Review

An update in the diagnosis and management of juvenile

Juvenile dermatomyositis (JDM) is a rare pediatric rheumatic disease. It belongs to the group of idiopathic inflammatory of childhood. JDM is the most frequent of the idiopathic inflammatory myopathies (it represents 85% of cases) among children. JDM is classified by the Bohan and Peter criteria set in 1975. New criteria are being developed and newly developed diagnostic tools are being used in daily clinical practice. This review focuses on recent publications regarding the epidemiology, pathogenesis, classification and treatment of JDM, and will discuss some relevant publications from the adult literature.

KEYWORDS: childhood dermatomyositis n children n dermatomyositis n juvenile Marinka Twilt1,2 dermatomyositis & Brian M Feldman*1,2 1The Hospital for Sick Children, Idiopathic inflammatory myopathies (IIM) rep- the Caucasian population, polymorphisms of the 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada resent a group of autoimmune muscle conditions IL-1 receptor antagonist gene were found to be 2University of Toronto, University of with variable organ involvement amongst the dif- associated with an increased risk for JDM [11]. Toronto, 27 King’s College Circle, Toronto, Ontario, M5S 1A1, Canada ferent types [1]. Juvenile dermatomyositis (JDM) A recent study of plasma proteomic profiles in *Author for correspondence: is the most prevalent subgroup among children disease-discordant monozygotic twins suggest [email protected] (accounting for up to 85% of cases), while poly- that disease pathology is likely influenced by myositis, and dermato- post-meiotic genetic events (e.g., copy number myositis are most common in adults [2]. JDM is variations between monozygotic twins), differ- primarily a capillary vasculopathy affecting the ent epigenetic modifications, epistatic protein muscles and skin, but involvement of multiple interactions, and/or environmental exposures organ systems have been reported. The course that promote proinflammatory biologic pathways of JDM is variable. Approximately one-third of [12]. This indicates that proteomic profiles may patients have a monocyclic disease course. This play an important role in disease pathogenesis. review will focus on classification and treatment An increased prevalence of autoimmune dis- of JDM. eases ( and Type 1 diabetes) in families of children with JDM, suggest shared pathogenic Epidemiology factors [13]. The incidence of JDM has been estimated at Environmental triggers, such as two to three per million children per year [3–5]. [14,15], sun exposure, vaccines and medication, The average age at onset is 7 years old, however, have been suggested in the pathogenesis of JDM. approximately one-quarter of the patients are less Several studies reported symptoms consistent than 4 years of age at diagnosis [2]. All groups of with an prior to the development of childhood IIM, including JDM, are more fre- JDM [14,15]. No consistent serological or tissue quent in females [2,4–7]. The racial distribution evidence of an infectious agent playing a direct reported in the US and UK national registries role in the pathogenesis has been reported [16]. show a predominance of Caucasian children Both the humoral (autoantibodies and (65–83%), followed by African–American immune complexes) and cellular (T and B cells) children (8–11.4%) [2,3]. components of the adaptive are thought to contribute to the pathogenesis of Etiology & pathogenesis JDM. Myositis-associated antibodies and myo- The etiology of JDM is becoming better under- sitis-specific autoantibodies (MSAs) have been stood. A genetic predisposition is strongly sug- reported to be positive in up to 40% of children gested by the predisposition for certain HLA with JDM and in up to 70% of adults with types in patients with JDM [8]. As well as HLA IIM [17,18]. With increasing knowledge of new predisposition, the TNF-a-308A allele has been autoantibodies this number may rise and may associated with increased disease severity, calci- increase our understanding of the pathogenesis. nosis, ulceration and duration of JDM [9,10]. In A major mechanism of vessel damage in JDM is part of

10.2217/IJR.12.23 © 2012 Future Medicine Ltd Int. J. Clin. Rheumatol. (2012) 7(3), 1–xxx ISSN 1758-4272 1 Review Twilt & Feldman An update in the diagnosis & management of juvenile dermatomyositis Review

complement activation inducing further cytokine capillaries in the muscle, and on electron micros- release and vessel injury via the membrane attack copy, tubuloreticular inclusions are often seen. complex. JDM patients show an overexpression of The sensitivity and specificity of the Bohan and MHC-I and b2-microglobulin in affected muscle Peter criteria have never been validated for chil- tissue [19]. JDM patients also show a preference dren; it is thought that individually they are prob- of expressing ICAM-1-type adhesion molecules ably 45–90% accurate [2]. According to the 1975 in the affected muscle vessels, while adult derma- criteria, a definite diagnosis of JDM is considered tomyositis (DM) patients have a preference for when patients present with three criteria in addi- VCAM-1 [20]. Tubuloreticular inclusion bodies tion to the , and a probable diagnosis is con- are present in JDM and adult DM patients and sidered if a patient presents with two criteria in have been reported in circulating blood cells of addition to the rash [26]. Electromyography and other patients treated with IFN-a and in cul- muscle biopsy are both invasive tests and have tured endothelium cells in response to treatment slowly been replaced by the noninvasive muscle with interferons [21–23]. Tubuloreticular inclusion MRI at many centers, especially in patients with bodies likely indicate increased IFN pathway a classic rash and proximal symmetrical muscle signaling [24]. weakness. MRI findings suggestive for muscle There has been increasing evidence that the include symmetrical muscle edema

innate immune system also plays a role in JDM. in the thigh muscle on fat-suppressed T2-weighted In JDM, and other IIM types, the presence of or short tau inversion recovery sequences. An T lymphocytes indicate an ongoing perma- international survey in 2006 of 92 centers from nent immune response. This ongoing immune 32 countries showed that currently, 70% of the response requires the presence of dendritic cells. centers have access to muscle MRI and only 61 Dendritic cells are known to bridge the innate and 55% used muscle biopsy and electromyog- and adaptive immune responses [25]. Although raphy in the investigation of children with sus- the understanding of the pathogenesis of JDM pected myositis, respectively [27]. Muscle MRI has improved, more knowledge is needed to fully has been used more often and clinical scoring comprehend and associate the clinical features systems are being developed [28–31]. These scor- and initiate targeted treatment regimens. ing system are acceptable for the single reader, but there is more variability between readers [28]. In Diagnostic criteria a study with 102 patients with childhood myosi- The diagnosis of JDM is considered in a patient tis, 78 patients had MRI abnormalities consistent with a typical rash on the or body and sym- with myositis [2]. A recent study showed no cor- metrical . The 1975 criteria of relation between the severity of the MRI findings Bohan and Peter are still the most widely used of muscle or fascia with the clinical outcome in [26]. These criteria comprise: first, symmetri- patients with newly diagnosed JDM, however, an cal weakness of the proximal muscles; second, abnormal subcutaneous fat signal appears to have characteristic cutaneous changes consisting of a significant association with a more aggressive heliotrope discoloration of the , which chronic disease course [32]. These new tests and may be accompanied by periorbital edema, and data suggest the need for new diagnostic criteria erythematous papules over the extensor surfaces based on modern methods of diagnosis. Another of joints, including the dorsal aspects of the meta- test that should be considered in the new diag- carpophalangeal and proximal interphalangeal nostic criteria is nailfold capillaroscopy, which joints, , or ankles (Gottron papules); shows a high correlation with disease activity and third, elevation of the serum level of one or more recovery during follow-up [33]. of the following skeletal muscle enzymes; creatine kinase, aspartate aminotransferase, alanine ami- Clinical manifestations notransferase, lactate dehydrogenase and aldolase; The clinical manifestations of JDM can be quite fourth, electromyographic demonstration of the diverse. In larger series the most common, extra- characteristics of muscle irritability and denerva- muscular clinical manifestations are cutaneous tion; and fifth, muscle biopsy documenting his- (80–90%), arthritis (25%), constitutional fea- tological evidence of myositis. The most typical tures (16–18%), pulmonary involvement (11%) histologic features of JDM are perifascicular atro- and gastrointestinal involvement (5%) [2,7]. phy, centralization of nuclei, degenerating fibers, regenerating fibers, and a scattered inflammatory „„Constitutional features infiltrate (often around vessels). Specialized stain- Fever, anorexia and adenopathy are seen in ing will often show a decrease in the number of 10–15% of JDM patients. A recent study looking

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at sleep and and the relationship with surfaces of the proximal interphalangeal, meta- pain in patients with JDM and juvenile idio- carpophalangeal and distal interphalangeal pathic arthritis reported increased pain and joints of the . The extensor surface of the decreased quality of life in patients with sleep elbows, knees, and the medial malleoli are less disturbances and fatigue [34]. Sleep disturbance frequently involved; the toes are rarely affected. and fatigue were present in almost half of the Nailfold capillary changes may be observed in patients with JDM, suggesting that better strate- clinic using a water-based gel and a magnify- gies aimed at improving sleep and fatigue might ing glass (e.g., otoscope or ophthalmoscope) or ® improve the quality of life in these patients [34]. a DermLite . Characteristic nailfold capillary features of JDM include capillary dilatation, tor- „„Musculoskeletal manifestations tuosity, hemorrhage and drop-out. Nailfold cap- One of the hallmarks of JDM is symmetrical illary density appears to be a marker of skin and muscle weakness. Muscle weakness is most muscle disease activity, and can be an important often present in all muscle groups but is most marker of disease activity and recovery during obvious in the limb-girdle musculature, the patient follow­up [33,39]. Reduced nailfold density anterior neck flexors, and the trunk muscles. should be considered for inclusion as a diagnostic Findings on physical examination may include criteria as it has a high sensitivity. the Gower’s sign and the Trendelenburg sign. Gingival capillary changes are also observed These tests can be challenging in very young in patients with JDM. A unique gingival pat- patients. Affected muscles may, on occasion, tern characterized by erythema, capillary dila- be tender, edematous or indurated. tation and bush-loop formation was observed and dysphonia are manifestations of weakness only in JDM patients (61% compared with 0% of the palatal and pharyngeal muscles and may in healthy controls) [40]. This might indicate be a risk for aspiration and regurgitation of liq- that recognition of gingival telangiectases and uid through the nose. Arthralgia and arthritis capillary changes as an important diagnostic are frequently present during the JDM disease marker of JDM, which could lead to an earlier course [7,35]. The arthritis is usually nondestruc- diagnosis [40,41]. tive and non­deforming. Arthritis is often seen Ulcerative cutaneous manifestations are seri- in the beginning of the disease course and fre- ous and potentially life-threatening (in that they quently involves the knees, but large and small often indicate serious internal organ involve- polyarthritis with tenosynovitis can also been ment) in JDM. Ulceration reflects significant seen [7,35]. vasculopathy in the skin with tissue hypoxia and necrosis. A severe course with a higher likelihood „„Dermatological manifestations of a poorer outcome and persistent weakness are Cutaneous manifestations are often the first to associated with ulcerations of the skin. appear, or become present with or just after the Calcinosis usually develops within a few years onset of muscle symptoms [2]. JDM can pres- of diagnosis and is hypothesized to develop ent with several different , but only two through a dystrophic mechanism, whereby rashes are pathognomonic; Gottron’s papules involved muscle releases mitochondrial calcium and heliotrope rash over the eyelids [36]. In 80% into matrix vesicles, which then promotes min- of patients, a pathognomonic rash is present at eralization [42]. Dystrophic calcinosis occurs in presentation; in the remainder, a less charac- approximately one-third (12–43%) of children teristic rash occurs [5]. The three most typical during the disease course and is less frequently cutaneous manifestations are heliotrope discol- present at diagnosis (3–23%) [2,7,43]. Calcium oration of the upper eyelids, Gottron’s papules, deposits may occur in subcutaneous plaques or and periungual erythema with capillary loop nodules (usually on the extremities), as deep abnormalities [36,37]. The heliotrope rash classi- large tumorous deposits in muscle groups, as cally occurs over the upper eyelids and has a vio- calcifications within fascial planes, bridging laceous, or reddish purple tint. The heliotrope is joints, or as an extensive subcutaneous exoskel- often accompanied by edema of eyelids and face eton [44,45]. Risk factors for calcinosis include and capillary telangiectasia [38]. Patients delay to diagnosis and a longer duration of with eyelid rash often also have a facial rash that untreated disease, longer duration of active dis- may mimic the malar rash seen in systemic lupus ease, inadequate treatment, underlying cardiac erythematosus. Gottron’s papules are papulo- or pulmonary disease and the need for aggres- squamous areas of skin with a red appearance sive second-line immunosuppressive treatment and are especially common over the extensor [44,46]. Calcinosis can lead to complications,

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including joint , localized pain, by a progressive, slow and symmetrical loss of inflammatory reactions (which may be indistin- subcutaneous fatty tissue that mainly involves guishable from cellulitis or abscess) and uncom- the upper body [56]. monly patients can develop an exoskeleton of calcinosis. Treatment No prospective, double-blind, randomized „„Cardiopulmonary disease studies of immunosuppressive therapy in JDM Cardiovascular complications in JDM are have been completed. After the introduction thought to be rare. Nonspecific sinus tachycar- of corticosteroids, the mortality was reduced dia is sometimes reported, and murmurs and markedly compared with historical controls. cardiomegaly with or without ECG abnor- A team approach and general supportive care, malities have also been reported [7,46]. A recent including individualized physiotherapy in study comparing the cardiac function of JDM combination with drug therapy are essential. patients with matched controls from the popu- Treatment regimens are based on observational lation, showed subclinical left ventricular dia- studies, expert opinions and clinical experience. stolic dysfunction only in the JDM patients A JDM treatment survey amongst pediatric (22% compared with 0%) [47]. Findings of rheumatologists in North America reported this study do suggest subclinical heart disease the use of corticosteroids in combination with related to the systemic nature of JDM. A study another immunosuppressive agent (mostly of adults 29 years after onset of JDM showed an [MTX]) by almost all respond- increased intima media thickness, impairment ers [57]. The dose and administration route of of endothelial cell function was measured by corticosteroids varied widely amongst respond- brachial arterial reactivity, and higher systolic ers. Consequently the and diastolic blood pressure than healthy con- and Research Alliance devel- trols [48]. These adult patients had continued oped three consensus treatment protocols that active JDM. In adult and DM reflect current initial treatment of children with interstitial lung disease is a frequent compli- moderately severe JDM [58]. These protocols cation and is associated with high morbidity are combinations of intravenous methylpred- [49,50]. Data regarding pulmonary involvement nisolone (IVMP; pulses for 3 days), MTX, oral in JDM are sparse. Asymptomatic pulmonary and intravenous immunoglobulin impairment was found in five out of 12 patients (IVIG). Using these protocols, a comparison of with JDM in a longitudinal study [51]. Recently different approaches to the treatment of JDM Sanner et al. showed smaller lung volumes in in North America is possible. This will enhance JDM patients compared with controls, with a future understanding of the optimal treatment restrictive ventilatory defect in 26% and high- approach. A recent international multicenter resolution CT abnormalities in 37% [52]. Again study demonstrated that patients with recent- the high frequency of mostly subclinical pul- onset JDM were more likely to show signifi- monary involvement highlights the systemic cant clinical improvement (up to 90%), when nature of JDM. compared with patients treated for a disease flare over a 24-month period. Differences in „„Gastrointestinal involvement initial treatment were observed among the four The GI tract can be involved in JDM, there- geographical areas analyzed [59]. fore monitoring for signs and symptoms of Corticosteroids are usually initiated as the GI vasculopathy is necessary. GI vasculopa- onset of action is rapid, and treatment usually thy can occasionally lead to bowel ischemia, allows early control of the disease process. The necrosis, ulcerations and perforation [53,54]. clinical efficacy of corticosteroids can be seen Malabsorption with decreased absorption of within days to weeks. If patients receive high- nutrients and, most notably, oral prednisone dose corticosteroids (2 mg/kg/day) within the has been described [55]. first 4 months of disease onset, better func- tional outcome and less calcinosis is seen than „„Lipodystrophy in patients treated with lower doses or later in Acquired lipodystrophy is being increasingly the disease course [44]. Corticosteroid treatment recognized in patients with JDM. These changes may lead to troublesome side effects, including are rarely seen at presentation, but develop growth retardation, Cushingoid appearance, later in the course of the disease in 14–25% of elevation of blood pressure, cataracts, vertebral patients [7,56]. Lipodystrophy is characterized fractures and osteoporosis. At The Hospital For

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Sick Children (Toronto, Canada) patients are administered on a monthly basis for up to treated initially with 2 mg/kg/day of predni- 2 years. IVIG treatment is sometimes added sone divided into three doses. After 6 weeks, months into the disease if patients experience if clinical improvement is seen, prednisone is steroid resistance or dependence. In severe consolidated to twice daily and shortly after- cases, IVIG is used earlier in the disease course. wards to once-daily dosing. As long as the dis- Another widely used steroid-sparing agent is ease stays clinically controlled, prednisone is cyclosporine, which appears effective in clinical tapered by approximately 10% every 2 weeks practice; however, evidence is sparse. A recent [60]. If GI vasculopathy, dysphagia, dysphonia PRINTO study reported use of cyclosporine or pulmonary disease is present, the initial in patients with a disease flare [59]. PRINTO treatment is usually IVMP (30 mg/kg/day, is currently conducting an international, mul- with a maximum of 1 g). Many surveyed rheu- ticenter randomized trial to compare initial matologists prefer IVMP over oral prednisone treatment with corticosteroids with treatment on a routine basis (see above) [57]. A compara- with corticosteroids and MTX or cyclosporine. tive study did not find a difference in 3-year In our experience, cyclosporine seems to be outcomes between patients treated with IVMP effective but treatment is often complicated by and oral prednisone; the most severe patients, hypertension and hirsutism. however, were all treated with IVMP and could Mycophenolate mofetil has also been used not be matched [61]. In cases of incomplete or in patients with JDM [65,66]. In a recent study, absent response, IVMP is often given with the 50 JDM patients were treated with mycophe- assumption that oral corticosteroids are not nolate mofetil and showed decreased skin and being properly absorbed [55]. muscle disease activity. Mycophenolate mofetil MTX is prescribed as a corticosteroid-sparing was steroid sparing and was well tolerated [66]. agent for many rheumatologic conditions. A Cyclophosphamide has been used in severe shorter average time to discontinuation of pred- cases, usually refractory disease complicated nisone and a lower average cumulative predni- with severe pulmonary involvement, ulcerative sone dose was reported in newly diagnosed JDM skin disease or GI vasculopathy. In a study of patients treated with MTX (15 mg/m2/week) 12 patients receiving monthly cyclophospha- and prednisone (2 mg/kg/day) compared mide pulses, ten showed clinical improvement with historical controls [60]. Currently MTX after 6 months, without serious side effects, and is widely used at the start of treatment as a two died shortly after treatment was initiated steroid-sparing agent [58]. Low-dose MTX has [67]. In most centers, including ours, cyclophos- also been reported in the treatment of DM skin phamide is reserved for patients with severe disease [62]. IVIG has been used as an adjunc- refractory disease or life-threatening organ tive treatment, typically for two groups of JDM involvement. patients: corticosteroid-resistant patients who The use of , an anti-TNF-a mono- do not respond adequately to corticosteroids clonal antibody has been described in five early in the disease course, and corticosteroid- patients with refractory JDM with reported dependent patients who respond initially but clinical improvement [68]. In adults with DM, are unable to be weaned off steroid therapy. however, no sustained benefit has been shown. The efficacy of IVIG was first proven in a trial The efficacy of rituximab, anti-CD20, was sug- of adult DM patients [63]. After three monthly gested in four JDM patients [69]. Recently the infusions, strength, neuromuscular symptoms, French Autoimmunity and Rituximab Registry skin rash and histopathological findings all reported on their small series of nine JDM improved. Recently Lam et al. reported the patients treated with rituximab. Rituximab efficacy of IVIG in 78 JDM patients, especially may be effective for treating muscle and skin in patients with steroid resistant disease [64]. involvement in a small subset of JDM patients Although patients treated with IVIG achieved with refractory disease, with a satisfactory quiescence later than controls in the unadjusted safety profile[70] . However, studies in adult DM ana­lysis, an effect was noted after the applied have been conflicting regarding the efficacy of bias reduction methods; corticosteroid-resistant anti‑CD20 treatment for DM, and a recent ran- patients, especially, showed marked improve- domized placebo phase trial, including patients ment over a prolonged follow-up. At our insti- with JDM, DM and polymyositis was not able tution, IVIG (2 g/kg/dose, maximum 70 g) is to prove a benefit [71]. Further studies into administered as a single infusion every 2 weeks efficacy and safety of rituximab in JDM are for the first five doses, and then generally necessary before firm conclusions can be made.

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Other immunosuppressive agents that than two affected organs, and disease duration have been used for disease control include of >4 years increased the risk of calcinosis and hydroxychlorquine and [72–75]. continuous muscle dysfunction [77]. The median disease duration was 13.9 years in this group of Course of disease & outcome 53 patients. A case–control study including 59 As discussed above, the outcome of JDM before JDM patients examined a median of 16.8 years corticosteroid therapy was introduced was after disease onset were compared with 59 age- poor. After the introduction, the mortality rate and sex-matched controls [52]. JDM patients were dropped below 10% and functional outcome weaker than controls based on muscle weak- has improved markedly. As previously discussed, ness/reduced endurance in 31–42% of patients delayed diagnosis and treatment appears to lead and MRI detected muscular damage in 52% to poorer outcome and more calcinosis [44]. The of patients. Active disease and muscle damage course of JDM can be variable and is divided present 1-year postdiagnosis were predictors for into monocyclic, chronic continuous or poly- poorer outcome. cyclic disease. Monocyclic disease occurs in approximately one-third of the patients and Conclusion permanent disease remission occurs within In the past decade important steps have been 2–3 years after onset [76]. Patients with a mono- made in the understanding of the pathogenesis cyclic disease course often have a good response and the treatment of childhood DM. Large to standard treatment. The remaining two- international multicenter collaborations have thirds of the patients have a chronic continuous been initiated and consensus treatment proto- disease course, which may include periods of cols are now available for use in daily clinical medication-controlled quiescence and periods of practice. These collaborations and protocols are flare[76] . In a Canadian cohort, 37% of patients necessary to get an even better understanding had a monocyclic disease, and the remainder of of the pathogenesis and to develop prediction patients had a chronic disease course; polycyclic models to tailor future treatment. Although out- disease (in which there is medication-free remis- come has improved drastically compared with sion followed by relapse) is distinctly unusual [76]. historic controls, a large number of patients still None of these patients reported interference of experience impairment years after disease onset. the disease in their ability to work. The median time to remission in this cohort was 4.67 years. Future perspective The presence of a persistent rash at 3 months Increased understanding of environmental risk was a predictor for a poorer outcome [76]. In a factors, genetic susceptibility and pathogenesis recent long-term follow-up study of 490 patients will lead to better understanding of the disease. with JDM, monocyclic disease was reported in This will lead to more tailored treatment options 41% of the patients and chronic polycyclic or and better long-term outcomes. continuous in 58.7% [46]. Poor outcome predic- tors included either a polycyclic or continuous Financial & competing interests disclosure disease course. Severe impairment was seen in The authors have no relevant affiliations or financial less than 10% of the patients, however, 40.7% of involvement with any organization or entity with a finan- the patients had decreased functional outcome. cial interest in or financial conflict with the subject matter The mortality rate was 3.1% [46]. In a cross- or materials discussed in the manuscript. This includes sectional follow-up study by Mathiesen et al. a employment, consultancies, honoraria, stock ownership or disease duration of >4 years increased the risk options, expert testimony, grants or patents received or of damage (predominantly cutaneous scarring pending, or royalties. 39.6% and muscle dysfunction 34%); disease No writing assistance was utilized in the production of onset age >7.4 years increased the risk of more this manuscript.

Executive summary ƒƒ Incidence of juvenile dermatomyositis is two to three per million children per year. ƒƒ Postmeiotic genetic events, different epigenetic modification, epistatic protein interactions and environmental exposure influences the disease pathology. ƒƒ Revised diagnostic criteria should include the use of muscle MRI and nailfold capillaroscopy. ƒƒ Treatment consensuses have been developed for juvenile dermatomyositis. ƒƒ Functional impairment is present in 50% of juvenile dermatomyositis patients years after disease onset.

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nn Important paper in the discussion to include 44 Bowyer SL, Blane CE, Sullivan DB, Cassidy 56 Huemer C, Kitson H, Malleson PN et al. MRI in the new diagnostic criteria. JT. Childhood dermatomyositis: factors Lipodystrophy in patients with juvenile predicting functional outcome and dermatomyositis – evaluation of clinical and 33 Schmeling H, Stephens S, Goia C et al. Nailfold capillary density is importantly development of dystrophic calcification. metabolic abnormalities. J. Rheumatol. 28, associated over time with muscle and skin J. Pediatr. 103, 882–888 (1983). 610–615 (2001). disease activity in juvenile dermatomyositis. 45 Blane CE, White SJ, Braunstein EM, Bowyer 57 Stringer E, Bohnsack J, Bowyer SL et al. Rheumatology (Oxford) 50, 885–893 (2011). SL, Sullivan DB. Patterns of calcification in Treatment approaches to juvenile childhood dermatomyositis. Am. J. dermatomyositis (JDM) across North nn Important paper in the use of nailfold Roentgenol. 142, 397–400 (1984). America: the Childhood Arthritis and capillary density at diagnosis and follow-up. 46 Ravelli A, Trail L, Ferrari C et al. Long-term Rheumatology Research Alliance (CARRA) 34 Butbul Aviel Y, Stremler R, Benseler AM et al. outcome and prognostic factors of juvenile JDM Treatment Survey. J. Rheumatol. 37, Sleep and fatigue and the relationship to pain, dermatomyositis: a multinational, multicenter 1953–1961 (2010). disease activity and quality of life in juvenile study of 490 patients. Arthritis Care Res. 58 Huber AM, Giannini EH, Bowyer SL et al. idiopathic arthritis and juvenile (Hoboken) 62, 63–72 (2010). Protocols for the initial treatment of dermatomyositis. Rheumatology (Oxford) 50, moderately severe juvenile dermatomyositis: 2051–2060 (2011). 47 Schwartz T, Sanner H, Husebye T, Flato B, Sjaastad I. Cardiac dysfunction in juvenile results of a Children’s Arthritis and 35 Tse S, Lubelsky S, Gordon M et al. The dermatomyositis: a case-control study. Ann. Rheumatology Research Alliance Consensus arthritis of inflammatory childhood myositis Rheum. Dis. 70, 766–771 (2011). Conference. Arthritis Care Res. (Hoboken) 62, syndromes. J. Rheumatol. 28, 192–197 219–225 (2010). (2001). 48 Eimer MJ, Brickman WJ, Seshadri R et al. Clinical status and cardiovascular risk profile nn Recommended treatment protocol for initial 36 Dugan EM, Huber AM, Miller FW, Rider of adults with a history of juvenile treatment of moderately severe juvenile LG. Review of the classification and dermatomyositis. J. Pediatr. 159, 795–801 dermatomyositis. assessment of the cutaneous manifestations of (2011). the idiopathic inflammatory myopathies. 59 Hasija R, Pistorio A, Ravelli A et al. Dermatol. Online J. 15, 2 (2009). 49 Fathi M, Dastmalchi M, Rasmussen E, Therapeutic approaches in the treatment of Lundberg IE, Tornling G. Interstitial lung juvenile dermatomyositis in patients with 37 Dugan EM, Huber AM, Miller FW, Rider disease, a common manifestation of newly recent-onset disease and in those experiencing LG. Photoessay of the cutaneous diagnosed polymyositis and dermatomyositis. disease flare: an international multicenter manifestations of the idiopathic inflammatory Ann. Rheum. Dis. 63, 297–301 (2004). PRINTO study. Arthritis Rheum. 63, myopathies. Dermatol. Online J. 15, 1 (2009). 3142–3152 (2011). 50 Fathi M, Lundberg IE, Tornling G. 38 Akikusa JD, Tennankore DK, Levin AV, Pulmonary complications of polymyositis and 60 Ramanan AV, Campbell-Webster N, Ota S Feldman BM. Eye findings in patients with dermatomyositis. Semin. Respir. Crit. Care et al. The effectiveness of treating juvenile juvenile dermatomyositis. J. Rheumatol. 32, Med. 28, 451–458 (2007). dermatomyositis with methotrexate and 1986–1991 (2005). aggressively tapered corticosteroids. Arthritis 51 Trapani S, Camiciottoli G, Vierucci A, 39 Ostrowski RA, Sullivan CL, Seshadri R, Rheum. 52, 3570–3578 (2005). Pistolesi M, Falcini F. Pulmonary Morgan GA, Pachman LM. Association of involvement in juvenile dermatomyositis: a 61 Seshadri R, Feldman BM, Ilowite N, normal nailfold end row loop numbers with a two-year longitudinal study. Rheumatology Cawkwell G, Pachman LM. The role of shorter duration of untreated disease in (Oxford) 40, 216–220 (2001). aggressive corticosteroid therapy in patients children with juvenile dermatomyositis. with juvenile dermatomyositis: a propensity Arthritis Rheum. 62, 1533–1538 (2010). 52 Sanner H, Kirkhus E, Merckoll E et al. score analysis. Arthritis Rheum. 59, 989–995 Long-term muscular outcome and 40 Savioli C, Silva CA, Fabri GM et al. Gingival (2008). predisposing and prognostic factors in capillary changes and oral motor weakness in juvenile dermatomyositis: a case–control 62 Hornung T, Ko A, Tuting T, Bieber T, Wenzel juvenile dermatomyositis. Rheumatology study. Arthritis Care Res. (Hoboken) 62, J. Efficacy of low-dose methotrexate in the (Oxford) 49, 1962–1970 (2010). 1103–1111 (2010). treatment of dermatomyositis skin lesions. 41 Goncalves LM, Bezerra-Junior JR, Clin. Exp. Dermatol. 37(2), 139–142 (2011). 53 Mamyrova G, Kleiner DE, James-Newton L, Gordon-Nunez MA, Liberio SA, de Fatima Shaham B, Miller FW, Rider LG. Late-onset 63 Dalakas MC, Illa I, Dambrosia JM et al. Vasconcelos Pereira A, da Cruz MC. Oral gastrointestinal pain in juvenile A controlled trial of high-dose intravenous manifestations as important symptoms for dermatomyositis as a manifestation of immune globulin infusions as treatment for juvenile dermatomyositis early diagnosis: ischemic ulceration from chronic dermatomyositis. N. Engl. J. Med. 329, a case report. Int. J. Paediatr. Dent. 21, 77–80 endarteropathy. Arthritis Rheum. 57, 881–884 1993–2000 (1993). (2011). (2007). 64 Lam CG, Manlhiot C, Pullenayegum EM, 42 Ichiki Y, Akiyama T, Shimozawa N, Suzuki 54 Feldman BM, Rider LG, Reed AM, Pachman Feldman BM. Efficacy of intravenous Ig Y, Kondo N, Kitajima Y. An extremely severe LM. Juvenile dermatomyositis and other therapy in juvenile dermatomyositis. Ann. case of cutaneous calcinosis with juvenile idiopathic inflammatory myopathies of Rheum. Dis. 70, 2089–2094 (2011). dermatomyositis, and successful treatment childhood. Lancet 371, 2201–2212 (2008). nn with diltiazem. Br. J. Dermatol. 144, 894–897 Important paper addressing the efficacy and (2001). 55 Rouster-Stevens KA, Gursahaney A, Ngai safety of intravenous immunoglobulin in the KL, Daru JA, Pachman LM. treatment of juvenile dermatomyositis. 43 Huber AM, Lang B, LeBlanc CM. et al. Pharmacokinetic study of oral prednisolone Medium- and long-term functional outcomes 65 Dagher R, Desjonqueres M, Duquesne A et al. compared with intravenous in a multicenter cohort of children with Mycophenolate mofetil in juvenile in patients with juvenile juvenile dermatomyositis. Arthritis Rheum. dermatomyositis: a case series. Rheumatol. Int. dermatomyositis. Arthritis Rheum. 59, 43, 541–549 (2000). 32(3), 711–716 (2010). 222–226 (2008).

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66 Rouster-Stevens KA, Morgan GA, Wang D, patients. Arthritis Rheum. 56, 3107–3111 73 Warde N. MF for juvenile dermatomyositis. Pachman LM. Mycophenolate mofetil: a (2007). Nat. Rev. Rheumatol. 6, 555 (2010). possible therapeutic agent for children with 70 Bader-Meunier B, Decaluwe H, Barnerias C 74 Hassan J, van der Net JJ, van Royen-Kerkhof juvenile dermatomyositis. Arthritis Care Res. et al. Safety and efficacy of rituximab in A. Treatment of refractory juvenile (Hoboken) 62, 1446–1451 (2010). severe juvenile dermatomyositis: results from dermatomyositis with tacrolimus. Clin. 67 Riley P, Maillard SM, Wedderburn LR, Woo 9 patients from the French Autoimmunity Rheumatol. 27, 1469–1471 (2008). P, Murray KJ, Pilkington CA. Intravenous and Rituximab registry. J. Rheumatol. 38, 75 Olson NY, Lindsley CB. Adjunctive cyclophosphamide pulse therapy in juvenile 1436–1440 (2011). use of in childhood dermatomyositis. A review of efficacy and 71 Oddis CV, Reed AM, Aggarwal R. dermatomyositis. J. Rheumatol. 16, safety. Rheumatology (Oxford) 43, 491–496 Rituximab in the treatment of 1545–1547 (1989). (2004). refractory adult and juvenile idiopathic 76 Stringer E, Singh-Grewal D, Feldman BM. 68 Riley P, McCann LJ, Maillard SM, Woo P, dermatomyositis (DM) and adult Predicting the course of juvenile Murray KJ, Pilkington CA. Effectiveness of polymyositis (PM) – the RIM study. dermatomyositis: significance of early clinical infliximab in the treatment of refractory Arthritis Rheum. 62(Suppl.), 3844 and laboratory features. Arthritis Rheum. 58, juvenile dermatomyositis with calcinosis. (2010). 3585–3592 (2008). Rheumatology (Oxford) 47, 877–880 (2008). 72 Ogimi C, Honma N, Tanaka R, Oh-Ishi T. 77 Mathiesen P, Zak M, Herlin T, Nielsen SM. 69 Cooper MA, Willingham DL, Brown DE, Mycophenolate mofetil therapy for juvenile Long-term outcome in patients with juvenile French AR, Shih FF, White AJ. Rituximab dermatomyositis with immune dermatomyositis: a cross-sectional follow-up for the treatment of juvenile thrombocytopenic purpura. Mod. study. Scand. J. Rheumatol. 41(1), 50–58 dermatomyositis: a report of four pediatric Rheumatol. 22(2), 280–283 (2011). (2011).

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