Study of subcutaneous fat in children with juvenile dermatomyositis

Authors


Abstract

Objective

Lipodystrophy is a recently recognized complication of juvenile dermatomyositis (juvenile DM). Until now, the diagnosis has been based only on the physical appearance of the patient. We quantified the patterns of fat distribution in a cohort of patients with juvenile DM.

Methods

Twenty patients with juvenile DM were enrolled along with a matching number of controls. Both groups underwent standard anthropometric measurements including assessment of skinfold thickness using Harpenden Skinfold Caliper (Holtain, Dyfed, UK). Glucose tolerance test and serum lipid estimates were performed in the study group but not in controls.

Results

Patients with juvenile DM had lower mean weight, height, and mid–upper-arm circumference as compared with controls; these differences were statistically significant (P ≤ 0.05). Eight (40%) of 20 patients had lipodystrophy on physical appearance. When assessed by skinfold caliper, there was loss of subcutaneous fat at the mid-axillary site in 65% of patients, at the subscapular in 60%, and at the suprailiac site in 55%. Serum triglyceride levels were increased in 12 of the 18 patients who underwent this test. Oral glucose tolerance test results were normal in all 20 patients.

Conclusion

Sixty-five percent of our patients with juvenile DM were found to have loss of subcutaneous fat on quantification compared with 40% on physical appearance alone. Maximum fat loss occurred at the mid-axillary skinfold site. A significant number of patients with juvenile DM (66%) had hypertriglyceridemia. We hypothesize that lipodystrophy and hypertriglyceridemia could well be integral components of what may be an expanded juvenile DM syndrome.

INTRODUCTION

Juvenile dermatomyositis (juvenile DM) is the most common inflammatory myopathy in children (1). Onset of disease usually occurs between ages 4 and 10 years, and the female:male ratio is 2.7:1.0 among North American whites (2). The cardinal features of this disease are proximal muscle weakness and characteristic skin changes such as heliotrope rash of the upper eyelids, Gottron's papules, and periungual erythema with capillary loop abnormalities.

Recently, 2 new clinical findings have been reported in the literature: lipodystrophy and insulin-resistant diabetes (3–10). In 1990, Tucker et al (3) reported 3 cases of lipodystrophy among a cohort of 30 patients with juvenile DM. This report was followed by isolated case reports of patients with juvenile DM with lipodystrophy and associated features such as hepatomegaly, acanthosis nigricans, hypertrichosis, and insulin-resistant diabetes (4–10). Huemer et al (10) studied 20 patients with juvenile DM and found that lipodystrophy was present in 25%, whereas elevated triglyceride levels and insulin resistance were present in 50% of their cohort.

The diagnosis of lipodystrophy has previously been made only on the basis of clinical appearance of the patient, and no objective method has been used to quantify fat in these patients. In this study, we quantified subcutaneous body fat and evaluated oral glucose tolerance tests and lipid profiles in our cohort of children with juvenile DM.

PATIENTS AND METHODS

Patients

The study sample comprised 20 patients (13 boys, 7 girls) ages 3.5–17 years who were diagnosed with juvenile DM according to the criteria of Bohan and Peter (11, 12) (Table 1). These patients were enrolled consecutively from the Pediatric Rheumatology and Immunology Clinic of the Advanced Pediatric Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. An equal number of healthy children matched on age, sex, and socioeconomic status (13) were enrolled from the Growth Clinic of Advanced Pediatric Centre, PGIMER as controls. The study was conducted over a period of 14 months from July 2003 to August 2004. The Institute Ethics Committee approved the study protocol.

Table 1. Clinical and biochemical profile of patients with juvenile dermatomyositis*
PatientsAge, years/sexMuscle weaknessLipodystrophyHirsutismHeliotrope rashCalcinosisGottron's papulesTriglyceride level (mg, %)
  • *

    + = present; — = absent; NA = not applicable.

  • Cardiac involvement (ventricular ectopics).

  • Weak gag reflex.

17.5/M++++77.5
212/M+++154.3
314/M++++++142.2
49/F++++++325.8
56.5/F++++193.1
613/M++82.8
713/M+++++219.7
84.5/F+++++155.8
917/M++95.8
105/M++85.9
117/F+++80.6
1211/F+++120.9
135.5/F+++NA
143.5/M++++253.2
159/M+++196.4
1614/M+++128.5
1714/M+++329.2
1815/M++349.8
1913/F++NA
2012.5/M+++82.1

Oral prednisolone was used in all patients except 1 (patient 4), with the mean duration of treatment being 1.77 years. Patient 4 had presented very late and had severe wasting. Corticosteroids were not used in this patient. She also had severe osteoporosis and calcinosis, requiring alendronate therapy (14). Two patients with severe disease and dysphagia at onset (patients 8 and 20) were given intravenous methylprednisolone (30 mg/kg/day) for 5 days followed by oral prednisolone. Prednisolone was administered in a dosage of 2 mg/kg/day (maximum 60 mg) for 1 month, and was then tapered over a period of ∼2 years. Methotrexate, azathioprine, and hydroxychloroquine were used in selected patients depending on the clinical requirements.

The mean ± SD followup period for patients was 2.2 ± 1.7 years (range 0.5–7 years). During the study period, 2 patients (patients 9 and 12) finished treatment successfully and were taken off drugs. One of our study patients (patient 7) died at home during followup, possibly due to aspiration pneumonia secondary to pharyngeal muscle weakness. Two of our patients (patients 2 and 6) had relapses during followup and had to be restarted on steroids along with methotrexate.

Study methods

Patients and controls underwent the following anthropometric measurements using standardized techniques and instruments in the growth laboratory on a preappointed date and time: body weight (in kg), crown-heel length/height (in cm), head circumference (in cm), chest circumference (in cm), mid–upper-arm circumference (in cm), biceps skinfold thickness (in mm), triceps skinfold thickness (in mm), subscapular skinfold thickness (in mm), mid-axillary skinfold thickness (in mm), medial calf skinfold thickness (in mm), medial thigh skinfold thickness (in mm), suprailiac skinfold thickness (in mm), paraumbilical skinfold thickness (in mm), and body mass index (BMI; in kg/m2). Body weight was measured on an electronic weighing scale (Avery Kolkata, West Bengal, India; least count 50 gm). Height was measured with a stadiometer (Holtain, Dyfed, UK; least count 1 mm). Circumference was measured with a fiberglass tape measure (least count 1 mm). Harpenden Skinfold Caliper (Holtain; least count 0.2 mm) was used to measure skinfold thickness. All skinfold measurements were taken on the left side of the body. The magnitude of interobserver error with regard to skinfold thickness varied between 0 mm and 0.4 mm, whereas it varied between 0 mm and 2 mm for height, 0 gm and 50 gm for body weight, and 0 mm and 2 mm for circumferential measurements.

Glucose tolerance tests (15) and serum lipid estimations (16) were carried out only in patients and not in controls. All investigations were conducted in the Hypertension Research Laboratory of the Department of Experimental Medicine and Biotechnology, PGIMER.

The mean ± SD and coefficient of variation were calculated for each body parameter. In view of non-Gaussian distribution of skinfold thickness, all absolute skinfold thickness measurements were transformed into their logarithms according to the formula given by Edwards et al (17) to contain the higher magnitude of variability. The magnitude of intergroup difference was quantified for each absolute as well as log-transformed measurement using Wilcoxon's signed rank test.

RESULTS

The clinical and biochemical profiles of all 20 patients comprising the study group are detailed in Table 1. Boys (n = 13) comprised 65% of the sample and had a mean ± SD age of 11.5 ± 3.7 years, whereas girls (n = 7) had a mean ± SD age of 8.0 ± 3.6 years (18).

Five patients (20%) had severe muscle weakness in the form of weak gag reflex and dysphagia and required prolonged tube feeding. One patient had ventricular ectopics and arrhythmia. Heliotrope rash was observed in 16 patients (80%), Gottron's papules in 14 (70%), hirsutism in 7 (35%), and lipodystrophy in 8 (40%). Three children had calcinosis (15%), 1 patient had vasculitic ulcers, and 1 patient had acanthosis nigricans (5%).

Patients with juvenile DM had lower weight, shorter height, and lower mid–upper-arm circumference when compared with healthy controls (Table 2); these differences were statistically significant (P ≤ 0.05). The mean ± SD difference in weight between controls and patients was 7.6 ± 4.4 kg, and 75% of patients with juvenile DM weighed less than controls. The mean ± SD difference in height between controls and patients was 13.2 ± 6.3 cm, with 90% of patients with juvenile DM being shorter than controls. Similar trends with respect to mid–upper-arm circumference were found, with 65% of patients having lower measured values (mean ± SD 3.7 ± 2.2 cm) when compared with controls. The mean ± SD BMI in patients with juvenile DM was less compared with controls (13.7 ± 1.4 kg/m2 versus 15.5 ± 1.4 kg/m2). This difference, however, was not statistically significant.

Table 2. Mean ± SD different parameters of patients with juvenile dermatomyositis and controls
Body parametersGroup A (n = 6)Group B (n = 6)Group C (n = 6)Total (n = 20)
Weight, kg
 Patients21.0 ± 9.224.7 ± 14.427.8 ± 10.724.5 ± 10.8
 Controls28.2 ± 10.629.2 ± 12.431.5 ± 11.129.2 ± 11.0
Height, cm
 Patients120.4 ± 19.5115.4 ± 23.1130.4 ± 18.8122 ± 19.4
 Controls133.7 ± 21.2127.6 ± 26.7140.2 ± 18.9132.9 ± 22.9
Head circumference, cm
 Patients50.6 ± 1.951.2 ± 2.352.3 ± 2.351.4 ± 2.0
 Controls50.0 ± 2.150.3 ± 2.753.7 ± 3.051.4 ± 2.9
Chest circumference, cm
 Patients57.7 ± 7.161.1 ± 13.664.1 ± 8.660.7 ± 9.6
 Controls58.9 ± 7.066.6 ± 11.562.7 ± 8.460.5 ± 8.8
Mid–upper-arm circumference, cm
 Patients13.4 ± 2.518.0 ± 5.417.7 ± 2.916.5 ± 4.0
 Controls17.4 ± 2.319.5 ± 3.518.2 ± 2.318.2 ± 2.7
Body mass index, kg/m2
 Patients13.8 ± 1.617.2 ± 4.515.7 ± 2.513.7 ± 1.4
 Controls15.1 ± 1.2716.9 ± 1.715.5 ± 1.415.5 ± 1.4

Of the 8 skinfold sites considered (Table 3), the mid-axillary was found to be the most affected (65%), followed by the suprailiac (60%), subscapular (55%), medial calf (50%), paraumbilical (50%), triceps (45%), medial thigh (35%), and biceps (25%). The mean ± SD net subcutaneous fat loss was 1.5 ± 0.7 mm in the biceps, 2.3 ± 1.4 mm in the triceps, 1.7 ± 0.8 mm in the subscapular, 1.8 ± 1.2 mm in the mid-axillary, 2.4 ± 2.3 mm in the medial calf, 6.2 ± 3.8 mm in the medial thigh, 2.5 ± 1.9 mm in the suprailiac, and 1.8 ± 1.7 mm in the paraumbilical. On transforming absolute skinfold thickness into logarithms, the magnitude of relative variability or coefficient of variability was found to be reduced. The difference between absolute and logarithm transformed values ranged from 59% to 72%.

Table 3. Mean ± SD skinfold thicknesses of patients with juvenile dermatomyositis and controls*
SkinfoldsGroup A (n = 6)Group B (n = 6)Group C (n = 6)Total (n = 20)
  • *

    Values within parentheses represent log-transformed values.

Biceps, mm
 Patients4.4 ± 2.0 (125.8 ± 46.1)8.4 ± 7.2 (163.5 ± 42.1)7.2 ± 6.4 (149.1 ± 59.7)6.9 ± 5.4 (149.0 ± 47.6)
 Controls4.1 ± 1.2 (128.4 ± 35.8)6.6 ± 3.0 (161.5 ± 25.1)3.1 ± 0.6 (113.4 ± 28.4)4.5 ± 2.2 (132.5 ± 34.0)
Triceps, mm
 Patients4.9 ± 1.6 (140.6 ± 34.2)10.8 ± 7.7 (186.2 ± 28.5)9.6 ± 7.5 (175.3 ± 43.2)8.7 ± 6.2 (169.4 ± 37.7)
 Controls6.0 ± 1.2 (160.8 ± 12.0)9.7 ± 3.5 (187.0 ± 17.3)4.9 ± 0.6 (150.2 ± 8.5)6.8 ± 2.8 (165.1 ± 19.3)
Subscapular, mm
 Patients3.7 ± 0.7 (126.8 ± 16.5)9.8 ± 7.6 (174.8 ± 38.9)9.5 ± 8.1 (172.1 ± 46.2)7.9 ± 6.5 (149.0 ± 47.6)
 Controls5.9 ± 2.6 (153.9 ± 29.0)8.0 ± 3.2 (174.8 ± 21.4)4.7 ± 0.9 (146.9 ± 14.3)6.1 ± 2.6 (157.4 ± 23.3)
Mid-axillary, mm
 Patients2.8 ± 0.4 (99.7 ± 17.2)7.1 ± 5.9 (150.7 ± 45.5)6.6 ± 4.7 (156.2 ± 52.9)6.1 ± 4.9 (131.1 ± 45.8)
 Controls4.5 ± 0.9 (140.8 ± 15.9)8.1 ± 4.7 (171.7 ± 28.5)3.7 ± 0.7 (127.7 ± 22.6)5.3 ± 3.1 (145.1 ± 27.6)
Suprailiac, mm
 Patients8.0 ± 4.4 (166.5 ± 40.4)11.3 ± 5.7 (190.5 ± 27.7)9.1 ± 5.8 (172.9 ± 33.3)9.2 ± 5.0 (176.2 ± 32.4)
 Controls7.4 ± 2.4 (176.6 ± 19.8)9.5 ± 2.0 (187.8 ± 11.8)5.8 ± 3.1 (156.9 ± 22.6)7.5 ± 2.8 (170.5 ± 22.5)
Paraumbilical, mm
 Patients10.5 ± 5.1 (188.1 ± 43.4)15.9 ± 7.2 (209.9 ± 23.8)15.9 ± 9.3 (211.0 ± 24.8)15.0 ± 7.5 (203.5 ± 33.3)
 Controls31.8 ± 6.4 (200.9 ± 29.9)15.4 ± 8.6 (206.7 ± 26.0)7.4 ± 3.6 (178.7 ± 33.8)12.6 ± 7.1 (194.4 ± 29.6)
Medial calf, mm
 Patients4.6 ± 1.1 (142.1 ± 15.5)11.3 ± 8.8 (180.0 ± 42.2)12.2 ± 11.6 (181.8 ± 146.6)9.9 ± 8.4 (172.2 ± 39.8)
 Controls7.1 ± 2.1 (169.4 ± 20.7)11.3 ± 6.2 (19.1 ± 25.7)3.7 ± 1.8 (156.7 ± 1.7)7.7 ± 4.3 (170.1 ± 24.6)
Medial thigh, mm
 Patients7.1 ± 3.2 (166.2 ± 24.9)11.2 ± 9.9 (176.7 ± 40.0)11.5 ± 11.6 (175.5 ± 49.7)10.6 ± 8.5 (177.2 ± 39.7)
 Controls6.0 ± 1.7 (159.2 ± 19.1)10.2 ± 4.9 (186.1 ± 25.5)5.9 ± 2.8 (153.8 ± 27.9)7.2 ± 3.6 (165.8 ± 26.1)

None of the patients had an impaired or abnormal glucose tolerance test result or clinical features suggestive of diabetes mellitus. Lipid profile testing was performed in 18 patients. Triglyceride levels were found to be high in 12 (66%) patients (Table 1). Five patients had high serum cholesterol levels and 3 had low high-density lipoprotein (HDL).

Based on physical appearance and results of tests of serum triglyceride levels, the study sample was categorized into 3 subgroups arbitrarily: group A consisted of patients with juvenile DM with severe loss of subcutaneous fat on physical appearance and increased serum triglyceride levels, group B consisted of patients with normal physical appearance and increased serum triglyceride levels, and group C consisted of patients with DM depicting variable fat deposition on physical appearance and normal serum triglyceride levels. Patients in group A had lower mid-axillary, subscapular, and medial calf skinfold thicknesses as compared with controls; these differences were statistically significant (P ≤ 0.05). Patients in group B had lower fat at the mid-axillary skinfold site. However, the difference was not statistically significant.

DISCUSSION

Juvenile DM has recently been associated with a number of seemingly unrelated abnormalities such as lipodystrophy, insulin-resistant diabetes, and hypertriglyceridemia (3–10). Our study suggests that lipodystrophy may be one of the cardinal features of this condition. Lipodystrophy has previously been diagnosed only on the basis of physical appearance. This is the first study to quantify loss of body fat in patients with juvenile DM.

The work of Huemer et al (10) suggests that patients with juvenile DM have compromised height and weight attainments. Our study reiterates this point. Skinfold thicknesses were significantly lower in study patients as compared with controls, but loss of body fat was not uniform at all sites. Our results suggest that the mid-axillary, suprailiac, and subscapular skinfolds are the most affected. This observation is difficult to explain and may be related to the release of inflammatory mediators and cytokines in this disease.

Glucose tolerance test results were normal in all patients in our study. This is in contrast to the results of Huemer et al (10) who demonstrated impaired and abnormal glucose tolerance test results in 2 patients, each with lipodystrophy. The followup period in the latter study was longer than ours, and it is possible that some children in our study may go on to develop impaired glucose tolerance later in life. Other possible explanations for these differences could be related to genetic, dietary, and lifestyle differences. Measurement of insulin levels may have provided additional information, but investigation of insulin levels could not be carried out due to technical reasons.

Serum lipid estimations showed that 12 of 18 study group patients had elevated triglyceride levels, 5 patients had high serum cholesterol, and 3 patients had low HDL. Children with juvenile DM may need lipid-lowering agents as part of their initial treatment regimen as well as at followup, even when the muscle weakness has remitted. When subcategorizing the study patients based on physical appearance and serum triglyceride levels, we found that patients in group A (n = 6) had lower mid-axillary, subscapular, and suprailiac skinfold thickness as compared with controls; these differences were statistically significant (P ≤ 0.05). Hirsutism was seen in 5 patients in this group. Patients in group B (n = 6) had lower mid-axillary skinfold thickness, but this was not statistically significant. Four patients in group B had hirsutism. None of the patients in group C (n = 6) had decreased skinfold thickness or hirsutism. These findings suggest that hypertriglyceridemia is the first metabolic abnormality to appear in children with juvenile DM, followed by the appearance of hirsutism and lipodystrophy.

To conclude, juvenile DM appears to be a more generalized disorder rather than one that involves only the muscles and skin. Many children with juvenile DM may go on to develop hypertriglyceridemia, lipodystrophy, and later, perhaps, insulin-resistant diabetes.

Ancillary