Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

The effect of salicylate on the metabolism of normal and stimulated human lymphocytes in vitro.

The effect of salicylate on the metabolism of peripheral blood lymphocytes in tissue culture was investigated. Lymphocytes incubated with sodium salicylate at a concentration of 30 mg/100 ml showed increased glucose consumption, lactic acid production, and oxygen consumption, evidence for uncoupling of oxidative phosphorylation. No decrease in cell number or viability (trypan blue dye exclusion) was noted in salicylate-treated cultures. Normal DNA, RNA, and total protein synthesis measured by radioisotope incorporation was depressed in the salicylate-treated cultures. Increased DNA synthesis after the addition of a mitogen (PHA) or antigen (PPD) to the culture was strikingly suppressed by salicylate. The degree of suppression was proportional to the concentration of salicylate used. The effect on RNA and protein synthesis in stimulated lymphocytes was much less pronounced. Acetylsalicylic acid was found to be as active as sodium salicylate in suppressing DNA synthesis, but the p-OH congener (p-OH benzoic acid) did not alter cell respiration, glycolysis, viability, or DNA synthesis. The salicylate effect was reversible as evidenced by return of cellular reactivity upon removal of the drug from the media.

Vitamin D metabolism in rats with adjuvant-induced arthritis.

Adjuvant-induced arthritis in rats shares many of the features of humans with rheumatoid arthritis, including the development of osteopenia in areas distal to erosive joint disease. We established adjuvant arthritis in male and female Sherman strain rats and then studied external calcium balances and vitamin D metabolism during the period of acute active clinical, serologic, and pathologic arthritis and osteopenia and in the preclinical period. While ingesting a calcium-sufficient vitamin D-replete diet (0.6% calcium, 0.65% phosphorus, and 2.2 IU D3 per g food), female rats with arthritis demonstrated reduced calcium balance (arthritic, 36 +/- 8 versus control, 169 +/- 13 mg per 6 days, p less than 0.02) because of inefficient gastrointestinal absorption of calcium (arthritic 9.7% versus control 37%). This was associated with calcitriol deficiency (arthritic 52 +/- 7 versus control 70 +/- 10 pg/ml) and reduced osteocalcin levels. Male rats with arthritis demonstrated an inability to raise serum calcitriol levels to the same degree as control rats (200 +/- 30 versus 440 +/- 70, respectively) while ingesting a calcium-deficient diet (0.002% calcium, 0.34% phosphorus, and 2.2 IU D3 per g food) and also had reduced balance (59 +/- 7 versus 85 +/- 10 mg per 6 days, respectively) due in part to decreased efficiency of absorption (55 versus 67%). No abnormalities in calcium balance or in serum calcitriol levels on the sufficient diet were present in the preclinical period. Physiologic calcitriol replacement to arthritic female rats increased osteoid available for mineralization and increased mineral apposition rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Torg osteolysis syndrome.

We describe a 9-year-old girl who initially presented at age 4 with evidence of arthritis in her hands, feet, and large joints. Although she had a partial response to anti-inflammatory medications and had some laboratory results consistent with inflammatory disease, radiographs showed carpal and tarsal osteolysis associated with interphalangeal joint erosions. There was also widening of the shafts of the metacarpals and metatarsals with thinning of the cortices. Based on both the clinical progression of her illness and the radiologic characteristics, this child most likely has the Torg syndrome.

Cor pulmonale secondary to upper airway obstruction. Cardiac catheterization, immunologic, and psychometric evaluation in nine patients.

Previous reports of cor pulmonale due to upper airway obstruction have not noted that chronic hypoxemia due to alveolar hypoventilation can lead to left as well as right ventricular failure in these patients. We found elevated left ventricular end-diastolic pressure in four of five patients. Although these patients have frequent respiratory infections, no investigation of their immune status has previously been reported. We performed such investigations but could not demonstrate an immunologic deficiency. Although nine of 44 patients previously reported were mentally retarded, no psychometric data were available. We studied five patients but could not determine the role of mental subnormality in this syndrome. Diagnosis of this syndrome should be suspected when clinical and roentgenographic findings of biventricular heart failure are associated with right ventricular hypertrophy on electrocardiogram. The diagnosis of alveolar hypoventilation is confirmed by blood gas findings and examination of the upper airways. Surgical removal of obstructive tissue reverses the cardiac involvement.

Cryoprecipitates in Kawasaki syndrome: association with coronary artery aneurysms.

Cryoprecipitates are postulated to play a role in the pathogenesis of several vasculitis illnesses and infectious diseases. To investigate the presence of cryoprecipitates in Kawasaki syndrome, we studied sera from 25 children with acute Kawasaki syndrome. None of the subjects was treated with intravenous gamma-globulin. Cryoprecipitates were detectable in sera of 11 of 25 (44%) children studied. The mean (+/- SE protein concentration of the cryoprecipitates was 88.0 (+/- 20.2) micrograms/ml serum. Cryoprecipitates consisted primarily of IgG and IgM; no complement components were detected but highly sensitive methods were not used. The presence of cryoprecipitates in the serum of children with acute Kawasaki syndrome was associated with the subsequent development of coronary artery aneurysms detected by echocardiogram (P less than 0.05). There was no association between detectable cryoprecipitates and either peak platelet count or erythrocyte sedimentation rate. In one patient, measurement of cryoprecipitates in serial samples showed a reduction in concentrations that paralleled subsidence of disease activity. We speculate that cryoprecipitates may be a marker for increased risk of coronary aneurysm formation and may play a role in the pathogenesis of the cardiac disease in Kawasaki syndrome.

Correction of neutropenia and hypogammaglobulinemia in X-linked hyper-IgM syndrome by allogeneic bone marrow transplantation.

X-linked hyper-IgM (X-HIM) syndrome is a primary immunodeficiency disease characterized by defects in both cellular and humoral immunity. X-HIM is caused by mutations in the gene for CD40 ligand (CD40L), a T cell membrane protein that mediates T cell-dependent immune functions. We report the case of a 6-year-old male with X-HIM due to an intronic mutation resulting in aberrant CD40L RNA splicing and absence of detectable CD40L protein. The patient had a history of multiple infectious complications and chronic neutropenia requiring treatment with recombinant granulocyte colony-stimulating factor, and underwent allogeneic bone marrow transplantation from an HLA-matched sibling donor. Following successful engraftment, T cell CD40L expression and immunoglobulin isotype switching were reconstituted and neutropenia resolved. Allogeneic bone marrow transplantation can correct neutropenia and reconstitute immune function in X-HIM.

Inflammatory myopathy in children.

The symptoms of inflammatory muscle disease in children can be characterized as either acute or chronic in nature; acute muscle complaints are usually associated with viral or bacterial infectious agents. Throughout the world, most of the acute inflammatory myopathies may be a consequence of bacterial or parasitic infection, but in North America, acute myositis is more often a viral cause. A child with chronic inflammatory myositis may have some symptoms that are similar to those seen in adults who develop one of the idiopathic inflammatory myopathies. These myopathies comprise a very diverse group of syndromes that have in common chronic muscle inflammation of unknown pathophysiology resulting in damage and affecting muscle function.

Radiological approaches in the evaluation of joint disease in children.

In summary, the newer technologies in radiology have allowed us to visualize more clearly the manifestation of joint disease in children. The presence of small erosions and cartilage damage can be seen much better with magnetic resonance imaging than with any other modality short of arthrography, a much more invasive examination. Joint effusion, although sometimes visualized with conventional radiography, is probably best recognized with ultrasound or magnetic resonance imaging, although it can be detected with computed tomography as well. For the evaluation of avascular necrosis that can be associated with steroid use in joint disease, bone scintigraphy is a simple, sensitive method. Magnetic resonance may be as or more sensitive and gives additional information as well. In the detection of change with time, conventional radiography probably will remain the standard as it is still the simplest, least expensive examination; however, it has many limitations in specific cases. Bone scintigraphy may be of value in selected cases. Although we have still not had enough experience with magnetic resonance imaging to use it as a way of evaluating progress of joint disease, it promises to be the most sensitive radiologic measure of evaluating progress as small anatomical changes can be detected within the cartilage, which cannot be done easily with other means.

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.

Evaluation of a psychological treatment package for treating pain in juvenile rheumatoid arthritis.

We examined the utility of psychological treatment procedures for children with high levels of pain associated with juvenile rheumatoid arthritis (JRA). By the use of a multiple baseline across subjects design, four children were assigned to an immediate treatment group, and four children to a delayed treatment group. The six-session treatment included relaxation training, electromyogram, and thermal biofeedback for the child; mothers were trained in the use of behavioral techniques for managing physical therapy and school attendance. Visual inspection of the data indicates small changes on children's self-reported pain diary scores for mean pain and ratings of high (greater than 5 on a 10-point visual analogue scale) pain periods, with 50% to 62% showing at least a 25% reduction in pain immediately after treatment, and 62% to 88% showing a 25% reduction by 6-month follow-up. Maternal reports of changes paralleled those of the children. Comparisons of Mann-Whitney U-tests conducted pre- and posttreatment indicated no differences for children's ratings of mean pain or +5 pain ratings between the immediate and delayed treatment groups; greater improvement for the immediate treatment group was noted on maternal reports of both mean pain (p < 0.05) and +5 pain (p < 0.5) ratings. The reduction of pain reports from pretreatment to follow-up was significant for children's mean pain (p = 0.02), +5 pain ratings (p = 0.02), and mother's reports of mean pain (p = 0.03) and +5 pain periods (p = 0.01). Maternal reports of the number of pain-related behaviors that the child exhibited also declined (p < 0.05). No reduction in physical therapist's ratings of pain during evaluation were noted. No increases in maternal reports of child's psychological adjustment problems were reported following treatment. Results provide modest support for the use of psychological interventions with patients with JRA.

Juvenile dermatomyositis (JDMS): new clues to diagnosis and pathogenesis.

The localization of focal inflammatory myopathy (IM) is aided by MRI, which facilitates diagnostic testing (muscle biopsy or EMG). Antibodies to antigens involved in protein synthesis are specific for IM and characterize distinct subsets of adult IM, but are rare in pediatric IM. In definite juvenile dermatomyositis, serological indicators of disease activity include neopterin and von Willebrand factor antigen, markers of macrophage activation, and endothelial cell damage, respectively; nailfold capillarioscopy documents small blood vessel involvement. Monitoring the percentage of circulating B cells may indicate the response to therapy.

Liposyn infusion increases plasma prostaglandin concentrations.

To determine whether Liposyn infusion results in increased plasma prostaglandin (PG) concentrations, the following study was performed in 33 adult rabbits with chronically implanted arterial and venous catheters. Plasma PG concentrations were determined by radioimmunoassay for two vasodilators, PGE2 and PGI2 (as measured by its metabolite 6-keto-PGF1 alpha), and two vasoconstrictors, thromboxane (TX) A2 and PGF2 alpha, as measured by their metabolites TXB2 and PGF2 alpha-M, respectively. A 1-hour infusion of Liposyn at 4 ml per kg resulted in statistically significant increases in arterial and venous concentrations of PGE2 and 6-keto-PGF1 alpha (p less than 0.001) and of TXB2 (p less than 0.04). There were no significant changes in PGF2 alpha-M plasma concentrations. Liposyn infusion also resulted in a small but statistically significant increase in PaO2 of 4.7 +/- 1.5 torr (p less than 0.01). It is concluded that Liposyn infusion results in statistically significant increases in plasma concentrations of PGE2, 6-keto-PGF1 alpha, and TXB2.

Effect of sodium salicylate on hamster cells in vitro.

Doses of sodium salicylate greater than 100 mug/ml increased the generation time of baby hamster kidney (BHK 21) cells in culture from 16 to 35 hr. Exposure to similar doses of salicylate for 18-44 hr resulted in a marked reduction of RNA synthesis. The species of RNA synthesized in the presence of sodium salicylate appeared to be similar to those synthesized by normal cells in the absence of sodium salicylate. Sodium salicylate did not alter the oxidative phosphorylation of BHK cells.

Juvenile dermatomyositis.

Myositis in childhood is characterized by elevated serum levels of muscle-derived enzymes, proximal symmetrical muscle weakness, abnormal EMG findings, and a muscle biopsy, which frequently documents an inflammatory process. In the pediatric age group, JDMS, which has characteristic cutaneous involvement in addition to myositis, is much more common than PM and is more common among female patients. With the use of steroids, mortality has been reduced from 33 per cent to 7 per cent. The development of calcifications can be the most debilitating consequence of JDMS. It is our premise that JDMS is a distinct disease entity and that the increase in HLA-B8 and DR3 in JDMS suggests that genetic background may predispose to disease development. There are conflicting data concerning immunologic abnormalities in JDMS, but there appears to be impairment of natural killing and evidence of complement activation. Results of tests for ANA frequently are positive in JDMS, but Jo-1 antibody, found in some adults with PM, has not been found in JDMS. Most newly diagnosed JDMS patients have antibodies to coxsackie B that may be related to the pathogenesis of this disease. Specific pathologic findings of endothelial cells containing reticulotubular inclusions are associated with small vessel occlusion, subsequent obliteration, and increased factor VIII levels in clinically active disease. In addition to physical therapy, steroids are used most frequently, but other immunosuppressive agents and plasmapheresis have been tried in severely ill children. Rigorous evaluation of the efficacy of these modalities is needed.

Juvenile dermatomyositis. Pathophysiology and disease expression.

In summary, the child who develops the symptoms of the specific rash, proximal muscle weakness, or fatigue should seek medical care promptly. With the advances in physical and medical therapy, many of the consequences of the disease can now be ameliorated. Data suggest that JDMS and PM may each have a different pathophysiology, but more evidence is needed. The next few years will be exciting as there is a national effort by an increased number of investigators to determine the epidemiologic and genetic factors that influence JDMS disease susceptibility and severity.