We found that LD is a late complication of JDM and is associated with more severe, chronic disease and with other disease sequelae such as calcinosis. IR, overt diabetes, and hypertriglyceridemia were common metabolic findings, particularly in patients with generalized and partial LD, and this was independent of steroid use. We discovered a number of distinct features associated with the 3 LD phenotypes suggesting a gradient of sequelae, with the most severe and greatest number of findings in the generalized LD phenotype (). To our knowledge, the current study is the most comprehensive review of these patients ever published; it required significant multidisciplinary collaboration to examine these patients adequately.
Features Associated With the 3 Major LD Phenotypes in JDM
Acquired LD has been reported in a number of systemic and organ-specific autoimmune diseases other than JDM39,40
. However, JDM patients may develop LD more frequently than patients with other autoimmune diseases46
. Reported prevalence rates for acquired LD associated with JDM vary from 12% to 40%31,37,56,62
, whereas we observed acquired LD in almost 8% of a large registry of patients with JDM. The most likely reason for this lower frequency of LD in our registry is referral bias, with an overestimation of LD in other reports that have included small cohorts from tertiary centers. Our study may be more generalizable due to the broader referral base of the nationwide registry of juvenile myositis in our study. Our study may also underestimate the prevalence, however, due to the under-recognition of LD in JDM.
Although LD is associated with JDM, LD has been infrequently reported in adult DM. The reasons for this lack of association with adult myositis are unclear. We found several features of DM to be associated with the development of LD, including joint contractures, muscle atrophy, panniculitis, and calcinosis. If LD is related to panniculitis or calcinosis of the adipocytes, as we observed in this study, differences in pathogenesis between JDM and adult DM may also be responsible. Of note, polymyositis is not associated with acquired LD in either adults or children.
DM patients with the generalized LD phenotype had more LD disease features compared to DM patients with the partial or focal LD phenotype. These features include buccal fat loss, acanthosis nigricans, hypertrichosis, hyperpigmentation, menstrual irregularity, and decreased leptin levels. In addition, abnormalities of glucose and lipid metabolism, as well as hyperandrogenism, were more prevalent. Patients with focal LA tended not to have metabolic sequelae and appear to represent a distinct group. However, the frequency distribution of many of these LD features did not differ between the LD subgroups, possibly due to small sample sizes.
Our definition of acquired generalized LD is similar to that of Misra and Garg39
. However, our definition of acquired partial LD differs from both Misra and Garg and the Barraquer-Simons phenotype, which involves abdominal fat loss but sparing of fat loss from the thighs40
. The majority of our patients with partial LD had no abdominal fat loss, but a little over half lost fat in the thighs. Our patients with focal LA had fat loss limited to sites of dystrophic calcification, most often in the extremities, but occasionally involving the trunk. Buccal fat loss occurred in all of our patients with generalized LD and in the majority of patients with partial LD, but not in focal LA. Patients in the current series were similar to other acquired LD patients in that bone marrow fat was preserved. This differs from congenital LD, where there is loss of bone marrow fat. Although many of our patients were treated with corticosteroids, we observed a different pattern of fat distribution from corticosteroid-induced LD. Corticosteroids typically cause subcutaneous fat accumulation in the face (“moon facies”), dorsocervical region (“buffalo hump”), and abdomen while subcutaneous fat is often decreased in the limbs17
. Our patients did not demonstrate increased fat in the face or posterior neck/upper back region, thus differentiating them from patients with corticosteroid-induced LD.
Some of the patients in the current series had a normal total percentage body fat measured by DXA. This may seem inconsistent with a diagnosis of LD, but may be explained by the observed redistribution of fat. No difference in total percentage body fat on DXA is found between HIV patients with LD and HIV controls13
. Normal percentage body fat on DXA has been reported in a patient with familial partial LD associated with mandibuloacral dysplasia55
and in a patient with acquired generalized LD39
. A 2007 study61
found a total percentage body fat by DXA ranging from 16.6% to 27.6% in 3 female patients with Dunnigan familial partial LD, 23.1% in 1 female with Barraquer-Simons acquired partial LD, and 5.1% in a patient with congenital generalized LD. Two of these patients with Dunnigan partial LD had normal total percentage body fat. It may be that acquired LD associated with DM is a less severe form of LD than congenital generalized LD, thus explaining why fewer LD patients with DM had low DXA scores. Nevertheless, average values for total percentage body fat by DXA in an LD population are unknown and clearly differ based on the subtype of LD. Long-term corticosteroid usage in these DM patients with long-standing active disease may also be contributing to higher total body fat content despite the presence of these regional losses17
While DXA is excellent for measuring total body fat mass, MRI is superior to DXA for measuring regional fat, which is of special importance in LD54
. The pattern of fat loss and redistribution varies between congenital and acquired LD and between generalized and partial LD39,47
. We observed a loss of subcutaneous fat in the thigh in generalized and partial LD patients compared to patients with DM without LD. While LD patients clearly lost fat from anterior, posterior, and lateral compartments of the thigh, they had less clear fat loss medially and thus had a pattern of greater medial to lateral subcutaneous fat in the thigh. Thus, MRI may be a useful tool to diagnose LD or to monitor a patient’s response to therapy.
We found disease-associated dyslipidemia in DM patients with all 3 subgroups of LD. The majority of our patients developed hypertriglyceridemia along with low HDL, including the 2 patients with focal LA. Although corticosteroids are known to increase triglycerides, they usually cause concurrent elevation in HDL cholesterol16,32
. Previous studies have shown that total cholesterol, LDL, and triglycerides correlate with prednisone dose in lupus patients and that these lipids are higher in lupus patients on steroids compared to those not on steroids15,20
. Elevated serum total and LDL cholesterol were seen in some of our LD patients, but not in the majority. Hence, the lipid profile present in our cohort of LD patients, namely that of hypertriglyceridemia and low HDL, is not consistent with steroid-induced dyslipidemia.
IR and overt diabetes were frequent metabolic sequelae in our patients with generalized and partial LD, but not focal LA. Misra and colleagues39,40
reported similar results in their autoimmune subgroup of acquired generalized LD, but a low frequency of these metabolic abnormalities in acquired partial LD patients with a number of different autoimmune diseases. Another report of 8 patients with JDM and LD found a similar frequency of hypertriglyceridemia, but did not examine glucose or insulin metabolism62
. Further, in a series of 23 patients with acquired LD in which JDM was the underlying diagnosis in the majority, none of the patients had diabetes and the frequency of hyperlipidemia was low46
. The reason for the higher frequency of glucose metabolic abnormalities in our patients may be related to more in-depth testing in our cohort and possible referral bias.
Loss of adipose tissue, IR, and hypertriglyceridemia play a critical role in the pathogenesis of fatty liver disease. Thus, it is not surprising that NASH was present in some of our patients. Some patients may have clinically asymptomatic hepatomegaly or evidence of steatosis on liver imaging. Only 2 of our 8 generalized LD patients had hepatomegaly, compared to 100% of another series of patients with acquired generalized LD associated with autoimmunity39
. We found liver ultrasound to be useful in detecting liver pathology and identifying those patients who require biopsy.
The etiology of acquired LD following JDM remains unknown. It has been hypothesized that an immune-mediated destruction of adipocytes or pre-adipocytes occurs. LA has been reported in association with panniculitis, and a “panniculitis variety” of acquired generalized LD has been described39
. While Misra and Garg39
differentiate the panniculitis variety from the autoimmune variety of acquired LD, there is clearly some overlap. Panniculitis was frequent in our patients with focal LA and may have been under-reported in our patients with JDM. In our patients, panniculitis and calcification typically predated the development of LA and occurred at the site of the focal LA. The skin biopsies of 1 patient showed calcification of the adipocytes and fat atrophy but did not demonstrate panniculitis; however, the biopsies were performed 1–4 months after LD was clinically appreciated.
Another potential mechanism for the development of LD is decreased fat uptake by adipocytes due to autoantibodies interfering with adipocyte function. Auto-antibodies to the cell surface insulin receptor have been reported to occur frequently in the presence of other auto-immune diseases, such as systemic lupus erythematosus5
. However, anti-insulin receptor antibodies were not present in the 3 patients tested, nor in 3 patients tested from another group of JDM patients31
. While antinuclear antibodies were present in similar frequencies in JDM patients with and without LD, the p155 myositis-associated autoantibody was more prevalent in our patients with generalized LD. The p155 autoantibody is directed to transcriptional intermediary factor 1 gamma, a transcription factor known to be present in erythroid, mesenchymal, and epithelial cells which regulates differentiation through a TGFβ-dependent pathway by binding Smad2/327,59
. Interestingly, in patients with Dunnigan familial partial LD, Smad-2 abnormally co-localizes on the nuclear membrane with lamin A/C, which differs from healthy individuals or patients with limb girdle muscular dystrophy57
. It is unclear if the p155 autoantibody is related to the development of LD or the transcription of adipocyte or muscle specific genes, but, in any case, generalized LD is a newly described phenotype associated with the anti-p155 autoantibody.
Cytokines might also play a role in the immunopathogenesis of LD. The increased levels of IL-1 and TNF-α that occur in DM may contribute to the development of IR or LD19,36
. A mouse knockout model of TTP deficiency results in systemic autoimmunity and subcutaneous fat loss related to an excess of TNF-α60
. TNF-α may act by decreasing leptin production18,23
or by preventing production of adiponectin and other adipocyte genes12
. We examined TNF-α promoter and TTP polymorphisms to determine if certain alleles might lead to increased susceptibility to LD, but did not find any associations with the development of LD in JDM patients. This may in part be due to our small sample size. Other genetic polymorphisms were possibly increased in frequency in white JDM patients with LD compared to those without LD, including HLA alleles DRB1*0801, DQA1*0201, and IL-1β−511
TT. Interestingly, this IL-1 genotype is associated with higher stimulated levels of IL-1 β in vitro25
Several previously studied mechanisms of LD appeared not to be operative in our patients. C3 nephritic factor, an IgG antibody that breaks down C3 and lyses adipocytes, has been associated with acquired partial LD40
. Misra and colleagues40
found that 12 of their 18 (67%) patients with acquired partial LD had a low C3 level, and 72 of 87 (83%) reported patients with acquired partial LD had a C3 nephritic factor. However, the majority of patients in the current series had normal C3 levels, including all of those tested with partial LD, and this is similar to previous reports29,34
Another possible cause of LD might be disrupted differentiation of adipocytes. Mutations in the nuclear lamin A gene, critical for adipocyte development, are associated with Dunnigan-type familial partial LD, as well as with Emery-Dreifuss muscular dystrophy1,33
. Lamin A mutations were not found in 3 patients with acquired partial LD associated with DM. We also analyzed the dlk 1 protein, an epidermal growth-factor-like protein that is highly expressed by pre-adipocytes and inhibits adipocyte differentiation35
. We did not find any abnormalities in dlk 1 serum levels in our patients. However, adipogenesis may depend on the equilibrium between dlk 1 and the newly described dlk 2 protein41
. It is possible that other genes regulating adipocyte differentiation, such as PPARγ and 1-acylglcerol-3-phosphate-O
-acyltransferase 2 (AGPAT2), which have been associated with congenital LD phenotypes2
, are implicated, but these have not been examined in our patients.
The optimal treatment of DM-associated LD is not known. The metabolic aberrations in other forms of LD respond to metabolic therapies such as thiazolidinediones and leptin replacement6
. Further research is needed to study the safety and efficacy of these and other metabolic therapies for LD in JDM patients.
Physicians should monitor JDM patients closely for evolving LD and the accompanying metabolic abnormalities, particularly several years after the onset of DM in patients with continuing disease activity. Three phenotypes of LD, generalized LD, partial LD, and focal LA, exist in patients with JDM and these have diverse patterns of fat loss and associated features of LD (summarized in ). In particular, JDM patients with calcinosis, joint contractures, and muscle atrophy are at highest risk of developing LD. Furthermore, a chronic continuous disease course, malar rash or erythroderma, and the p155 autoantibody are also associated with LD or its subsets. Panniculitis is associated with focal LA, which develops at sites of calcinosis. These 3 subphenotypes of LD have a gradient in the frequency and severity of associated metabolic sequelae, apparently related to the extent of fat loss. Glucose intolerance, hypertriglyceridemia, NASH, and other features of LD are frequent in patients with generalized and partial LD. Thigh MRI is useful in demonstrating patterns of fat loss and relative sparing of the medial thigh that may help in confirming a diagnosis of LD, particularly in patients with generalized or partial LD. The increased morbidity in JDM incurred by having these coexisting metabolic problems necessitates proper identification and treatment.