Rheumatol Int (2017) 37:1513–1517 DOI 10.1007/s00296-017-3770-x
Rheumatology INTERNATIONAL
EPIDEMIOLOGY OF RMD
Phenotypic characteristics and outcome of juvenile dermatomyositis in Arab children Sulaiman M. Al‑Mayouf1,7 · Nora AlMutiari1 · Mohammed Muzaffer2 · Rawiah shehata3 · Adel Al‑Wahadneh4 · Reem Abdwani5 · Safia Al‑Abrawi6 · Mohammed Abu‑shukair4 · Zeyad El‑Habahbeh4 · Abdullah Alsonbul1
Received: 16 December 2016 / Accepted: 29 June 2017 / Published online: 6 July 2017 © Springer-Verlag GmbH Germany 2017
Abstract This study describes the disease characteristics and outcome of Arab children with juvenile dermatomyositis (JDM) and compares the findings with other ethnicities. We retrospectively reviewed the hospital registries of the participating hospitals for children with JDM seen between 1990 and 2016 in three Arab countries. All patients fulfilled Bohan and Peter criteria for JDM, diagnosed before 14 years of age and were of Arab ethnicity. Clinical and laboratory features as well as the long-term outcomes including accrual disease damage were collected at the last follow-up visit. A total of 92 JDM patients (58 girls) were included. Mean age at the onset was 6 ± 3 years, with a mean follow-up duration of 5 ± 4.4 years. Fortythree patients (46.7%) had polycyclic disease course, 34 (36.9%) had a monocyclic course, while 15 (16.3%) had a continuous progressive course. Forty-five patients (48.9%) had arthritis, 14 (15.2%) patients had an upper airway and dysphagia, and 10 patients (10.9%) had lung involvement. Eight patients (8.7%) were admitted to the intensive care unit (ICU), 4 of them required mechanical ventilation. Methotrexate had been the most frequently used * Sulaiman M. Al‑Mayouf
[email protected] 1
Consultant and Section Head, Rheumatology, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Po Box 3354, Riyadh 11211, Saudi Arabia
2
King Abdulaziz University Hospital, Jeddah, Saudi Arabia
3
Maternity-Children Hospital, Jeddah, Saudi Arabia
4
Queen Rania Children Hospital, Amman, Jordan
5
Sultan Qaboos University Hospital, Muscat, Oman
6
Royal Hospital, Muscat, Oman
7
Pediatrics, Alfaisal University, Riyadh, Saudi Arabia
immunosuppressive drug (86%) and rituximab was used in eight patients. Additionally, 31 patients received IVIG. Most of the patients achieved a complete clinical response, but 16 ended up with permanent skin changes and 12 had a residual muscle weakness. Twenty-seven patients developed calcinosis. There were two deaths due to infection during the follow-up period. We report the largest phenotypic data on Arab children with JDM. Our patients have similar characteristics to previously described cohorts. Majority of the patients remained with inactive disease. Keywords Juvenile dermatomyositis · Outcome · Calcinosis · Disease damage · Arab
Introduction Juvenile dermatomyositis (JDM) is a systemic inflammatory disease affecting primarily the skin and muscles. JDM is the most frequent form of the juvenile idiopathic inflammatory myopathies with annual incidence ranging from 2 to 4 cases per million with racial difference [1–3]. Diagnosis of JDM is usually established based on the presence of inflammatory proximal muscle weakness and characteristic skin lesions [2, 4]. Patients sometimes presented with other manifestations, such as fatigue, fever, arthritis, abdominal pain, gastrointestinal tract bleeding, and interstitial pneumonitis [5, 6]. The disease course is variable and several clinical courses have been recognized; it can be either monocyclic, polycyclic or chronic continuous based on clinical and laboratory remission with 2 years of diagnosis [5, 7]. With the advanced therapeutic approach, mortality has now declined. Furthermore, functional outcomes have improved considerably among JDM
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patients. However, calcinosis remains a frequent long-term complication [8–10]. The clinical manifestations of JDM have been extensively described from different country groups [9, 11–14]. However, there is a paucity of data on this aspect from developing countries, particularly the Arab countries [15]. The purpose of this study was to describe the clinical features, course, and outcomes of Arab children with JDM seen in five six rheumatology clinics from three Arab countries and to compare them with the other series from different countries.
Methods This was an observational retrospective longitudinal study from the first to last visit of all children with JDM followed between 1990 and 2016 at five pediatric rheumatology clinics in three Arab countries. The participating hospitals were King Faisal Specialist Hospital-Research Center, Riyadh, Saudi Arabia; King Abdulaziz University hospital, Jeddah, Saudi Arabia; Maternity and Children hospital, Jeddah, Saudi Arabia; Queen Rania Children’s hospital, Amman, Jordan; Sultan Qaboos University hospital and Royal hospital, Muscat, Oman. All patients with JDM were retrieved from the registries of the participating hospitals. The records of patients were selected if they fulfilled the Bohan criteria and were of Arab ethnicity. Patients were excluded if they had lupus, mixed connective tissue disease, and overlap syndrome or neurological disorders. Medical records of all enrolled patients were reviewed at the last follow-up visit for demographic data, age at presentation, disease duration, follow-up duration, clinical and laboratory findings, treatment as well as outcomes. Disease duration was calculated from the onset of first symptom related to JDM. Follow-up length was considered from the date of the first clinic visit. Patients are usually seen every 3–6 months with a thorough physical examination in addition to appropriate laboratory evaluation and treatment adjusted as needed. To evaluate the long-term assessment and outcome at the last clinic visit, we considered the following measures: disease activity as per physician’s and parent’s global assessment, muscle strength, muscle enzymes using the PRINTO criteria [16], accrual disease damage, particularly calcinosis, chronic cutaneous changes, growth, lipodystrophy, respiratory failure, bowel perforation, severe osteoporosis/fracture, and death related to JDM. All collected data were the result of routine medical procedure and extracted from the patient’s file. Research affairs council at King Faisal Specialist Hospital-Research Center and other collaborative hospitals approved the study.
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The results are expressed as mean ± standard deviation (SD) for continuous variables and percentages for categorical variables.
Results A total of 92 JDM patients were enrolled; most of them were from Saudi Arabia (67%), whereas the numbers of patients from Jordan (17%) and Oman (16%) were comparable. Results are presented in Tables 1, 2, and 3. There were more girls (63%) in the study population than boys. The mean age at onset was 6 ± 3.0 years, whereas the mean age at diagnosis was 6.6 ± 3.0 years and the mean period to diagnosis was 1.5 ± 5.6 years. Most of the patients had regular follow-up with mean of 5 ± 4.4 years. Fifty-three patients had active follow-up, 27 patients transferred to adult rheumatology service, and 12 patients had lost followup. Forty-three patients had a polycyclic disease course, 34 patients had a monocyclic course, while 15 patients had continuous progressive course. All patients had muscle weakness and skin manifestations; the most common cutaneous findings were Gottron’s papules followed by a heliotrope rash. All patients had raised muscle enzymes; lactate dehydrogenase (LDH) was the most frequently elevated enzyme (82%) followed by creatine kinase (CK) (55%) and alanine aminotransferase (ALT) (55%). Sixty-five patients had a positive antinuclear antibody; most of the patients had negative extractable nuclear antigens. EMG was performed on 30 patients; low-amplitude and high-frequency pattern consisting myopathic findings was noticed in 75%. Seventy-five patients (86%) completed MRI study which showed abnormal findings, including edema, signal abnormalities in the affected muscles and muscle atrophy, and fatty replacement. Forty-four patients (48%) underwent muscle biopsy. However, 86% had abnormal findings in the form of perifascicular atrophy with perivascular inflammatory cell infiltration. Forty-five patients had polyarthritis; none of them had erosive or deformed joints. Fourteen patients had upper airway and dysphagia and ten patients had lung involvement in the form of interstitial pneumonitis; two of them were complicated by pneumothorax, pneumomediastinum, and pneumocardium. Eight patients were admitted to the intensive care unit (ICU), four of them required mechanical ventilation. Dysphagia, upper airway and lung involvement were statistically significantly associated with ICU admission. All patients received corticosteroids; 65 patients were treated with intravenous methyl prednisone pulse (IVMP). Methotrexate has been the most frequently used immunosuppressive drug (86%) while rituximab was used in eight patients. Additionally, 31 patients received IVIG and 12 patients received pamidronate.
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Table 1 Demographic and clinical manifestations
Patients, no. Female, no. (%) Age at disease onset, mean, years Time to diagnosis Follow-up duration, mean, years Course type (%) Monophasic Polycyclic/continuous Clinical features (%) Constitutional Weakness Gottron’s Heliotrope’s Arthritis Dysphagia Cutaneous ulcers Raynaud’s Pneumonitis Gut vasculopathy
Arab
European (11)
Latin American (11)
Chinese (14)
Japanese (13)
92 58 (63) 6.0 (±3) 1.5 (±5.6) 5.0 (±4.4)
248 169 (68.1) 6.9 (±3.7) 0.6 (±1.1) 7.7
242 152 (62.8) 7.0 (±3.8) 0.6 (±0.9) 7.7
39 26 (66.7) 6.8 (±3.9) NA NA
50 36 (72) 6.9 (±4) 0.7 7.0 (±5.5)
37.0 63.0
39.3 60.7
43.5 56.5
37.0 63.0
NA NA
40.0 94.0 78.0 70.0 49.0 15.0 8.0 4.0 11.0 13.0
28.6 86.3 65.7 58.1 34.7 20.2 6.3 5.3 NA 0.2
33.1 83.5 80.2 66.1 36.8 15.3 6.3 5.3 NA 0.2
NA 82.1 82.1 74.4 30.8 10.3 2.6 NA NA 7.7
70.0 92.0 86.0 80.0 NA NA NA NA 8.0 NA
NA not available
Table 2 Frequency of medications Oral corticosteroids Intravenous methyl prednisone pulses Methotrexate Cyclosporine Intravenous immunoglobulin Hydroxychloroquine Cyclophosphamide Biologic agents Pamidronate
Arab
European (11)
Latin American (11)
Chinese (14)
Japanese (13)
100.0 60.0 86.0 10.0 33.0 17.0 7.6 10.8 13.0
97.6 50.0 50.8 35.0 17.1 26.0 6.6 2.2 6.0
99.6 33.1 61.4 15.7 17.4 39.0 3.4 0.5 4.0
92.3 NA NA 56.4 41.0 76.9 NA 10.3 NA
57.0 43.0 59.0 NA NA NA 43.0 NA NA
NA not available
Most of the patients showed a clinical response after the initiation of treatment and remained well in control of disease activity, 63% required maintenance treatment. Sixteen patients ended with permanent skin changes and 12 had a residual muscle weakness. Twenty-seven patients developed calcinosis, 37 patients had growth failure, 15 had osteoporosis, 3 had lipodystrophy, and 1 patient developed mucinous cystic ovarian tumor. There were 2 deaths due to infection during the follow-up period.
Discussion In the present study, we retrospectively reviewed the disease characteristics and outcome of 92 Arab children with JDM seen over 15 years in five tertiary pediatric rheumatology clinics from three Arab countries. Comparison with JDM cohorts from Europe, Latin America, China, and Japan showed similarities in the main demographic and disease manifestations [11, 13, 14] (Table 1). The gender predilection of all cohorts was similar, there was higher
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Table 3 Frequency of cumulative damage Cutaneous Muscle dysfunction Calcinosis Lipodystrophy Pulmonary Gastrointestinal Osteoporosis Growth failure Death
Arab
European (11)
Latin American (11)
Chinese (14)
Japanese (13)
17.4 13.0 29.3 3.3 4.4 5.4 12.0 28.2 2.2
55.5 29.7 21.3 8.6 3.8 5.9 6.0 6.4 NA
50.2 39.5 26.0 10.9 8.1 11.4 5.9 9.8 NA
NA 28.2 38.5 NA 10.3 2.6 NA NA 5.1
NA NA 26.0 NA 8.0 NA NA NA 2.0
NA not available
proportion of girls than boys. Our patients were younger at the disease onset, but the mean interval between clinical onset and diagnosis was longer. Unfortunately, there was a delay in recognizing the clinical manifestations and referral to a pediatric rheumatologist. The presentation of JDM is variable; the frequency of presenting clinical manifestations was comparable with other cohorts [17]. As anticipated, proximal muscle weakness and the typical skin lesions were the most common clinical manifestations. Interstitial lung disease and gastrointestinal manifestations were reported more often in our patients, which may reflect the consequence of the delay in diagnosis or the severity of the disease. Unfortunately, myositis-specific antibody assays were not requested routinely in our clinics, but two patients with interstitial lung disease had positive anti-Jo-1 antibody. Recently, like others, we considered MRI more frequently to detect myositis. Accordingly, performing EMG and muscle biopsy was limited to patients with inconclusive MRI findings or in case of atypical presentation. Though, the clinical course of JDM improved over the last 50 years, unfortunately well-established predictors of the disease course are not available yet. Nonetheless, earlier studies showed that persistence of Gottron’s papules and nailfold abnormalities associated with the chronic disease course [5, 18]. In contrast, the evidence of the influence of age at disease onset on the clinical course and severity is still lacking [19, 20]. The disease course in our patients was comparable with other cohorts and consistent with previous reports. Table 2 shows the spectrum of medications that is used in different cohorts of JDM. Corticosteroids remain the mainstay of treatment of JDM. As expected, all patients were treated with corticosteroids either orally or by highdose IVMP. Most of our patients received methotrexate. Previously, we found that using of IVMP and methotrexate was a useful combination, particularly during the acuteness of the disease and flares [21].
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Therapeutic regimens are variable among different centers. Taking into consideration of lacking of evidence-based treatment, obviously the treatment is mostly based on the availability of medication and experience of the treating physician. Recently, consensus clinical treatment plans were developed for the treatment of JDM [22, 23]. Onethird of our patients received IVIG; furthermore, other steroid-sparing therapies have been introduced in patients who receive corticosteroids and methotrexate combination with a partial response. As of today, the experience of biologic agents and its efficacy in JDM are limited. However, like other centers, rituximab was introduced as a therapeutic option for the refractory cases. The use of biologic agent, namely rituximab, was comparable with Chinese cohort. Though there is no effective treatment for calcinosis yet, several case reports showed improvement of calcinosis using pamidronate, which was used frequently in our patients compared to other cohorts. We considered pamidronate treatment mainly for calcinosis-complicating JDM [24]. Patients with polycyclic or continuous disease course were likely to develop guarded outcome, the damage occurred most frequently in skin and muscle [12, 25]. Table 3 shows the frequency of cumulative disease damage. It is interesting to note that the cumulative muscle dysfunction and cutaneous damage in our patients were less frequent than other cohorts, while the calcinosis was comparable. Though our patients did not receive unified therapeutic regimen, it is possible that our patients received aggressive treatment, particularly corticosteroids. However, this observation should be interpreted with caution. In contrast, our patients suffered more frequently from osteoporosis and growth failure, which may be related to high cumulative corticosteroids treatment. All patients admitted to ICU had a severe interstitial lung disease. Fortunately, all of them including those that required mechanical ventilation survived. The overall mortality rate in our cohort during the follow-up period was similar to previous reports [13, 14].
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Obviously, we did not attempt to assess the efficacy of treatment in this study. Nevertheless, compared to our previous experience, a steady improvement in outcome, particularly calcinosis, is probably related to better therapeutic approach [15]. In conclusion, our cohort is representative for Arab JDM and showed similarities in phenotypic characteristics and outcome with other cohorts from different countries. It is noticeable that further efforts are required to elucidate the status of health-related quality of our patients. Compliance with ethical standards Funding This study was not funded by any agencies in the public, commercial, or not-for-profit sectors. Conflict of interest The authors declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Taking into consideration the nature of this retrospective work, informed consent was not required from patient or parent.
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