Clin Rheumatol (2014) 33:1675–1679 DOI 10.1007/s10067-014-2747-3
BRIEF REPORT
Mortality in children with juvenile dermatomyositis: two decades of experience from a single tertiary care centre in North India Surjit Singh & Deepti Suri & Roosy Aulakh & Anju Gupta & Amit Rawat & Rohit Manoj Kumar
Received: 24 March 2014 / Revised: 26 May 2014 / Accepted: 12 July 2014 / Published online: 23 July 2014 # International League of Associations for Rheumatology (ILAR) 2014
Abstract Survival and outcomes have improved considerably among patients with juvenile dermatomyositis (JDM) in the west. However, mortality continues to be high in the developing world. There is paucity of literature on this aspect of JDM from developing countries. We reviewed case files of all patients with JDM registered in the Pediatric Rheumatology Clinic, Advanced Pediatrics Centre at the Post Graduate Institute of Medical Education and Research, Chandigarh, during the period 1993–2013. Seventy-six children were diagnosed to have inflammatory myopathy during this period. Of these, 63 had JDM, 3 had polymyositis while 10 had an overlap syndrome. We had reported 2 deaths out of 33 (8.3 %) patients with JDM in 2004, and over the last 9 years, we have encountered five more deaths in this group, thereby accounting for a mortality rate of 11.1 % (7/63) over two decades of follow-up. In these five children now being described, the mean duration between onset of symptoms and institution of appropriate therapy was 9.2 months. Four children (80 %) had severe muscle weakness needing nasogastric tubes at the onset, three (60 %) had cutaneous ulcers and three (60 %) had superadded infections. Two children (40 %) had gastrointestinal vasculitis and one of these developed an intestinal perforation. Three patients (60 %) had progressive pulmonary disease and air leak was identified in two of them. Although the prognosis for survival in JDM has steadily improved, in S. Singh (*) : D. Suri : R. Aulakh : A. Gupta : A. Rawat Pediatric Allergy Immunology Unit, Department of Pediatrics, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India e-mail:
[email protected] R. M. Kumar Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
our experience the disease remains a serious illness and still carries significant mortality in the context of a developing country.
Keywords Children . Death . Inflammatory myopathy . Juvenile dermatomyositis . Mortality
Introduction Juvenile dermatomyositis (JDM) is an uncommon chronic inflammatory muscle disease, characterized by proximal muscle weakness, heliotrope rash and Gottron papules over the knuckles and elbows [1]. It can involve several other organ systems like the gastrointestinal tract, lungs and heart. Lipodystrophy with insulin-resistant diabetes is also a wellknown association [1, 2]. The primary lesion in JDM is a small vessel vasculopathy of varying severity. Unlike adults, in whom polymyositis (PM), inclusion-body myositis and cancer-associated myositis are common subsets of inflammatory myopathy, JDM remains the most common inflammatory myopathy in children [1]. In the pre-steroid era 1/3 children would die, 1/3 recovered and 1/3 of those who survived had significant residual problems of contractures and muscle atrophy [1, 3]. Over the last few decades, survival and outcome has improved considerably with aggressive immunosuppressive therapies. Mortality rate in children in the West is now reported to be less than 3 % [1, 4]. However, JDM is still associated with significant morbidity and mortality in our setting. We have recorded seven deaths among 63 (11.1 %) patients with JDM that we have managed during the period 1993–2013.
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Patients and methods
Patient 2: (2001–2007)
We reviewed case files of all patients diagnosed to have JDM and registered in the Pediatric Rheumatology Clinic, Advanced Pediatrics Centre of the Post Graduate Institute of Medical Education and Research, Chandigarh. Admission files and follow-up notes were analyzed for the purpose of the study. Our institute is a tertiary care referral center for North India. Diagnosis of JDM was based on Bohan and Peter criteria [1, 5, 6]. With easy accessibility and availability of magnetic resonance imaging (MRI) facilities in the institute since the year 2001, we have not been routinely performing muscle biopsy in these patients. Our treatment protocol is based on a standard regimen of glucocorticoids and methotrexate [1]. Of late, additional immunomodulation with rituximab and intravenous immunoglobulin has also been used in selected cases.
An 11-year-old boy was diagnosed as having JDM along with ventricular tachycardia in year 2001 [8]. Over 9 years of follow-up, he had a relapsing disease course and recurrent episodes of ventricular tachycardia. During his last relapse, he developed acute abdominal pain, perforation peritonitis and a massive gastrointestinal bleed and succumbed to it.
Results We diagnosed 76 children with inflammatory myopathy during the period January 1993–December 2013. Of these, 63 had JDM, 3 had polymyositis while 10 had an overlap syndrome. The total follow-up adds up to 256 patient years. We have recorded seven deaths during the study duration. Two out of these seven deaths have been reported by us earlier and are, therefore, excluded from this report [7]. In addition, five children with JDM were lost to follow-up; four out these five children did not report back after the initial few visits to the clinic, while one child’s parents opted to take therapy from another hospital. Of the five patients studied, there were three boys and two girls. Age of onset of disease ranged from 10 to 12 years. Mean duration between onset of symptoms and start of appropriate therapy was 9.2 months (range 1–24 months). Duration of treatment at our institute ranged from 1 month to 9 years. Brief case history and terminal events are described below and are summarized in Table 1. Patient 1: (2005) A 10-year-old girl presented with heliotrope rash and proximal muscle weakness for 4 months and a diagnosis of JDM was made. Pharyngeal weakness was also noted and nasogastric tube feeds were initiated. She received intravenous pulsed methylprednisolone for 3 days, followed by oral prednisolone and subcutaneous methotrexate. Three days following her discharge, she was brought to the Emergency Room with massive upper gastrointestinal bleed and suffered a cardiorespiratory arrest within a few minutes of arrival from which she could not be resuscitated.
Patient 3: (2005–2008) A 12-year-old boy, who had been unwell for 2 years, had presented with intermittent fever, malar rash, joint pains and increasing respiratory distress. A pneumothorax was detected at the referring hospital. At admission, he had respiratory distress and fine crepitations over both lung fields. He was also noted to have proximal muscle weakness, malar rash, Gottron papules and ulcers over elbows. MRI of thigh muscles showed diffusely increased T2-weighted signal intensity. High-resolution CT scan (HRCT) of chest showed features of right-sided bronchiolitis obliterans with organizing pneumonia (BOOP) and left lower lobe collapse consolidation. He was given pulse methylprednisolone along with antimicrobials. However, the pulmonary symptoms gradually worsened. He developed another pneumothorax while being ventilated and died. Patient 4: (2008–2009) In the year 2008, a 10-year-old boy was referred to our hospital for worsening respiratory distress. He had been diagnosed to have JDM at another centre 1 year ago when he had presented with prolonged pyrexia, muscle weakness, photosensitive malar rash, Gottron papules and ulcers over bony prominences. He had received intravenous methylprednisolone and subcutaneous methotrexate. A few months later, he had started having cough and progressive breathing difficulty. Chest radiographs revealed bilateral alveolar opacities and sputum smear examination yielded acid fast bacilli. Sputum culture was, however, sterile. Anti-tubercular therapy was initiated. At admission to our hospital, he was pale, cyanosed and hypoxic (SpO2 85 %). He had poor chest expansion and fine basal end inspiratory crepitations. Muscle mass was reduced and muscle power at shoulder and hip joint was 3/5. Flexors of neck were also weak. A clinical possibility of JDM was considered. HRCT scan chest showed diffuse ground glass opacities with patchy interlobar septal thickening and peri-bronchial thickening. Work up for tuberculosis was noncontributory. Echocardiography revealed mild pulmonary arterial hypertension and tricuspid regurgitation. A lung biopsy was planned but could not be performed as he developed high grade fever. Broad spectrum antimicrobial therapy was given but the respiratory status continued to worsen. He was put on
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Table 1 Clinical features, treatment given and terminal events of patients with JDM S. no. Age in years Duration of symptom Age in years Duration of Type of disease Drugs used at onset/sex in months prior at time of death therapy in months to treatment 1. 2.
10/F 11/M
4 5
10 20
1 108
First episode Relapsing
3.
12/M
24
14
24
Progressive
4.
10/F
12
11
12
5.
12/M
1
12
3
Monocyclic, progressive Monocyclic
Terminal events
MP, MTX P, MTX,
Upper gastrointestinal bleeding Recurrent ventricular tachycardia, intestinal perforation abdominal vasculitis MP, MTX BOOP, pneumonia with pneumothoraxa MP, MTX, ATT ILD, pneumonia MP, MTX
ILD, pneumothoraxb
MP methylprednisolone, MTX methotrexate, P prednisolone, ATT anti-tubercular therapy, BOOP bronchiolitis obliterans-organizing pneumonia, ILD interstitial lung disease a
Two episodes of pneumothorax: at first spontaneous and then, while on ventilator
b
Spontaneous pneumothorax
mechanical ventilation but continued to have refractory hypoxia and died. Patient 5: (2010–2011) A 12-year-old boy had presented with fever, pain, and weakness in limbs for 2 months. He had periorbital edema and erythema, Gottron papules, ulcers over elbows, weakness of neck flexors and proximal muscles. A diagnosis of JDM was made and he received pulses of methylprednisolone along with subcutaneous methotrexate. He showed marked improvement and was soon ambulatory without support but had to be readmitted 2 months later with insidious onset of dyspnoea for 20 days. He had also developed high grade fever and breathlessness. The ulcer over the elbow had reappeared. He then developed left-sided pneumonia with pneumothorax and extensive subcutaneous emphysema. HRCT chest showed evidence of interstitial lung disease (ILD). The air leak was drained and he was ventilated. Despite respiratory and hemodynamic support, his condition deteriorated and he died.
Discussion Before the use of corticosteroids, the prognosis for JDM was extremely poor, with mortality rates as high as 40 % having been reported [3, 9, 10]. However, with advances in management, mortality rates are now in the range of 1–3 % [1, 4]. Functional outcomes have also improved with only 8 % children developing moderate to severe disability [11]. Improved survival rates amongst children in Western countries are largely because of early institution of glucocorticoid therapy, use of
adjunctive medication (e.g. methotrexate), better clinical assessment and appropriate management of complications [12]. However, amongst adults, the response to therapy is less promising and mortality rates as high as 16–27 % continue to be reported [13–18]. Recent data suggest that only 20–40 % of adult patients who receive therapy achieve remission and almost 80 % of treated patients remain functionally disabled [13, 19]. Mortality rates in children with JDM continue to be high in our setting. We had reported 2 deaths out of 33 patients (8.3 %) in 2004, and over the last 9 years, we have encountered five more deaths amongst these patients, thereby accounting for a mortality rate of 11.1 % over two decades of follow-up [7]. Delays in diagnosis and treatment, late referrals, poor drug compliance (at times due to financial constraints) and increased risk for infections are major factors which contribute to an unfavourable disease outcome in our setting [7, 20]. Mean duration from onset of symptoms and institution of appropriate therapy was 9.2 months in our cohort. Other factors contributing to mortality were severe muscle weakness at presentation (4/5) and superadded infection (3/5). Important causes of death in JDM are vasculopathic complications (e.g. gastrointestinal vasculitis), interstitial pneumonitis, aspiration pneumonia, progressive unresponsive myositis, myocarditis and inter-current infections [20–23]. Table 2 shows a comparison of previous reports on the subject with the present series. Among the five deaths now being reported, two children (40 %) had significant gastrointestinal manifestations and one of these developed an intestinal perforation terminally. Three patients (60 %) had progressive pulmonary disease and air leak was identified in two of them.
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Table 2 Comparison of frequency and causes of mortality in pediatric case series on JDM reported in literature Authors
Study duration
No of deaths out of total cohort
Comments/causes
Miller et al. [9]
1962–1982
10 deaths out of 39 children (26 %)
Sullivan et al. [21] Ann Arbor series
1977
6 deaths out of 71 children (8.4 %)
Spencer et al. [22]
1984
7 deaths out of 66 children (10.6 %)
Huber et al. [11]
1984–1995
1 death out of 80 patients (1.25 %)
8 of these children were seen before 1972 and had not received glucocorticoids. No child who had received intensive glucocorticoid treatment died. All deaths were associated with bowel perforation or aspiration pneumonitis and occurred after average of 2.5 years after onset Cardiorespiratory collapse (1),gastrointestinal hemorrhage (3), subdural hematoma caused by a fall from a wheelchair (1), respiratory insufficiency(1). Sepsis (1), gastrointestinal perforation (2), unresponsive muscle weakness and pneumonitis (2), pulmonary fibrosis with cor pulmonale 9 years after disease onset (1), and suicide 16 years after onset (1) Myocardial infarction(1); median follow-up 7.2 years Median follow-up 3 years Outcome data between 2003–2006
Ponyi et al. [23] Ravelli et al. [4]
2005 1980–2004 . Pediatric case series from India Choudhary et al. [20] 1989–2001 India Singh et al. [7] 2004 India Current report 1993–2013
No deaths out of 36 children (0 %) 14 deaths out of 490 children (2.8 %)
No deaths out of 19 patients (0 %)
Median follow-up 12 months (range 2–96 months)
2 deaths out of 33 patients (8.3 %) 7 deaths out of 63 patients (11.1 %)
Gastrointestinal manifestations of JDM include dysphagia, bowel dysmotility and vasculitis with associated malabsorption [24]. Gastrointestinal ulceration is considered to be characteristic of JDM-associated vasculopathy and occasionally may lead to intestinal perforation and even pneumatosis intestinalis [25–27]. Abdominal pain in a patient with JDM which is persistent, progressive or severe should, therefore, not be disregarded and needs careful evaluation for associated vasculopathy. It is also important to realize that these abdominal findings can occur any time in course of illness, even when the underlying myositis is improving or only mildly active [28]. Further, gastrointestinal symptoms can be masked by use of glucocorticoids. The latter may also contribute to gastrointestinal ulceration and bleeding [29]. We observed that patient 1 had a massive upper gastrointestinal haemorrhage early in her course of disease and she died even before appropriate resuscitation efforts could be instituted. She was receiving oral prednisolone at that time. This could have aggravated the bleed. Patient 2 developed intestinal perforation in hospital while getting therapy for relapse of muscle disease. Although aggressive surgical intervention can sometimes be life-saving in such situations, this was not a suitable option in our patient due to the moribund condition [30, 31].
Including 2 previously reported patients
Pulmonary complications associated with JDM include ILD, diffuse alveolar damage and BOOP [32, 33]. ILD is uncommon in children but carries a poor prognosis. In the present series, two children (patient 4 and patient 5) had ILD while patient 3 had BOOP. Their clinical course was complicated by frequent flare of respiratory symptoms and repeated chest infections. Two of these children [patient 3 and patient 5] also had a pneumothorax. Air leak has been reported as a rare complication of JDM [33–35]. Risk factors for developing air leak include interstitial lung disease, presence of cutaneous vasculopathy and steroid use [36, 37]. Incidentally, we have noted that all the three children who had significant pulmonary complications also had cutaneous ulcers. Cardiac complications are said to be extremely rare in JDM in children. However, subclinical involvement may not be uncommon [38, 39]. We encountered an unusual clinical presentation of recurrent ventricular tachycardia in a child with relapsing JDM (patient 2) [8]. Huber et al. have also reported a young girl with JDM who died from a myocardial infarction [11]. To conclude, although the prognosis for JDM has steadily improved over the years, in our experience, the disease remains a serious illness and still carries significant mortality at
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least in the context of a developing country. This is the largest database applicable in a developing country setting.
Conflict of interest We certify that there are no competing or financial interests or commercial considerations with regard to this manuscript.
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