PubMed Health⌕ Search

Biomedical subjects

Ann M Reed

Publications and source records attributed to Ann M Reed.

At least 19 recordsLinked to original sources
PubMed2025

Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

Humans↗
PubMed2006

Spondyloarthropathy presenting at a young age: case report and review.

The diagnosis of juvenile spondyloarthritis (JSA) is rarely entertained in young children who present with back and leg pain. We present a case of a 6-year-old male who presented with a 3-year history of severe back and leg pain and a positive Gower's sign, and was given a presumed diagnosis of muscular dystrophy. Presenting serologic evaluation included a mildly elevated sedimentation rate and C-reactive protein (CRP). Computed tomography of the pelvis demonstrated large erosions affecting both sacro-iliac joints. Despite the unusually young age of this patient, ankylosing spondylitis seemed the most plausible diagnosis. Following rheumatological evaluation and treatment for JSA, he showed significant clinical improvement. His disease, however, has not entirely remitted with signs of enthesitis at the Achilles tendon and knees. We present this case to illustrate that JSA could account for symptoms at an early age and not considering it could lead to multiple medical visits and diagnoses. To our knowledge, based on a search of the World literature, this would appear to be the youngest case of JSA reported with demonstrable severe sacroiliitis.

Back Pain↗
PubMed2006

HLA polymorphisms in African Americans with idiopathic inflammatory myopathy: allelic profiles distinguish patients with different clinical phenotypes and myositis autoantibodies.

OBJECTIVE: To investigate possible associations of HLA polymorphisms with idiopathic inflammatory myopathy (IIM) in African Americans, and to compare this with HLA associations in European American IIM patients with IIM. METHODS: Molecular genetic analyses of HLA-A, B, Cw, DRB1, and DQA1 polymorphisms were performed in a large population of African American patients with IIM (n = 262) in whom the major clinical and autoantibody subgroups were represented. These data were compared with similar information previously obtained from European American patients with IIM (n = 571). RESULTS: In contrast to European American patients with IIM, African American patients with IIM, in particular those with polymyositis, had no strong disease associations with HLA alleles of the 8.1 ancestral haplotype; however, African Americans with dermatomyositis or with anti-Jo-1 autoantibodies shared the risk factor HLA-DRB1*0301 with European Americans. We detected novel HLA risk factors in African American patients with myositis overlap (DRB1*08) and in African American patients producing anti-signal recognition particle (DQA1*0102) and anti-Mi-2 autoantibodies (DRB1*0302). DRB1*0302 and the European American-, anti-Mi-2-associated risk factor DRB1*0701 were found to share a 4-amino-acid sequence motif, which was predicted by comparative homology analyses to have identical 3-dimensional orientations within the peptide-binding groove. CONCLUSION: These data demonstrate that North American IIM patients from different ethnic groups have both shared and distinct immunogenetic susceptibility factors, depending on the clinical phenotype. These findings, obtained from the largest cohort of North American minority patients with IIM studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms and/or different gene-environment interactions.

Adenosine Triphosphatases↗
PubMed2006

Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians.

OBJECTIVE: To define the relative importance (RI) of class II major histocompatibility complex (MHC) alleles and peptide binding motifs as risk or protective factors for juvenile dermatomyositis (DM), and to compare these with HLA associations in adult DM. METHODS: DRB1 and DQA1 typing was performed in 142 Caucasian patients with juvenile DM, and the results were compared with HLA typing data from 193 patients with adult DM and 797 race-matched controls. Random Forests classification and multiple logistic regression were used to assess the RI of the HLA associations. RESULTS: The HLA-DRB1*0301 allele was a primary risk factor (odds ratio [OR] 3.9), while DQA1*0301 (OR 2.8), DQA1*0501 (OR 2.1), and homozygosity for DQA1*0501 (OR 3.2) were additional risk factors for juvenile DM. These risk factors were not present in patients with adult DM without defined autoantibodies. DQA1 alleles *0201 (OR 0.37), *0101 (OR 0.38), and *0102 (OR 0.51) were identified as novel protective factors for juvenile DM, the latter 2 also being protective factors in adult DM. The peptide binding motif DRB1 (9)EYSTS(13) was a risk factor, and DQA1 motifs F(25), S(26), and (45)(V/A)W(R/K)(47) were protective. Random Forests classification analysis revealed that among the identified risk factors for juvenile DM, DRB1*0301 had a higher RI (100%) than DQA1*0301 (RI 57%), DQA1*0501 (RI 42%), or the peptide binding motifs. In a logistic regression model, DRB1*0301 and DQA1*0201 were the strongest risk and protective factors, respectively, for juvenile DM. CONCLUSION: DRB1*0301 is ranked higher in RI than DQA1*0501 as a risk factor for juvenile DM. DQA1*0301 is a newly identified HLA risk factor for juvenile DM, while 3 of the DQA1 alleles studied are newly identified protective factors for juvenile DM.

Adolescent↗
PubMed2006

Acute graft-versus-host disease after liver transplantation diagnosed by fluorescent in situ hybridization testing of skin biopsy specimens.

Acute graft-versus-host disease after orthotopic liver transplantation is an underrecognized entity with a guarded prognosis. We describe a patient who underwent orthotopic liver transplantation with an HLA-matched donor liver. She had an uneventful recovery from operation up until day 36 posttransplantation, when she developed a generalized, erythematous, mostly macular eruption, accompanied by ascites, diarrhea, and fever. The diagnosis of graft-versus-host disease was considered but a drug rash could not be excluded. A polymerase chain reaction-based chimerism assay failed to identify donor DNA in peripheral blood. A confirmatory fluorescent in situ hybridization analysis revealed significant numbers of donor lymphocytes in biopsied skin, with lesser amounts in biopsy specimens from the stomach and colon. Despite immunosuppressive treatment, the patient died of overwhelming sepsis 18 weeks after transplantation. We conclude that early testing of skin biopsy specimens using fluorescent in situ hybridization in sex-mismatched patients with orthotopic liver transplantation can serve as an early diagnostic tool for graft-versus-host disease.

Acute Disease↗
PubMed2006

Gene expression profiling in human autoimmunity.

Human autoimmune diseases are well suited for the application of gene expression profiling. Sampling of blood cells and target tissues has already revealed many important pathways contributing to this spectrum of disorders, and many commonalities are emerging. For instance, clinically distinct diseases such as systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, and psoriasis all show evidence for dysregulation of the type I interferon pathway. These data suggest that autoimmune diseases will eventually be categorized at the level of gene expression. This work has led to advances in our understanding of disease pathogenesis and in the future promises to facilitate assessments of disease activity and improve targeting of therapies. Here, we review the literature on gene profiling in human autoimmune diseases and provide perspective on the current state of the art.

Autoimmune Diseases↗
PubMed2006

Enzyme elevation in patients with juvenile dermatomyositis and steroid myopathy.

OBJECTIVE: Steroid myopathy can occur in patients with juvenile dermatomyositis (JDM) receiving chronic steroid therapy. We report an elevation of serum muscle enzymes, normal strength by manual muscle testing (MMT), and electromyographic (EMG) findings of steroid myopathy in children with JDM. METHODS: We prospectively studied children with JDM with a history of chronic steroid use (> 3 mo) and ongoing inflammatory myositis who were referred to our institution. RESULTS: We identified 5/9 children with JDM receiving longterm high dose steroids who had muscle enzyme elevation with no definable weakness and EMG findings consistent with steroid myopathy. All subjects improved after withdrawal of their steroid therapy. CONCLUSION: Longterm high dose steroids may lead to steroid myopathy with muscle enzyme elevation, previously reported only with acute steroid myopathy. We recommend that muscle derived enzyme levels should not be used to differentiate steroid myopathy from inflammatory myopathies.

Adolescent↗
PubMed2005

Cysteine-tailed class I-binding peptides bind to CpG adjuvant and enhance primary CTL responses.

Immunostimulatory CpG motifs in synthetic oligonucleotides can be effective adjuvants for the priming of CTLs. We first observed that a single male-specific peptide (KCSRNRQYL) (HY2) was more efficient than another male-specific peptide (WMHHNMDLI) (HY1) at priming IFN-gamma-secreting CTLs in vivo when combined with lipid A and CpG and that it also visibly precipitated CpG. The addition of the six N-terminal residues (KCSRNR) from HY2 to HY1 yielded a peptide, KCSRNR-HY1, that both precipitated CpG and primed increased numbers of HY1-specific CTLs. We refer to this type of peptide as a primotope that includes a class I binding peptide tailed with amino acids that increase priming. Ala residues were substituted for the Arg/Lys residues (ACSANA-HY1), and these substitutions did not reduce in vivo priming potential. However, the substitution of Ala for Cys (KASRNR-HY1) resulted in the complete loss of priming, demonstrating the importance of Cys for in vivo priming when mixed with CpG. This result suggested that increased priming was based in disulfide bonding between Cys residues and internal phosphorothioate groups of synthetic CpG. The addition of Cys-bearing primotopes to radiolabeled CpG with a single thioate group resulted in the appearance of a new band that was inhibited by 1) Cys > Ala substitution and 2) reduction and alkylation of CpG. These results reveal a novel mechanism for complexing class I binding peptides and CpG adjuvant for development of new peptide-adjuvant combinations for vaccines for cancer and infectious diseases.

Adjuvants, Immunologic↗
PubMed2005

Recent advances in juvenile dermatomyositis.

This paper reviews the knowledge we continue to gain in the areas of pathogenesis, evaluation of disease activity, and interventional strategies with regards to idiopathic inflammatory myositis. Potential new diagnostic criteria incorporate the use of magnetic resonance imaging and other imaging modalities along with the use of muscle biopsy pathologic features including that of immunologic markers. Specifically, this criterion reflects the upregulation of major histocompatibility complex molecules on muscle tissue during acute inflammation.

Dermatomyositis↗
PubMed2005

Antiphospholipid syndrome with catastrophic bleeding and recurrent ischemic strokes as initial presentation of systemic lupus erythematosus.

Bleeding is a rare manifestation of lupus anticoagulant-antiphospholipid syndrome unless associated with coagulation factor deficiency, thrombocytopenia, or intrinsic vascular defect. The authors report the clinical and laboratory findings in a 16-year-old boy with potent lupus anticoagulant who initially presented with recurrent epistaxis, hematuria, and gastrointestinal bleeding. Lupus anticoagulant potently inhibited assay systems for coagulation factors, but levels of factors II, IX, and XI appeared to be decreased (2-5% of mean normal levels). Within 2 weeks after diagnosis, spontaneous subdural hematomas developed. During hemostatic therapy, including plasmapheresis and infusions of recombinant activated factor VII and activated prothrombin complex concentrate, an ischemic stroke developed. Subsequent multifocal recurrent ischemic strokes developed despite immunosuppression. This case shows that lupus anticoagulant or antiphospholipid antibodies can cause both hemorrhagic and thrombotic complications in the same patient and may, in some patients, have multiple target antigens (eg, coagulation factors II, IX, XI).

Adolescent↗
PubMed2004

Normal scores for nine maneuvers of the Childhood Myositis Assessment Scale.

OBJECTIVE: To document and evaluate the scores that normal, healthy children achieve when performing 9 maneuvers of the Childhood Myositis Assessment Scale (CMAS). METHODS: A total of 303 healthy children, 4-9 years of age, were scored as they performed 9 CMAS maneuvers. The data were then evaluated to determine whether normal scores for some maneuvers are age and sex dependent. RESULTS: All children were able to achieve maximum possible scores for the supine to prone, supine to sit, floor sit, floor rise, and chair rise maneuvers. All but 2 4-year-olds achieved a maximum possible score for the arm raise/duration maneuver. Performance of the head lift and sit-up maneuvers varied significantly, depending primarily on age. Children in all age groups had less difficulty performing the leg lift than the head lift or sit-up. CONCLUSION: The normative data generated by this study are of value for interpreting the serial CMAS scores of children with idiopathic inflammatory myopathies.

Child↗
PubMed2004

Does HLA-dependent chimerism underlie the pathogenesis of juvenile dermatomyositis?

Juvenile dermatomyositis (JDM) is a multisystem autoimmune disease that at times resembles chronic graft-vs-host disease. This led us to suggest that nonself cells may play a role in the disease process. In this study we examined the relationship between HLA genotype and the presence of maternally derived chimeric cells in JDM patients and healthy controls, and assessed immunologic activity in the chimeric cells. We identified chimeric cells more often in children with JDM (60 of 72) than in their unaffected siblings (11 of 48) or in healthy controls (5 of 29). The presence of chimerism in the JDM patients, their healthy siblings, and unaffected control children was associated with a HLA-DQA1*0501 allele in the mother (p = 0.011). Further, we show that maternally transferred chimeric T cells are responsive to the host's (JDM childs') lymphocytes (33.75 +/- 8.4 IFN-gamma-producing cells from JDM cells vs 5.0 +/- 1.25 from maternal cells), and that this is a memory response. These combined data indicate that chimeric cells play a direct role in the JDM disease process and that the mother's HLA genotype facilitates the transfer and/or persistence of maternal cells in the fetal circulation.

Adolescent↗
PubMed2004

Validation and clinical significance of the Childhood Myositis Assessment Scale for assessment of muscle function in the juvenile idiopathic inflammatory myopathies.

OBJECTIVE: To examine the measurement characteristics of the Childhood Myositis Assessment Scale (CMAS) in children with juvenile idiopathic inflammatory myopathy (juvenile IIM), and to obtain preliminary data on the clinical significance of CMAS scores. METHODS: One hundred eight children with juvenile IIM were evaluated on 2 occasions, 7-9 months apart, using various measures of physical function, strength, and disease activity. Interrater reliability, construct validity, and responsiveness of the CMAS were examined. The minimum clinically important difference (MID) and CMAS scores corresponding to various degrees of physical disability were estimated. RESULTS: The intraclass correlation coefficient for 26 patients assessed by 2 examiners was 0.89, indicating very good interrater reliability. The CMAS score correlated highly with the Childhood Health Assessment Questionnaire (C-HAQ) score and with findings on manual muscle testing (MMT) (r(s) = -0.73 and 0.73, respectively) and moderately with physician-assessed global disease activity and skin activity, parent-assessed global disease severity, and muscle magnetic resonance imaging (r(s) = -0.44 to -0.61), thereby demonstrating good construct validity. The standardized response mean was 0.81 (95% confidence interval 0.53, 1.09) in patients with at least 0.8 cm improvement on a 10-cm visual analog scale for physician-assessed global disease activity, indicating strong responsiveness. In bivariate regression models predicting physician-assessed global disease activity, MMT remained significant in models containing the CMAS (P = 0.03) while the C-HAQ did not (P = 0.4). Estimates of the MID ranged from 1.5 to 3.0 points on a 0-52-point scale. CMAS scores corresponding to no, mild, mild-to-moderate, and moderate physical disability, respectively, were 48, 45, 39, and 30. CONCLUSION: The CMAS exhibits good reliability, construct validity, and responsiveness, and is therefore a valid instrument for the assessment of physical function, muscle strength, and endurance in children with juvenile IIM. Preliminary data on MID and corresponding levels of disability should aid in the clinical interpretation of CMAS scores when assessing patients with juvenile IIM.

Adolescent↗
PubMed2004

International consensus on preliminary definitions of improvement in adult and juvenile myositis.

OBJECTIVE: To use a core set of outcome measures to develop preliminary definitions of improvement for adult and juvenile myositis as composite end points for therapeutic trials. METHODS: Twenty-nine experts in the assessment of myositis achieved consensus on 102 adult and 102 juvenile paper patient profiles as clinically improved or not improved. Two hundred twenty-seven candidate definitions of improvement were developed using the experts' consensus ratings as a gold standard and their judgment of clinically meaningful change in the core set of measures. Seventeen additional candidate definitions of improvement were developed from classification and regression tree analysis, a data-mining decision tree tool analysis. Six candidate definitions specifying percentage change or raw change in the core set of measures were developed using logistic regression analysis. Adult and pediatric working groups ranked the 13 top-performing candidate definitions for face validity, clinical sensibility, and ease of use, in which the sensitivity and specificity were >/=75% in adult, pediatric, and combined data sets. Nominal group technique was used to facilitate consensus formation. RESULTS: The definition of improvement (common to the adult and pediatric working groups) that ranked highest was 3 of any 6 of the core set measures improved by >/=20%, with no more than 2 worse by >/=25% (which could not include manual muscle testing to assess strength). Five and 4 additional preliminary definitions of improvement for adult and juvenile myositis, respectively, were also developed, with several definitions common to both groups. Participants also agreed to prospectively test 6 logistic regression definitions of improvement in clinical trials. CONCLUSION: Consensus preliminary definitions of improvement were developed for adult and juvenile myositis, and these incorporate clinically meaningful change in all myositis core set measures in a composite end point. These definitions require prospective validation, but they are now proposed for use as end points in all myositis trials.

Adult↗
PubMed2004

Cushing's syndrome after intra-articular and intradermal administration of triamcinolone acetonide in three pediatric patients.

BACKGROUND: Intra-articular and intradermal steroids are often used for their antiinflammatory effect. There is limited experience with intra-articular and intralesional administration of corticosteroids in the pediatric age group. DESIGN/METHODS: We performed a retrospective chart review of 3 pediatric patients who developed Cushing's syndrome after local administration of triamcinolone acetonide (TCA). RESULTS: Two females 9 and 17 years old, received intra-articular injections of TCA. One patient received multiple injections of TCA into the interphalangeal joints (cumulative dose: 120 mg), whereas the other received a single injection of 40 mg, a dose that is considered to be in the therapeutic range, into the hip joint. The third patient, a 7-year-old female, received multiple intralesional injections of TCA. These patients developed signs and symptoms of hypercortisolism that appeared 4 to 6 weeks after local administration of TCA and lasted for 4 to 6 months after the last dose of TCA. TCA was detectable in the plasma and urine by the liquid chromatography/tandem mass spectrometry method 4 to 5 months after the last dose of the steroid. CONCLUSIONS: We noted evidence for Cushing's syndrome in 3 pediatric patients after intra-articular or intradermal administration of TCA. One of them had received a therapeutic dose of TCA. The possibility of hypothalamic-pituitary-adrenal axis suppression should be considered in patients who have received intra-articular or intradermal steroid injections, particularly in those who have had multiple or relatively high doses.

Adolescent↗
PubMed2003

Chimerism in myositis.

Bidirectional cell trafficking occurs between a mother and fetus during pregnancy. The trafficking is associated with the persistence of non-self cells. Persistence of these cells has been demonstrated after birth for many years in the child and mother. Children and adults with inflammatory myositis are reported to have persistence of microchimeric cells more often than healthy individuals in their peripheral blood and muscle tissue.

Adult↗