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Routine vs extensive malignancy search for adult dermatomyositis and polymyositis: a study of 40 patients.

OBJECTIVE: To identify potential risk factors and the yield of routine screens for early detection of malignancy associated with dermatomyositis (DM) and polymyositis (PM). DESIGN: Retrospective study of malignancies in all patients with DM or PM followed up between the years 1981 and 2000 and a review of the relationship of DM and PM to malignancy, the usefulness of various tests or examinations for malignancy search, and the patients' course. SETTING: Departments of internal medicine and dermatology in a teaching hospital. PATIENTS: Forty consecutive adult patients with DM (33 cases) or PM (7 cases). MAIN OUTCOME MEASURES: (1) Rate of false-negative results of routine workup and yield (percentage of positive results) of blind malignancy search and (2) comparison of 16 characteristics in patients with malignancy vs those without. RESULTS: Malignancy occurred in 16 patients: 13 with DM and 3 with PM. In all cases, the diagnosis of malignancy was made concurrently with or shortly after the diagnosis of DM or PM. Factors associated with malignancy were recruitment in the internal medicine department (P =.02), constitutional symptoms (P<.01), a rapid onset of DM or PM (P =.02), the lack of Raynaud phenomenon (P<.01), and a higher mean erythrocyte sedimentation rate (P<.01) and creatine kinase level (P<.01). Initial routine search failed to discover 4 malignancies, 3 of which were discovered at an advanced stage by more extensive investigations. The positive result yield of blind malignancy search was only 13% (11 of 87), but reached 28% (5 of 18) for blind abdominal-pelvic and thoracic computed tomographic scans. CONCLUSION: Extensive search for malignancy, particularly computed tomographic scans, may be warranted in at least a subset of patients with DM or PM and risk factors of malignancy.

Adult↗

Mycophenolate mofetil as an effective corticosteroid-sparing therapy for recalcitrant dermatomyositis.

BACKGROUND: Dermatomyositis (DM) is a multisystem idiopathic inflammatory disorder that most commonly affects the muscles and skin. Systemic corticosteroids are the mainstay of therapy but are limited by their long-term adverse effects. OBSERVATIONS: We sought to evaluate the effectiveness of oral mycophenolate mofetil in patients with cutaneous lesions of DM recalcitrant to other therapies through an open-label retrospective medical chart review of patients in a university-affiliated private practice setting. Twelve patients with DM who had skin lesions recalcitrant to traditional therapies or who developed toxic effects from traditional therapies began mycophenolate mofetil treatment at doses ranging from 500 mg to 1 g twice a day. Response was based on improvement in skin disease as judged clinically, an increase in strength, and/or an ability to decrease or discontinue concomitant therapies. Improvement was seen in 10 of the 12 patients, most within 4 to 8 weeks. Most patients tolerated mycophenolate mofetil treatment without problem; however, 1 patient developed a B-cell lymphoma of the central nervous system, and another developed abnormal levels of hepatic enzymes along with urinary symptoms. Resolution of these toxic reactions occurred with cessation of mycophenolate mofetil treatment in each patient. CONCLUSION: Mycophenolate mofetil may be an effective corticosteroid-sparing therapy for the treatment of some patients with DM.

Adult↗

Improvement in dermatomyositis rash associated with the use of antiestrogen medication.

BACKGROUND: Dermatomyositis (DM) is an autoimmune disorder that occurs more often in women than men and causes highly symptomatic and inflammatory cutaneous and proximal muscle disease. Corticosteroids have been the treatment of choice for myositis in DM, and antimalarial agents for the skin disease of DM, with methotrexate sodium, azathioprine, mycophenolate mofetil, cyclosporine, and intravenous immunoglobulin used as steroid-sparing agents. Recently, reports supporting a role for anti-tumor necrosis factor alpha (TNF-alpha) therapy in the treatment of DM have emerged. OBSERVATIONS: We describe 2 women who experienced an improvement in their DM-associated skin eruptions while taking antiestrogen medication. The first patient was taking tamoxifen, a selective estrogen receptor modulator that has been found to have anti-TNF-alpha properties. The second was taking anastrozole, an aromatase inhibitor. When tamoxifen therapy was discontinued after 4 years of use in the first patient, her DM rash worsened and remained difficult to control with conventional immunosuppressant medication. CONCLUSIONS: With the limited number of therapies available to manage DM skin eruptions, the discovery of novel agents effective in treating this disease is vital. Using antiestrogen medication in women with DM may result in a significant improvement in their rash, possibly via the inhibition of TNF-alpha production by immune or other cells. Further investigation into the use of antiestrogen therapy in DM is merited to evaluate long-term risks and benefits.

Adult↗

Membrane attack complex deposits in cutaneous lesions of dermatomyositis.

BACKGROUND AND DESIGN: The presence of membrane attack complex of complement (MAC) deposits in the intramuscular vasculature of biopsy specimens taken from patients with dermatomyositis (DM) has been implicated in the pathogenesis of this myopathy. The purpose of this study was to investigate the presence of MAC deposition in the skin lesions of patients with DM. Using immunohistochemical methods, we examined 22 biopsy specimens from lesional skin, six biopsy specimens from uninvolved skin, and 12 muscle biopsy specimens from patients with DM for the presence of MAC and vitronectin and CD59, two regulatory proteins of complement. RESULTS: The deposition of MAC was demonstrated in a large percentage of biopsy specimens obtained from the lesional skin of patients with DM. Deposits were found along the dermoepidermal junction in 19 (86%) of 22 biopsy specimens. Deposits on the vessel walls of the dermis were found in 17 (77%) of 22 biopsy specimens; but only in six of these biopsy specimens (27%) were deposits present in more than 10% of blood vessels. In contrast, deposits along the dermoepidermal junction and the vessel walls of the dermis were absent in specimens from uninvolved skin. In 12 muscle biopsy specimens obtained simultaneously from these patients, MAC deposits were found on the vessel walls in nine (75%), but only in six (50%) were deposits found in more than 10% of the intramuscular vessels. The pattern of vitronectin immunoreactivity in skin and muscle biopsy specimens obtained from patients with DM was similar to MAC deposits. The expression of CD59 was normal in all skin and muscle biopsy specimens. CONCLUSIONS: The deposition of MAC was found in a high percentage of biopsy specimens from the lesional skin of patients with DM; it was absent in uninvolved skin. These findings suggest that the complement system may be involved in the pathogenesis of the skin lesions of DM.

Adolescent↗

Sjögren's syndrome and polymyositis or dermatomyositis.

Of four patients with Sjögren's syndrome, three had polymyositis and one had dermatomyositis. In all, deposition of IgG, IgA, IgM, and C3 was observed in muscle by immunofluorescent techniques. Serologic studies revealed elevated levels of serum IgG and IgM, rheumatoid factor, and antinuclear antibody with specificity for SS-A and SS-B antigens. In muscle there was a mononuclear cell infiltrate with plasma cell predominance around small vessels and capillaries. Ultrastructural changes in the vessels included reduplication of the basement membrane, endothelial thickening, and numerous tubuloreticular and dense inclusions. In two patients, electrondense deposits were noted in the microvasculature. This combination of immunoglobulin deposition in muscle, prominent microvascular changes, and characteristic serology suggests that the myositis in Sjögren's syndrome may result from small-vessel injury by autoantibodies or circulating immune complexes.

Adult↗

In vitro study of cytotoxic factors against endothelium in childhood dermatomyositis.

In a previous report we showed that leukocytes from a group of patients with childhood dermatomyositis (CDM) were not cytotoxic toward cultured normal human skeletal muscle cells. Blood products from 11 patients with CDM and 12 age- and sex-matched controls were tested for cytotoxicity toward human endothelium using a chromium 51 assay. Mixed lymphocytes, monocytes, and serum alone or in combination did not produce endothelial cell death. The combination of serum and leukocytes, however, did produce some cytotoxic effects in three of 11 patients with CDM. We conclude that those factors tested in vitro are not responsible for the endothelial cell death but together may produce cytotoxic changes in some patients.

Adolescent↗

Fatal pulmonary involvement in dermatomyositis.

A 12-year-old boy with classic dermatomyositis developed a rapidly progressive pulmonary process that led to his death a month later. Physiologically, there was interference with the oxygenation of the blood even when 100% oxygen was delivered to the lungs under pressure. Microscopic examination of the lungs disclosed diffuse interstitial pulmonary fibrosis. We conclude that these pulmonary changes were a component of the basic disease.

Anti-Bacterial Agents↗

Required surgical therapy in the pediatric patient with dermatomyositis.

A review of 96 patients with the established diagnosis of childhood dermatomyositis revealed that 15 patients required surgical therapy in addition to diagnostic biopsy. Four of the patients had perforation of the esophagointestinal tract, and 11 required surgical therapy for abscesses, calcific deposits, or treatment of pneumothorax. The life-threatening lesions were perforations of the esophagus and intestine. The best surgical therapy is closure, resection, and adequate drainage. Prognosis depends on treatment of the underlying medical disease.

Abscess↗

Keratinocyte apoptosis and p53 expression in cutaneous lupus and dermatomyositis.

Keratinocyte apoptosis may be induced by ultraviolet-B radiation and represents a potential source of fragmented autoantigens in autoimmune diseases. This study investigates whether excessive keratinocyte apoptosis occurs in the skin lesions of cutaneous lupus (CLE) and dermatomyositis (DM) and the potential mechanisms responsible for this phenomenon. Skin biopsies have been studied from 19 patients with CLE and DM, eight with scleroderma, and five healthy controls. Apoptosis was detected by in situ end-labelling of fragmented DNA. The expression of Bcl-2, PCNA, p53, and Ki-67 proteins was studied by immunohistochemistry. In DM and CLE skin, the number of apoptotic keratinocytes was significantly increased (p=0.008) compared with normal skin. In both diseases, a large accumulation of apoptotic keratinocytes and apoptotic bodies was present in the disrupted basal zone. Unlike normal skin, a large number of keratinocytes, particularly those morphologically apoptotic, expressed p53 protein. A significant increase in the number of proliferating Ki-67 positive (p=0.0007) and PCNA-positive (p=0.0008) nuclei was also observed. In both CLE and DM, exaggerated and inappropriate keratinocyte apoptosis occurs. It is associated with increased expression of p53 and PCNA. This suggests that normal solar radiation alone or in combination with additional local factors induces DNA damage and excessive keratinocyte apoptosis in these autoimmune diseases of the skin. Apoptosis can mediate the severe epidermal lesions observed in both diseases and the release of fragmented autoantigens into the dermis.

Adult↗

Frequency of relapses in patients with polymyositis and dermatomyositis.

The frequency of clinical and biochemical relapses was determined in a group of 50 patients with polymyositis (PM), dermatomyositis (DM), or overlap syndromes who were followed for periods of up to 13 years. Relapses occurred in 30 of the 50 patients (60%) during the period of follow-up. The annual relapse rate was not significantly different in the three groups of patients. Subclinical relapses occurred in each group but were less frequent in the DM than in the PM and overlap groups. Relapses could occur at any time but were more frequent during periods of stable maintenance therapy. There was no correlation between relapses and initial disease severity, delay to diagnosis and commencement of treatment, or any class I or II histocompatibility locus antigen.

Anti-Inflammatory Agents↗

Analysis of 31P MR spectroscopy data using artificial neural networks for longitudinal evaluation of muscle diseases: dermatomyositis.

Classical myopathic dermatomyositis (DM) is a chronic autoimmune disease characterized by an erythematous rash and severe, proximal muscle weakness. A disease variant, amyopathic DM, presents with the typical rash but without clinical evidence of muscle weakness. Prednisone and immunosuppressive drugs alleviate symptoms in many patients. Accurate longitudinal evaluations of patients are important to limit serious side effects of these drugs, including osteoporosis, cataracts, and growth inhibition. Metabolic abnormalities detected with 31P magnetic resonance spectroscopy (MRS) provide the best quantitative data for evaluating these patients. With 31P MRS, the levels of inorganic phosphate (Pi), phosphocreatine (PCr), ATP, and phosphodiesters (PDE) were determined in the quadricep muscles of patients during rest and exercise. Artificial neural network (ANN) analyses of these data were previously used for accurate classification of patients with myopathic or amyopathic DM and normal controls. In the present investigation, an artificial neural network was employed for further analysis of the 31P metabolite levels in quantitative, longitudinal evaluations of the extent (percent) of clinical improvement or deterioration during treatment with prednisone and immunosuppressive drugs. The ANN results showed that adult patients in a severe myopathic state could improve with treatment to a clinical status of amyopathic DM. In contrast, severely weak juvenile patients in the myopathic state recovered to normal status. One juvenile patient did not improve and remained in the myopathic state. Additionally, a serious clinical relapse in an amyopathic patient was predicted with serial ANN analyses well in advance of the actual clinical event. These network analyses show potential utility for clinical applications in muscle diseases.

Adolescent↗

Decreased expression of interleukin-1alpha, interleukin-1beta, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis.

OBJECTIVE: To study the effects of immunosuppressive therapy, in particular, corticosteroids, on morphologic signs of inflammation and expression of cytokines, adhesion molecules, and class I major histocompatibility complex (MHC) antigen in muscle tissue from patients with polymyositis (PM) and dermatomyositis (DM) and to correlate the molecular changes with changes in muscle function. METHODS: Seven patients with PM and 4 patients with DM underwent muscle biopsy before and after 3-6 months of therapy. Ten of the 11 patients were initially treated with prednisolone 30-60 mg/day. The phenotypes of infiltrating inflammatory cells and the expression of interleukin-1alpha (IL-1alpha) and IL-1beta, adhesion molecules, and class I MHC antigen were studied by immunochemistry. Computerized image analysis was used for quantitation of staining. Muscle function was assessed with a muscle function index score. RESULTS: Pronounced improvement of muscle function during the treatment period was noted in 8 of the 11 patients. The changes in muscle function coincided with an almost complete disappearance of inflammatory cells, including CD3+ T cells, in the patients with clinical improvement. These patients also exhibited decreased expression of IL-1alpha, IL-1beta, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), leukocyte function-associated antigen 1alpha, and very late activation antigen 4alpha. Of note, there was persistent expression of IL-1alpha, ICAM-1, and VCAM-1 in capillaries and of class I MHC antigens on muscle fibers in several of the patients who, after corticosteroid treatment, still had muscle weakness despite the disappearance of inflammatory infiltrates. CONCLUSION: Changes in the muscle expression of key molecules in the inflammatory process, such as IL-1alpha and IL-1beta, ICAM-1 and class I MHC antigens, showed a consistent but not complete concordance with changes in and status of muscle function in patients with myositis who received the current standard treatment for the disease. These data indicate that it is possible to further evaluate various therapies for myositis using molecular analysis of muscle biopsy specimens obtained on repeated occasions. In addition, the data demonstrate a dissociation between muscle function and degree of inflammatory infiltration in the affected muscles and suggest that the functional defects are more related to the expression of molecules such as IL-1alpha in muscle capillaries than to the mere presence of inflammatory cells in the affected muscles.

Adrenal Cortex Hormones↗

Medium- and long-term functional outcomes in a multicenter cohort of children with juvenile dermatomyositis.

OBJECTIVE: To evaluate functional outcomes in a cohort of patients with juvenile dermatomyositis (DM). METHODS: A retrospective inception cohort of patients diagnosed as having juvenile DM between January 1, 1984 and January 1, 1995 was established at 4 Canadian tertiary care pediatric centers. Informed consent was obtained. Each subject was interviewed by telephone or in person. The primary outcome was physical function, as measured by the Childhood Health Assessment Questionnaire (CHAQ). Additional outcomes were educational and vocational achievement, growth, development of calcinosis, patient satisfaction with outcome, and development of other illnesses. Data regarding illness presentation, treatment, and disease course were obtained through chart review. RESULTS: Sixty-five of 80 patients (81%; 46 females and 19 males) could be contacted. The median followup time was 7.2 years (range 3.2-13.9 years), with a median age at followup of 13 years (range 7-26 years). Twenty-four patients (37%) had a monocyclic course, while the remaining 41 (63%) had a chronic continuous or polycyclic course. Sixty-two patients (95%) were treated with corticosteroids, while 41 (63%) received a second-line agent. Physical function was excellent, with a median CHAQ score of 0 (range 0-2.50). Eighteen patients had scores >0, and only 5 had moderate-to-severe disability, as defined by a CHAQ score >1.0. Females had higher CHAQ scores, and all but 1 of the patients with scores >0 were female (range 0-2.50; P = 0.015). Patients with a chronic continuous course also had higher CHAQ scores. Sixteen patients in the chronic continuous group had CHAQ scores >0 (range 0-2.50; P = 0.0009). Calcinosis developed in 22 patients (34%) and persisted to followup in 14. Development of calcinosis was not related to initial therapy, sex, or disease course, but was significantly associated with higher CHAQ scores (range 0-1.0 versus 0-2.5; P = 0.01). At the time of followup, 26 patients (40%) still had rash, 15 (23%) still reported weakness, and 23 (35%) continued taking medications, despite the fact that all were at least 3 years postdiagnosis. There was 1 death. CONCLUSION: In general, patients in this cohort had favorable outcomes. Most had CHAQ scores of 0, and only 8% met our definition of moderate-to-severe disability. However, many patients continued to have chronic disease, persistent rash, and continued taking medications >3 years after diagnosis. Further research is needed to improve outcomes for patients with juvenile DM.

Adolescent↗

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.

Adolescent↗

Muscle abnormalities in juvenile dermatomyositis patients: P-31 magnetic resonance spectroscopy studies.

OBJECTIVE: To characterize metabolic abnormalities in the muscles of children with the juvenile variant of dermatomyositis (JDM) by the use of noninvasive P-31 magnetic resonance spectroscopy (MRS). METHODS: Thirteen patients with JDM (ages 4-16 years) were studied. Biochemical status was evaluated with P-31 MRS by determining the concentrations of the high-energy phosphate compounds, ATP and phosphocreatine (PCr), ratios of inorganic phosphate (Pi) to PCr (Pi:PCr ratio), levels of free cytosolic ADP, and phosphorylation potentials (PPs) during rest, exercise, and recovery. RESULTS: Significant metabolic abnormalities were observed in the thigh muscles of 10 severely affected patients during rest, 2 graded levels of exercise, and recovery. Mean ATP and PCr levels in the muscles of JDM patients were 35-40% below the normal control values (P < 0.003). These data, along with elevated Pi:PCr ratios, higher ADP levels, and abnormal values for PPs, indicated defective oxidative phosphorylation in the mitochondria of diseased JDM muscles. MRS findings were normal in 2 additional patients who had improved with prednisone treatment and in 1 patient who had no muscle weakness (amyopathic variant of JDM). CONCLUSION: JDM patients can be monitored with noninvasive P-31 MRS without sedation. Biochemical defects in energy metabolism are concordant with the weakness and fatigue reported by JDM patients. Quantitative MRS data are useful for evaluating patients and optimizing drug treatment regimens.

Adolescent↗

TNFalpha-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications.

OBJECTIVE: To characterize the association between the TNFalpha-308A allele and 1) duration of active disease, 2) peripheral blood mononuclear cell (PBMC) synthesis of tumor necrosis factor alpha (TNFalpha) in vitro, and 3) pathologic calcifications in patients with juvenile dermatomyositis (DM). METHODS: The TNFalpha-308 alleles were determined by polymerase chain reaction in 37 white patients with juvenile DM and in 29 control subjects. Patients were grouped according to duration of immunosuppressive therapy: long (> or =36 months) or short (<36 months). Unstimulated PBMC were examined by enzyme-linked immunosorbent assay for TNFalpha production in vitro. Sixty-five white patients with juvenile DM were examined for pathologic calcifications. RESULTS: TNFalpha-308A was identified in 18 of 37 patients with juvenile DM, in contrast with 5 of 29 controls (P = 0.009). Sixteen of the 18 patients with juvenile DM who had the TNFalpha-308A allele had a disease course > or =36 months, compared with 6 of 19 patients with TNFalpha-308G (P = 0.001). PBMC from 16 of the 18 juvenile DM patients with TNFalpha-308A synthesized more TNFalpha (median 53 pg/ml) compared with PBMC from 9 of 19 patients with TNFalpha-308G (median 19 pg/ml) (P = 0.007). Nineteen of 22 juvenile DM patients requiring therapy for > or =36 months produced more TNFalpha (median 20.5 pg/ml) in comparison with 6 of 15 juvenile DM patients with a <36-month treatment course (median TNFalpha 0.0 pg/ml) (P = 0.005). Detectable calcifications were present in 3 of 8 children with juvenile DM who had TNFalpha-308AA, compared with 2 of 21 children with TNFalpha-308AG and 1 of 36 children who had TNFalpha-308GG (P = 0.017). CONCLUSION: A long course of juvenile DM and the presence of pathologic calcifications were associated with the TNFalpha-308A allele and with the increased production of TNFalpha, which may perpetuate the inflammatory response.

Alleles↗

The economic impact of intermittent high-dose intravenous versus oral corticosteroid treatment of juvenile dermatomyositis.

OBJECTIVE: To perform a cost-identification and cost-effectiveness analysis comparing oral corticosteroids (OCS) with high-dose intermittent intravenous corticosteroid (IVCS) regimens in the treatment of juvenile dermatomyositis (JDM). METHODS: Children previously diagnosed and treated for JDM (without myositis-specific or myositis-associated autoantibodies) at a single medical center by a single provider were identified. Two treatment protocols were compared: OCS and IVCS. Data on initial disease severity, time to remission, resource use, and costs generated were collected from patient records. Incremental cost-effectiveness ratios (ICE) were constructed. RESULTS: Patients treated with IVCS achieved median remission 2 years earlier at median increased cost of $13,736. The ICE ratio comparing IVCS to OCS is $6,868 per year of disease avoided. CONCLUSION: This study suggests that, although IVCS treatments are costly, they are cost-effective.

Administration, Oral↗

Cholestasis in juvenile dermatomyositis: report of three cases.

This report describes 3 cases of juvenile dermatomyositis (juvenile DM) complicated by cholestasis. All 3 patients had typical features of juvenile DM, and all developed a cholestatic syndrome within the initial months of their disease. Liver biopsy revealed mixed (cytoplasmic and ductal) cholestasis with no abnormalities in the intrahepatic ducts in all 3 cases. Cholestasis improved or was completely reversible upon treatment with prednisone. In the 2 patients who could be followed up long term, no sequelae remained. The possible role of inflammation in the pathogenesis of cholestasis in juvenile DM is discussed.

Adolescent↗