GAMMA-carboxyglutamate excretion and calcinosis in juvenile dermatomyositis

Proteins containing gamma-carboxyglutamic acid (Gla) are present in subcutaneous calcifications of adults with dermatomyositis or scleroderma. Sixteen children with juvenile dermatomyositis, including 7 with subcutaneous calcifications, were studied to determine if abnormal synthesis or turnover of Gla-containing proteins occurred. All study children had increased excretion of the amino acid that was greater than that of age-and sex-matched controls. Patients who had juvenile dermatomyositis with calcifications had a 3-fold increase in Gla excretion, and those without calcinosis had a 2-fold increase. Five other children with various connective tissue disorders and subcutaneous calcification had 2-fold increased Gla excretion. Decreased excretion of this amino acid was associated with salicylate therapy (80 mg/kg/24 hours). The data suggest an abnormal turnover of Gla-containing proteins in juvenile dermatomyositis. Metabolism of these proteins may be involved in the pathophysiology of soft-tissue calcification in children.     

Calcinosis in juvenile dermatomyositis: frequency,risk factors and outcome

The aim was to retrospectively estimate the prevalence of calcinosis in patients with juvenile dermatomyositis (JDM) and to identify risk factors associated with development of calcinosis in these patients. Retrospective chart review of 39 children diagnosed with JDM between 2004 and 2015 in a tertiary care hospital was done. Patients were divided into two groups, depending on the presence or absence of calcinosis, and the two groups were compared with respect to demographic, clinical, laboratory and therapeutic characteristics. Calcinosis developed in nine (23.1 %) patients. Delay in diagnosis and initiation of treatment, prolonged duration of disease, the presence of joint contractures and cardiac involvement were significantly associated with increased frequency of calcinosis. Six out of nine (66.7 %) patients with calcinosis received alendronate therapy, out of which four showed partial reduction in calcinosis. In one case, surgical removal of tumorous clumps was done. Calcinosis remains a common complication of JDM. We found an association between calcinosis and delay in diagnosis and initiation of treatment, prolonged duration of disease and cardiac involvement. Our study suggests that alendronate may be beneficial in management of calcinosis of JDM.     

Hypercalcemia during the resolution of calcinosis universalis in juvenile dermatomyositis.

Dystrophic calcification is seen in more than 50% of children with juvenile dermatomyositis and tends to resolve spontaneously in some patients. Calcinosis universalis is the least common type of calcification seen and rarely regresses. We describe a boy with juvenile dermatomyositis and calcinosis universalis who developed hypercalcemia during spontaneous regression of dystrophic calcification. The treatment and possible mechanisms of this complication are discussed.     

Magnetic resonance imaging detection of occult skin and subcutaneous abnormalities in juvenile dermatomyositis. Implications for diagnosis and therapy

OBJECTIVE: To assess the utility of magnetic resonance imaging (MRI) of skin, subcutaneous tissue, and fascia in evaluating disease activity in juvenile dermatomyositis (DM). METHODS: Short tau inversion recovery (STIR) MRI of the proximal thighs and buttocks, cutaneous assessment, and other measures of disease activity were prospectively obtained in 26 children meeting criteria for probable or definite juvenile DM. Also undergoing STIR MRI assessment were 8 subjects who were being evaluated for muscle disorders and who were not diagnosed as having juvenile DM. RESULTS: Skin, subcutaneous, or fascial edema of the thighs and buttocks were seen on STIR MRI in up to 85% of juvenile DM patients at baseline evaluation compared with no more than 38% of the comparison group without juvenile DM. In juvenile DM, STIR MRI skin and subcutaneous edema scores correlated (r(s) = 0.51, P = 0.008), as did fascial and muscle edema scores (r(s) = 0.58, P = 0.002). Skin global disease activity scores correlated with MRI skin edema scores (r(s) = 0.41, P = 0.04), and serum aldolase levels correlated with both MRI skin and subcutaneous edema scores (r = 0.44 and 0.40, P = 0.03 and 0.05 respectively). The extent and severity of STIR MRI changes in the skin, subcutaneous tissue, and fascia were not predicted by most other measures of juvenile DM disease activity. Five juvenile DM patients with thigh MRI subcutaneous edema developed clinically apparent calcinosis at the same location within 9 months. CONCLUSION: Edema or inflammation in the skin, subcutaneous tissue, and fascia, found on STIR MRI, is common in juvenile DM patients and is often undetected by standard assessments. These MRI changes can precede the development of calcinosis. STIR MRI may be a useful adjunct for assessing disease activity and guiding the treatment of juvenile DM.     

Calcinosis in juvenile dermatomyositis: a possible role for the vitamin K-dependent protein matrix Gla protein

Objectives. The aims of the present study were to investigatewhether the calcification inhibitor matrix Gla protein (MGP)is expressed in muscle biopsies of patients with juvenile dermatomyositis(JDM), and whether different forms of MGP are differentiallyexpressed in JDM patients with and without subcutaneous calcifications. Methods. Muscle tissue from six JDM patients (three withoutcalcinosis, two with calcinosis and one recently diagnosed patient),four patients with muscular dystrophy, three patients with IBMand five normal histological control subjects was used for immunohistochemistrystaining using novel antibodies to different conformations ofMGP. Results. In the JDM patients, all forms of MGP [non-carboxylatedMGP (ucMGP), carboxylated MGP (cMGP), non-phosphorylated MGP(serMGP) and phosphorylated MGP (pserMGP)] were more intenselystained in the perifascicular compared with the central musclefibres. In addition, these MGP species were demonstrated inthe pathological muscle fibres of IBM and dystrophy patients,but hardly in normal histological muscle tissue. In JDM patientswith calcifications, only pserMGP was increased compared withthose without calcifications. All forms of MGP were also foundin various staining intensities in the microvasculature andmacrophages of normal histological and disease biopsies. Conclusions. MGP was expressed at the site of muscle damagein JDM patients as well as in patients with muscular dystrophyand IBM. The difference in staining intensity of pserMGP appearedto distinguish between JDM patients with and without calcifications,whereas cMGP, the other functional form, was equally expressed. KEY WORDS: Vitamin K-dependent proteins, Matrix Gla protein, Juvenile dermatomyositis, Immunohistochemistry, Muscle Submitted 23 July 2007; revised version accepted 6 December 2007.     

Using imaging methods to assess severe calcinosis in juvenile dermatomyositis: A case report

Calcinosis and lipodystrophy are severe complications of juvenile dermatomyositis (JDM). Up to 20% of patients have calcinosis, and the onset of calcinosis usually occurs 1 to 3 years after that of the illness. We report a case of JDM with severe complications of calcinosis and lipodystrophy, and we assess calcinosis using a variety of imaging methods. To evaluate the patient's inflammatory state, bone scintigraphy was performed, which demonstrated increased uptake in the right scapula, in addition, multiple calcifications are present subcutaneously on the shoulder and back, and inflammatory imaging features are also present in the right knee joint.     

Economics of Stratified Medicine in Rheumatoid Arthritis

Calcinosis is one of the hallmark sequelae of juvenile dermatomyositis (JDM), and despite recent progress in the therapy of JDM, dystrophic calcification still occurs in approximately one third of patients. This review discusses our current, albeit limited, understanding of risk factors for the development of calcinosis in JDM, as well as approaches to assessment, and current views on its pathogenesis. Anecdotal approaches to treating calcinosis associated with JDM, including both anti-inflammatory therapies and agents aimed at inhibiting the deposition of calcium hydroxyapatite, are reviewed. An improved understanding of the pathogenesis of calcinosis, the establishment of standardized measurement tools to assess calcinosis, and randomized controlled trials employing more sensitive outcome measures are needed to develop efficacious therapies for this often disabling complication.     

Calcinosis in dermatomyositis: Origins and possible therapeutic avenues

Calcinosis, insoluble calcium compounds deposited in skin and other tissues, is a crippling sequela of dermatomyositis. Prolonged disease associated with ongoing inflammation, ischemia, repetitive trauma, and certain autoantibodies are associated with calcinosis. Herein, we describe potential pathogenic mechanisms including the role of mitochondrial calcification. There are no widely effective treatments for calcinosis. We review available pharmacologic therapies for calcinosis including those targeting calcium and phosphorus metabolism; immunosuppressive/anti-inflammatory therapies; and vasodilators. Mounting evidence supports the use of various formulations of sodium thiosulfate in the treatment of calcinosis. Although the early institution of aggressive immunosuppression may prevent calcinosis in juvenile dermatomyositis, only limited data support improvement once it has developed. Minocycline can be useful particularly for lesions associated with surrounding inflammation. Powerful vasodilators, such as prostacyclin analogs, may have promise in the treatment of calcinosis, but further studies are necessary. Surgical removal of lesions when amenable is our treatment of choice.     

Staphylococcal infections in childhood dermatomyositis--association with the development of calcinosis, raised IgE concentrations and granulocyte chemotactic defect.

There is a high incidence of staphylococcal infection in children with dermatomyositis, which is limited to those children who either already have or subsequently develop calcinosis. Of 15 children followed up for 3-10 years after diagnosis, all nine who developed calcinosis had infections with Staphylococcus aureus compared with none of six without calcinosis. Of these nine, the occurrence of staphylococcal infections before calcinosis was observed in four, suggested by history in two, and unclear in three children. Granulocyte chemotaxis to Staphylococcus aureus was more severely depressed in those children with calcinosis, whereas those without calcinosis did not differ significantly from controls. The chemotactic defect was due to a serum factor (patients' serum depressed control chemotaxis and control serum corrected the patients' chemotaxis). The nine children with calcinosis also had significantly higher serum IgE concentrations than non-atopic age matched controls; the six without calcinosis did not differ from controls. The increased IgE concentrations appeared to develop after staphylococcal infection and before calcinosis. Two of five patients with calcinosis had increased antistaphylococcal IgE antibodies; neither of the two patients without calcinosis had such increased antibodies. This suggests preceding immunological differences in patients with dermatomyositis who do and do not subsequently develop calcinosis, either increasing susceptibility to Staphylococcus aureus infection or potentially resulting from such infections.     

Calcinosis cutis universalis in a patient with systemic lupus erythematosus

Deposition of calcium salts in the skin and subcutaneous tissue occurs in a variety of rheumatic diseases, being most commonly associated with scleroderma, CREST (calcinosis, Raynauds phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia), dermatomyositis, and overlap syndromes but is a rare complication of systemic lupus erythematosus (SLE). Calcinosis is classified into four subsets: dystrophic, metastatic, idiopathic, or calciphylaxis/iatrogenic. The pathophysiology of calcinosis cutis remains unclear. Our patient developed extensive areas of calcifications in the trunk and extremities (calcinosis universalis) 8 years after SLE diagnosis, which would correspond to a form of dystrophic calcification. No response was observed after treatment with oral diltiazem for 3 months. We review the literature on the pathogenesis and prevalence of calcinosis universalis in SLE.     

Composition of calcifications in children with juvenile dermatomyositis: association with chronic cutaneous inflammation

OBJECTIVE: Calcific deposits develop in 20-40% of children with juvenile dermatomyositis (juvenile DM), contributing to disease morbidity and mortality. This study was undertaken to define the structure and composition of these deposits and to characterize their association with chronic inflammation. METHODS: We examined calcific deposits from 5 children with juvenile DM (2 boys and 3 girls). The crystal structure and mineral content of the deposits was analyzed by x-ray diffraction, Fourier transform infrared spectroscopy, and imaging. The protein content of the deposits, following solubilization, was assayed by Western blotting. RESULTS: All 5 children had both a young age at disease onset (mean +/- SD 3.3 +/- 1.9 years) and, despite therapy, persistent cutaneous inflammation (mean +/- SD duration 81.3 +/- 58.7 months). The bone proteins, osteopontin, osteonectin, and bone sialoprotein, were identified in the protein extracts; the only mineral detected was hydroxyapatite, but the tissue was distinct from bone, with an extremely high mineral content and an irregular distribution of mineral. CONCLUSION: These results indicate that chronic cutaneous inflammation may contribute to the formation of hydroxyapatite-containing pathologic calcifications in children with juvenile DM.     

Juvenile dermatomyositis: a tertiary center experience

Juvenile dermatomyositis (JDM) is a rare chronic inflammatory disease of unknown etiology and primarily involves muscle and skin. It is the most common idiopathic inflammatory myopathy of childhood. This study aimed to evaluate demographic and clinical features, laboratory data, treatment modalities, and outcome of patients with JDM at a referral pediatric rheumatology center in Turkey. We retrospectively reviewed medical records of patients diagnosed with JDM between the years 2003–2016 at the Pediatric Rheumatology Department Cerrahpasa Medical Faculty. A total of 50 patients (35 females), median age at the onset 6.1 ± 4.1 years, were identified. Mean follow-up period was 74.5 ± 49.7 months. Presenting clinical symptoms included heliotrope rash (100%), Gottron papule (96%), muscle weakness (90%), erythroderma (88%), and calcinosis (38%). All patients had elevated muscle enzymes at the disease onset. Sixty-eight percent of the patients had anti-nuclear antibody positivity. Electromyography on 27 patients and muscle biopsy on 14 patients were performed, and all of them showed signs of juvenile dermatomyositis. Early aggressive treatment with corticosteroids mostly in combination with methotrexate was used. Cyclosporine was added to 48% of the patients’ treatment regimen in case of severe or refractory disease. All patients except two cases, who were referred to our clinic after long disease duration with widespread calcinosis, achieved remission. Early diagnosis and early initiation of intensive therapy are important in reducing JDM complications. International collaboration is needed in order to better understanding and management of the disease.     

Treatment of Achilles tendon calcinosis in juvenile dermatomyositis with external ilizarov fixator

Calcinosis is a devastating complication of juvenile dermatomyositis and a challenging therapeutic problem. We report the use of an external Ilizarov fixator for the treatment of Achilles tendon calcinosis causing severe disability in a young girl with juvenile dermatomyositis.     

Clinical significance of subcutaneous fat and fascial involvement in juvenile dermatomyositis

Abstract

Objectives: Subcutaneous involvement, including calcinosis and panniculitis, is a more common complication in juvenile dermatomyositis (JDM) than in adult dermatomyositis. Magnetic resonance imaging (MRI) is useful for evaluating disease distribution. We investigated the clinical significance of subcutaneous involvement in JDM.

Methods: Thighs and hips in 18 newly diagnosed JDM patients were evaluated with fat-suppression MRI. Bilateral muscle, fascial and subcutaneous fat involvement were scored from 0 to 8 points according to the severity of distribution on MRI. Associations between clinical manifestations, serum muscle enzymes, and MRI scores were also evaluated.

Results: Abnormal MRI findings in muscle, fascia and subcutaneous fat were observed in 18, 18, and 10 patients, respectively. Subcutaneous fat scores were significantly higher in early-diagnosed JDM patients (diagnosed less than 2 months from onset) than in late-diagnosed JDM patients (diagnosed later) (p?=?.025). Serum aldolase was elevated in all patients, although only eight demonstrated elevated serum creatine phosphokinase. Serum aldolase was significantly correlated with MRI scores for subcutaneous fat (p?<?.0001, ρ?=?.787) and fascia (p?=?.013 ρ = 0.574), but not muscle. Additionally, serum aldolase was significantly correlated with serum triglycerides (p?=?.009, ρ?=?0.629).

Conclusion: Subcutaneous fat involvement is a characteristic finding in early-diagnosed JDM and correlates with elevated serum aldolase.     

Rapid improvement of calcinosis in juvenile dermatomyositis with alendronate therapy

A 6-year-old boy with improving juvenile dermatomyositis (JDM) developed severe and debilitating calcinosis, unresponsive to diltiazem and probenecid. Alendronate produced dramatic improvement within 1 month and by 12 months calcinosis had virtually resolved. The response was followed by bone mineral content measurements.     

Twelve years experience of juvenile dermatomyositis in North India

The aim of this study was to evaluate outcome in children with juvenile dermatomyositis (JDMS) at a tertiary care center in North India and have a long term follow-up. Medical records of children with JDMS managed at a tertiary care hospital were reviewed during a 13-year period to determine (1) interval between onset of symptoms and diagnosis, (2) treatment modalities used and (3) long term functional outcome. Thirty three patients diagnosed with JDMS met the inclusion criteria. Mean age at diagnosis was 8.7 ± 3.3 years. Mean duration of disease prior to treatment was 1.18 years (range 1 months–5 years). The total follow-up period was 136.7 patient-years. Immunosuppressive therapy was given in 31/33 and a distinct monocyclic course was seen in 72.7% cases. Lipodystrophy was seen in 10/33 (30.3%), calcinosis in 7/33 (27.3%), cutaneous ulcers in 6/33 (18.2%), dysphagia in 5/33 (15.2%), and contractures in 4/33 (12.1%) cases. A steady and sustained response was seen in patients who had received “adequate” doses of steroids at the time of initiation of treatment. Methotrexate, hydroxychloroquine, azathioprine and intravenous immunoglobulin were used in patients with poor response to corticotherapy. There were two deaths in our series. Stepwise, aggressive treatment directed at achieving rapid and complete control of muscle inflammation is highly successful in minimizing the long-range sequelae of JDMS. Our patients seem to have a different clinical profile on follow-up as compared to series published from the West.     

Efficacy of probenecid for a patient with juvenile dermatomyositis complicated with calcinosis

Calcinosis of juvenile dermatomyositis (JDM) is a crucial problem because it is refractory to various therapies. An 11-year-old boy who had been treated for JDM with interstitial pneumonia developed calcinosis of both legs despite treatment with corticosteroid and cyclosporin A. Images of his knees showed massive calcinosis with restricted range of motion. Probenecid was used to reduce calcinosis, resulting in remarkable improvement of calcinosis accompanied by normalization of serum phosphorus level and disability after 17 months of administration. We suggest that probenecid is useful for the treatment of calcinosis of JDM.     

Calcinosis in rheumatic diseases

BACKGROUND: Calcinosis, or dystrophic soft-tissue calcification, occurs in damaged or devitalized tissues in the presence of normal calcium/phosphorus metabolism. It is often noted in the subcutaneous tissues of connective tissues diseases--primarily systemic lupus erythematosus, scleroderma, or dermatomyositis--and may involve a relatively localized area or be widespread. The calcinotic accumulations may lead secondarily to muscle atrophy, joint contractures, and skin ulceration complicated by recurrent episodes of local inflammation and infection. OBJECTIVES: To review the classification, pathogenesis, clinical features, and treatment of calcinosis in rheumatic diseases. METHOD: A MEDLINE search of articles from 1972 to 2004 was conducted utilizing the index word "calcinosis" with the coindexing terms "scleroderma," "lupus," "dermatomyositis," and "dystrophic calcification." RESULTS: Calcinosis may be the source of both pain and disability in connective tissue disease patients. Illustrative cases of patients with severe calcinosis are described. The literature available was critically reviewed. While warfarin, colchicine, probenecid, bisphosphonates, diltiazem, minocycline, aluminum hydroxide, salicylate, surgical extirpation, and carbon dioxide laser therapies have been used, no treatment has convincingly prevented or reduced calcinosis. CONCLUSIONS: Calcinosis is common in the conditions reviewed and a number of agents have been used for treatment. However, the approach to calcinosis management is disorganized, beginning with the lack of a generally accepted classification and continuing with a lack of systematic study and clinical therapeutic trials.     

Juvenile dermatomyositis: clinical profile and disease course in 25 patients

A retrospective analysis of 25 Arab patients with juvenile dermatomyositis (JDMS) was conducted between 1988 and 1996. The mean age at disease onset was 8.25 years (range 1.5-15 yrs) with a male: female ratio of 1.5:1. The disease duration before diagnosis was 1-108 months. Two patients had a family history of JDMS. The clinical features included fever in 14 patients (56%), weight loss in 20 (80%), muscle weakness in all 25 (100%), and muscle pain in 14 (56%). Skin lesions included Gottron's papules in 15 patients (60%), heliotrope in 13 (52%), erythematous malar rash in 8 (32%), and pigmentary changes in 12 (48%). Seventeen of the 25 patients had arthralgia (68%) and 16 patients had arthritis (64%). Gastrointestinal symptoms were noted in 19 patients (76%). Myocarditis with cardiac failure was the initial presentation of 1 patient, while 2 had conduction defect. Twelve patients (48%) had respiratory symptoms. The course of the disease was complicated by calcinosis in 10 patients (40%). All of the patients were treated with prednisone; 15 were also treated with methotrexate. The duration of follow up ranged from 6-108 months (mean 54.5 months). Twenty-three patients improved, including those who had calcinosis at the time of presentation, with a current muscle power of 4/5 in 10 patients (40%) and 5/5 in 13 patients (52%). No deaths were reported in our series and no patients are currently bedridden.     

CD5 positive B lymphocytes in seronegative juvenile arthritis.

We investigated the levels of circulating CD5+ B cells in 43 patients with seronegative, HLA-B27 negative juvenile arthritis, 7 patients with juvenile dermatomyositis (DM) and 16 children with systemic lupus erythematosus (SLE). We found that CD5+ B cell levels were high in juvenile arthritis (p less than 0.01), normal in juvenile DM and decreased in SLE (p less than 0.01) compared to 33 age matched controls. In juvenile arthritis, the increase of CD5+ B cells appeared to be independent of discuss activity and was present in all the onset types except in a subset of patient with late onset pauciarthritis.