affect cutaneous dis-ease, but could also potentially trigger muscle disease in individ-uals with JDM.

Physical therapy and rehabilitation is recommended with theinitial onset of severe muscle weakness and disease. Moderate ex-ercise, stretching, and a range of motions are recommended dur-ing the acute phase so as not to inflame muscles, but it has beenshown that once the acute inflammatory process is subsiding ac-tive physical therapy can be helpful in improving long-term func-tional outcomes, including range of motion, and strength.[47]

4.1 Vitamin D, Calcium

It has been demonstrated that any child with autoimmuneinflammatory disease can become osteopenic because of both dif-

fuse systemic inflammation and other potential mediators.[48] Itis recommended that the diet of these children is supplementedto meet their daily calcium requirements: 800 mg/day in childrenaged between 1 and 5 years 1200 mg/day between 6 and 10 years,and 1500 mg/day between 11 and 24 years. It has also been rec-ommended that vitamin D therapy of >400 IU/day be utilized,primarily in areas where there is decreased sun exposure andwhen dietary intake is inadequate.

There is no adequate treatment for calcinosis, which has beena long-term complication. There are several reports of studiesusing diltiazem, aluminum hydroxide, bisphosphonates, magne-sium sulfate, and lactate that have shown improvements in dys-trophic calcifications, and others with variable benefit noted.[49-56]

Diltiazem has been used for 1 to 12 years in doses of 240 to 480mgdaily, with some improvement of calcifications.[51,52] Aluminumhydroxide and magnesium sulfate have shown improvement incalcinosis in case reports. One study using alendronate demon-strates stability of bone loss with a suggestion of improvementwhen corticosteroids were used in JDM.[53]

5. Conclusions

Standard treatment for JDM with steroids and supportivecare has made a dramatic improvement in outcome, both survivaland sequelae, over the past half century; however, several chil-dren continue to have a poor outcome, with some ending in death.Advances and willingness to use additional immunosuppressiveagents has allowed for a reduction in corticosteroid adverse ef-fects, and for improvements in children with refractory disease.

Relying on small studies or case reports has hampered cur-rent approaches to treatment. Recent advances in the ability tostudy larger groups of children are under way with internationalcollaborative efforts to establish study design and outcome mea-sure, as well as the commencement of large multicenter clinicaltrials. Additional advances include the formation of a pediatricrheumatology network, including the US and Canada, whose roleis to foster collaborative studies.

The hope is that these studies will include the new biologicagents which block cytokines such as anti-TNFα and a recombi-nant human interleukin-1 receptor antagonist. Additional agentsinclude anti-complement agents and anti-B cell agents, with otheragents rapidly appearing in testing. These agents allow more tar-geted treatment, potentially with better tolerability.

Acknowledgments

The authors gratefully acknowledge the clerical assistance of ElizabethTimm.



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Correspondence and offprints: Dr Ann M. Reed, Division of Rheumatology,Chief of Pediatric Rheumatology and Associate Professor of Pediatrics,Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.E-mail: [email protected]



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Juvenile Dermatomyositis