Research Article
Juvenile Dermatomyositis in Iranian Children; a Case Series Report Reza Shiari1- 2, Azadeh Kiumarsi1, Fatemeh Adibe Eshgh1, Mohammad Mahdi Allameh1
1 Division of Pediatric Rheumatology, Mofid Children’s Hospital, Shahid Behshti University of Medical Sciences; 2 Pediatric Infectious Research Center (PIRC), Tehran, Iran
Corresponding author: Reza Shiari, Shariati Ave, Hosseinieh Ershad, 1546815514, Tehran, Iran. e-mail:
[email protected] Received: October 09, 2011 Accepted: December 01, 2011 Ann Paediatr Rheum 2012; 1: 58-64 DOI: 10.5455/apr.120120111140
Abstract Objective: Juvenile dermatomyositis (JDM) is the most common inflammatory myositis in children, distinguished by proximal muscle weakness and a characteristic rash. Underlying pathology in this disorder is infiltration of inflammatory cells in microscopic vessels of muscles and skin resulting in vascular inflammation. Extramuscular manifestations include joint contracture, dysphagia, cardiac disturbances, pulmonary symptom and subcutaneous calcifications. The study describes the clinical features and outcomes of juvenile dermatomyositis (JDM) in Iranian children and compares these with findings reported by similar studies from other parts of the world. Methods: We retrospectively studied 14 patients diagnosed with juvenile dermatomyositis in accordance with the Bohan and Peter’s diagnostic criteria during a period of 7 years. Results: Average onset age was 7 years. Muscle weakness occurred in 85%; heliotrope rash 57%; Gottron papules 35%, calcinosis 14.2%; and 74.9% had at least one abnormal muscle enzyme result. Muscle biopsy and electromyogram were abnormal in 90.9% and 85.7% of cases, respectively. All patients received corticosteroids; some patients were also treated with one or more of the following medications: methotrexate, hydroxychloroquine, IV immunoglobulin, or cyclosporin. Conclusion: This study indicates that early diagnosis and aggressive treatment is highly successful in minimizing the long term sequelae of JDM, including calcinosis. Key words: Juvenile dermatomyositis, inflammatory myositis, calcinosis, heliotrope rash, gottron papules
Introduction Juvenile dermatomyositis (JDM) is a rare, potentially life-threatening systemic autoimmune vasculopathy of the skin and muscle and is the most common idiopathic inflammatory myositis
in children causing symmetric proximal weakness and a characteristic skin rash [1]. In children, the annual incidence is 2-3 per million [2, 3]. Although rash and muscle weakness of specific distribution are the most important diagnostic clues, JDM has
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Juvenile Dermatomyositis in Iranian Children
extramuscular manifestations which may involve the gastrointestinal tract, myocardium, joints and lungs [4-6]. Diagnosis of dermatomyositis requires the presence of characteristic rash as well as at least three signs of muscle inflammation and weakness. Diagnosis is often delayed because of the insidious nature of disease onset [5, 6]. However, in children with amyopathic dermatomyositis which is a rare form of JDM, the patients show skin rash of JDM without apparent muscle inflammation [7]. Early diagnosis and aggressive treatment can lead to remission and prevention of severe complications [8, 9]. In this retrospective study we reviewed the clinical, laboratory, and pathological features and outcome of Iranian children with JDM treated at our referral children hospital over the last 7 years and compared them with other studies.
Methods We reviewed the records of 14 patients diagnosed as having JDM in the rheumatology unit of a referral hospital in Iran from 2005 until 2011. The diagnosis of JDM was in accordance with Bohan and Peter’s diagnostic criteria [10, 11], i.e. presence of characteristic rash as well as at least three signs of muscle inflammation and weakness; symmetric proximal muscle weakness, increased muscle enzymes (Creatine kinase, Aspartate aminotransferase, Lactate dehydrogenase, Aldolase), myopathic changes on electromyography, and typical histological findings on muscle biopsy. We gathered the following data from each patient’s records: gender, age, presenting symptoms and clinical features, time to diagnosis (duration between onset of symptoms and diagnosis), presence of extramuscular manifestations such as joint contractures, dysphagia, cardiac disturbance, pulmonary symptoms, and subcutaneous calcifications, laboratory values at time of diagnosis, electrophysiological study findings and muscle biopsy results, disease course, duration of follow-up, treatment, outcome, and complications. Laboratory findings included creatine kinase (CK), aspartate aminotransferase (ALT or SGOT) and alanine aminotransferase (AST or SGPT), lactate dehydrogenase (LDH), white blood cell (WBC) counts, hemoglobin (Hgb), erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), Anti dsDNA, Anti JO-1 Ab, rheumatoid factor (RF) and urinalysis. DOI:10.5455/apr.120120111140
Results We studied the records of 14 patients admitted to Mofid Children’s Hospital during the study period; 7 males and 7 females, (M:F=1:1). The mean age of disease onset was 7 years with a range between 2 to 13years. The average duration of disease before diagnosis was 2.5 months ranging between 10 days to 9 months. Onset of symptoms occurred during the winter (n=2), autumn (n=1), summer (n=7) and spring (n=2). The season in which symptoms appeared in 2 patients could not be determined. Follow-up duration was ranged between 1 and 6 years (mean 36 months) (Table-1). Table 1. Laboratory findings in Iranian patients with Juvenile dermatomyositis Patients
CPK
LDH
SGOT
SGPT
CRP
ESR
1
2700
3126
2
8700
504
3
354
4 5
ANA
193
301
2+
55
-
95
119
-
3
-
1468
70
33
-
8
-
8310
1882
173
261
-
21
-
106
704
24
37
-
24
-
6
45
310
26
21
-
8
-
7
1190
1456
170
310
3+
81
-
8
1800
1220
97
38
-
53
-
9
290
1187
380
173
-
102
-
10
188
773
41
25
-
45
-
11
320
724
76
29
-
35
-
12
120
793
32
24
3+
18
+
13
30
463
15
13
1+
61
-
14
3250
646
150
55
-
60
-
Two of 14 patients, (14.2%) presented with fever in the range of 38 0C to 40 0C; in 11children, (78.5%) early fatigue was the initial symptom; in another 11 cases the disease started with generalized weakness and in 3 patients, (21.4%) the presenting symptom was myalgia. In 10 patients (71.4%) the first clinical manifestation was cutaneous (i.e. Periungual erythema, heliotrope (reddish purplish) rash over the upper eyelid, Gottron sign over the dorsal aspect of several of the metacarpalphalangeal and interphalangeal joints) (Table-1). On physical examination, 92.8% of patients revealed evidence of symmetrical proximal muscle weakness. None showed decreased force in facial, extraocular or neck extensor muscles. Dermatological signs were dominated by heliotrope rash in 8 (57%), Gottron´s papules in 5 (35%) and nonspecific www.aprjournal.org
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rashes in 1 (7.1%) of patients. Eye examination was normal in all our cases. In the follow up visits, 2 patients (14.2%) showed dysphagia. Subcutaneous calcinosis was detected in 2 patients, (14.2%). Pathological proteinuria was not detected in any child. Skin and soft-tissue infections in the form of perianal abscess occurred in one patient, obesity in 2, depression in 1, osteoporosis in 2, and contracture in 1. Although 2 children, (14.25%) had respiratory symptoms including cough and dyspnea on exertion, chest radiography and lung volume spirometry were normal in all patients. Cardiac involvement was noticed in one of the patients who had a mild TR in echocardiography. One patient had overlap syndrome with psoriatic arthritis and one patient developed autoimmune hepatitis during follow-up. Table 2. Clinical characteristic of patients with juvenile dermatomysositis
Electromyography (EMG) was done in all patients and was indicative of a myopathic pattern in 85.7% of cases. Surgical biopsy of the Quadriceps muscle was taken in 11 (78.5%) patients; it revealed focal necrosis and phagocytosis of muscle fibers, fiber regeneration, endomysial proliferation, inflammatory cell infiltrates and vasculitis in 90.9%. Table 3. Medications used in patients with juvenile dermatomysositis
1
9/Female
6
2
Winter
Rash/ Weakness
2
12/Female
4
3
Winter
Muscle pain
3
13/Male
2
5
Spring
Rash/ Weakness
M-PSL 30mg/kg/pulse
HCQ 6mg/kg/day
MTX 15mg/m2/week
CSA 3-7mg/kg/day
IVIG 2gr/kg/month
Follow Season of Up Presenting complaint onset (Years)
PSL 1-2mg/kg/day
Duration before diagnosis (Month)
Eight patients were tested for specific antibodies; antinuclear antibodies were seen in only one of them (7.1%), rheumatic factor and Anti dsDNA was detected in none, Anti Jo-1 was detected in 7.1% of patients and complements were normal in all of them.
Patients
Age at onset Patients (Years)/Sex
elevated in 85.7% and creatininine phosphokinase (CPK) in 64.2%. The mean±SD level of CPK and LDH were 1957±2900 IU/l (range 30-8700 IU/l) and 1090±740 IU/l (range 3103126 IU/l), respectively. The mean±SD level of SGOT and SGPT were 110±98 IU/l (range 15-380 IU/l) and 293±64 IU/l (range 13-310 IU/l), respectively. Urine analysis, Blood urea nitrogen and creatinine were within normal range in all patients (Table-2).
4
7/Male
1
1
?
Weakness/Edema
1
+
+
+
+
-
-
Rash
2
+
-
+
+
-
-
5
9/Female
7
4
Summer
6
12/Female
4
4
Summer
Weakness
3
+
+
+
+
-
-
7
11/Female
5
6
Spring
Weakness
4
+
+
+
+
+
+
8
2/Female
1
1
Autumn Rash/Weakness/Edema
5
+
+
+
+
-
+
9
6/Male
0.3
2
Summer
Rash/Weakness/Fever
6
+
+
+
+
-
-
+
-
-
-
+
+ +
10
3/Female
?
2
?
Rash/Weakness
7
11
2.5/Male
1
2
Winter
Rash/Weakness
8
+
+
+
+
-
12
11/Female
1
3
Summer
Rash/Weakness
9
+
+
+
+
-
-
+
+
+
+
+
+
13
4.5/Male
4
2
Summer
Rash/Weakness/Fever
10
14
4/Male
1
5
?
Rash/Weakness
11
+
-
-
+
-
-
12
+
+
+
-
+
-
13
+
-
-
+
-
-
14
+
+
+
+
-
-
At the time of admission, the mean ±SD WBC counts were 8285±3975/mm3 (range 4800-21100/mm3). The mean ±SD level of Hgb was 12.2±1.7 g/dl (range 10.1-15.1). The mean ±SD level of ESR was 41±29.5 mm/h with a range of 3-102 mm/h. Serum Lactate dehydrogenase, (LDH) was Annals of Paediatric Rheumatology
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Oral prednisolone was prescribed for all patients in a daily dose of 1-2mg/kg. In 11 patients who had significant skin rash, hydroxychloroquine sulfate was added at a dose of 6.5 mg/kg/day. 12 patients were given intra-muscular methotrexate (10 -15mg/m2/week) as well. Three days pulses of intravenous (IV) methylprednisolone were given to 10 patients, (71%) with extensive skin rash and whose muscle strength had not improved enough, and 4 (28%) were given cyclosporin A. For 5 patients intravenous immunoglobulin, (IVIG) was started as a steroid sparing agent with a dose of 2g/kg initially every month for 6 months and then every other month for six courses. These patients exhibited a good response at follow up visits (Table-3).
quent in the winter [18]. There are some publications which have described the onset of JDM occurring more frequently in the winter and spring [19, 20].
All patients were followed up, the average duration being 36 months. At the last follow-up, 11 children (78.5%) were in remission and 2 patients (14.2%) had partial improvement. One patient in our study died because of massive gastrointestinal bleeding, seizure and loss of consciousness. This case had been referred to out-patient clinic of rheumatology 9 months after disease onset.
Rash develops as the first symptom in 50% of cases and appears concomitant with weakness only 25% of the time. The characteristic heliotrope rash is a blueviolet discoloration of the eyelids that may be associated with periorbital edema. Classic Gottron papules are bright pink or pale, shiny, thickened or atrophic plaques over the PIP joints and DIP joints and occasionally on the knees, elbows, small joints of the toes, and ankle malleoli [1]. In our study, dermatoligical signs were dominated by heliotrope rash (57%), Gottron´s papules (35%) and nonspecific rashes (7.1%). In Saudia Arabia, heliotrope rash was detected in 52% of cases and Gottron papules in 60% [25].
Discussion Juvenile dermatomyositis is a multisystem-likely autoimmune-disease of unknown etiology that results from inflammation of the small vessels of the muscle, skin, gastrointestinal (GI) tract, and other organs. It has an incidence of 2-3 per 1,000,000 per year [12-15]. According to our findings, sex-ratio was (M/F) 1:1. However, It is reported by Mastaglia et al. that females outnumber males by 2: 1 [16, 17], and more over a study in Turkey also showed female predominance [18]. In another study from France male to female ratio was 0.75 [21]. Peak age of disease onset is between 4 and 10 yr. There is a second peak of dermatomyositis onset in late adulthood (45-64 yr), but adult-onset dermatomyositis appears to be a distinctly separate entity in prognosis and etiology. The mean age of disease onset in our study was 7 years which is similar to other studies [16-18]. In our study, the onset of symptoms was more frequent in the summer season. Nevertheless, in the study done by Tulpar et al. in Turkey the occurrence of symptom was more freDOI:10.5455/apr.120120111140
Children with JDM present with either rash, insidious onset of weakness, or both. Fevers, dysphagia or dysphonia, arthritis, muscle tenderness, and fatigue are also commonly reported at diagnosis. In our findings, early fatigue (78.5%), muscle weakness (78.5%) and cutaneous manifestations (71.4%) were the most common clinical features of the disease. Myalgia (21.4%) and fever (14.2%) were not common. In studies from India, Hungaria, America and Saudi Arabia, all of patients suffered from symmetrical proximal muscle weakness [22, 23, 25, 26].
Cardiac involvement is rare in JDM. Only one of our patients had TR in his echocardiography and no cardiac symptoms were detected. In one study, three patients had tachycardia among 35 patients with JDM [26]. Heart murmurs, pericarditis, and electrocardiogram (ECG) abnormalities are also seen in JDM [27]. Esophageal symptoms occur in 6-41% of patients with JDM [28]. In the follow up visits, 2 patients (14.2%) showed dysphagia, the same as Turkish study [18]. The rash of JDM is sometimes mistaken for eczema or psoriasis. One of our patients presented with a psoriatic rash and the skin biopsy confirmed the diagnosis of psoriasis but after about a year the patient developed muscle weakness. The muscle biopsy showed evidences of JDM. It seems to be an overlap syndrome between these two diseases. www.aprjournal.org
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Calcinosis is reported in up to 30% of children with JDM, but the prevalence is thought to be lower in children who are treated early and aggressively. Subcutaneous calcinosis was detected in (14.2%) of our patients, one of these 2 patients were referred to us from another center after about a year of unsuccessful treatment and the other developed calcinosis in the third year of his treatment. Infection may have had a triggering effect on the calcinosis development in this patient. However, delay in diagnosis was associated with calcinosis. Tendency toward infection may increase due to JDM itself and also because of treatment with immunosuppressive agents. Skin-subcutaneous infection developed in two cases of the Turkish study [18]. Perianal abscess occurred in one of our patients. Obesity, depression, osteoporosis, and contracture were the complications detected on follow-ups of our patients similar to other studies [18, 22, 23]. WBC, hemoglobin and ESR were normal in most of our cases. Similar to other studies serum levels of muscle enzymes were elevated in our patients as well [18, 19, 22-26]. In contrast to a study from the US where antinuclear antibodies were present in 43% of patients with JDM, ANA was positive in only one of our cases [29]. Anti Jo-1 was detected in 7.1% of our patients but none of the other studies reported this finding. Unlike in adults with JDM, presence of myositisspecific autoantibodies (MSAs) is rare in children; positive test results for anti-Jo-l, anti-Mi-Z, and other MSAs may portend more significant disease. Electromyography was indicative of a myopathic pattern in 85.7% of our cases and 90.9% of our patients revealed inflammatory myopathic changes in muscle biopsy. In Spain report all of cases who had EMG, demonstrated myopathic changes in muscle biopsy [30]. Another study in America revealed that 19% of patients had normal EMG [20]. Corticosteroids are the mainstay of treatment in JDM [1] and were started soon after diagnosis in all our patients. Hydroxychloroquine and methotrexate was added to the regimen in most of our patients. Intravenous immunoglobulin, mycophenolate mofetil, cyclosporine, and cyclophosphamide are considered to be beneficial in severe unresponsive disease [1]. Among our patients 4 (28%) were given cyclosporin A, 5 patients received intravenous gammaglobulin (IVIG), for only one of the patients mycophenolate mofetil Annals of Paediatric Rheumatology
was prescribed, and none were given cyclophosphamide. In a study by Heckmatt et al. in fourteen children with JDM who had not responded fully to steroids and other immunosuppressants and who had had chronic active disease for an average of 3 years were successfully treated with cyclosporine. As in what we interpreted in our study, a low dose of cyclosporin (2·5-7·5 mg/kg daily) was sufficient and no serious side-effects in other studies [31]. Nine children attending to a dermatomyositis clinic who have been treated with intravenous immunoglobulin were studied by Sansome et al. All nine showed clinical improvement at some point in their treatment with intravenous immunoglobulin [32]. The mortality rate in JDM has decreased since the advent of corticosteroids, from 33% to currently about 1% [1-3]. Nonwhite adult females have the highest mortality, while children with inflammatory myositis have a low mortality rate [24]. We had one case of mortality among one of our male patients. Within the follow up period, 78.5% of our cases were in remission and 14.2% had had partial improvement. In one study, 63.6% of juvenile DM patients achieved remission whereas 36.3% partially improved and no patient was bedridden [2]. Similar findings were achieved in other studies [2, 25]. The limitations of this study were the low number of patients and the fact that the study was done in only one referral hospital. Multicenter studies could be more informative.
Conclusion Muscle weakness and skin rashes should be considered significant in children given that early diagnosis and aggressive treatment directed at achieving rapid and complete control of muscle inflammation is highly successful in minimizing the long term sequel of JDM, including calcinosis. Competing interests: The authors declared no competing interest. Funding: None. Provenance and peer review: Not commissioned; externally peer reviewed.
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