The current focus of this research team is the pathophysiology of Juvenile Dermatomyositis (JDM) the most common of the pediatric inflammatory myopathies, in which small blood vessels are attacked by the immune system. Little is known about the environmental and genetic risk factors associated with the development of the classic clinical symptoms of rash and often profound weakness. There is less information about the physical outcome of this chronic and sometimes fatal illness-including one of the most troubling complications, pathological calcifications-which are a major contributor to morbidity. A specific goal of this laboratory is to identify the most effective route/dose of the most commonly used drug for JDM, prednisone, and to develop targeted, effective interventions. To accomplish these specific aims, the following resources have been amassed, after obtaining informed consent:
Regional: sequential protocol based clinical and diagnostic laboratory testing, quality of life, and family history of autoimmune disease from over 290 children with JDM or other inflammatory myopathies, spanning over 25 years.
National: Structured interview and limited laboratory data at diagnosis and three year follow-up from 323 children with JDM and their families
For the regional data base, the research laboratory has sequential samples of DNA, RNA, and peripheral blood mononuclear cells and their supernatant fluid, which are keyed to the child's coded ID number. The research team is composed of two interlocking arms, Epidemiology and Immunobiology.
- Characterization of the IFN-alpha/beta induced response in children with JDM before and after therapy. The purpose of this study is to determine the association of MXA gene expression in peripheral blood with clinical evidence of disease activity and cytokine expression (K. O'Connor, PhD et al.).
- The association of DQA1*0501with specific gene clusters in gene expression profiles obtained from muscle biopsy material from untreated children with JDM compared with other inflammatory myopathies. The purpose of this study is to identify the association of genetic and clinical variables on gene expression profiles: gender, age, duration of untreated disease, the presence of calcifications, etc, as well as to identify functional gene clusters that may be associated with the evolving pathophysiology of the inflammatory response. (LM Pachman, K. O'Connor, Yi-Wen Chen-DC Children's, Center for Genetic Medicine).
- Characterization of pathological calcifications in children with JDM: This study identifies non-collagenous bone matrix proteins in pathological calcifications as well as the physical structure as determined by micro CT, x-ray diffraction (laboratory of S. Stock, PhD, nanotechnology) and FTIR (Laboratory of Adele L. Boskey, PhD, Hospital For Special Surgery, NYC). The impact of specific bone matrix proteins and cytokines on a mouse injury model is under investigation (Y Zhao, MD/PhD, LM Pachman, MD, Roopa Seshadri, PhD, and AL Boskey, PhD).
- Bone Density in Children with JDM--a) untreated children at diagnosis--association with RANKL/RANK and OPG and b) longitudinal studies (Rouster-Stevens, Langman, Pachman).
- The Pharmacokinetics of Prednisolone in Children with JDM: The purpose of this study is to determine the impact of the extent of small vessel vasculitis on the bioavailability of prednisolone as measured over an 8 hour time course (K. Rouster-Stevens MD/PharmD, A. Gursahaney, MD).
- Nailfold Capillary Studies are associated with skin involvement and reflect outcome (Stephanie Christian-Zaech, MD, Amy Paller MD, Kathy Abbott, LM Pachman).
- Circulating lympocyte subsets are a sensitive indicator of immune activation in JDM (MRG O'Gorman, PhD, K O'Connor, PhD, A. Gursahaney MD and M. Kuroda, PhD).
- Outcomes of JDM: This study will describe the association of family history of autoimmune disease as well as various genetic markers (e.g.TNFalpha-308 A allele, DQA1*0501) with the physical findings, evidence of immune activation (dysregulation of lymphocyte phenotypes) and quality of life at 36 months or more after diagnosis of JDM (Epidemiology team).
Pachman, LM, Boskey AL. Clinical Manifestations and Pathogenesis of Hydroxyapatite Crystal Deposition in Juvenile Dermatomyositis" Curr Rheumatol Rep. 8:236-243, 2006.
Pachman LM, Liotta-Davis M, Hong D, Kinsella TR, Mendez E, Kinder J and Chen EH. TNFa-308A allele in juvenile dermatomyositis-association with increased TNFa production, disease duration, and pathological calcifications. Arthritis Rheum, 43:2368-2377, 2000.
Fedczyna TO, Lutz J, Pachman LM. Expression of TNFa by muscle fibers in biopsies from children with untreated juvenile dermatomyositis: association with the TNFa-308A allele. Clin Immunol 100:236-239, 2001.
Tezak Z, Hoffman EP, Lutz JL, Fedczyna TO, Stephan D, Bremer EG, Krasnoselska-Riz I, Kumar A, and Pachman LM. Gene expression profiling in DQA1*0501+ children with untreated dermatomyositis: A novel model of pathogenesis. J Immunol. 168:4154-4163, 2002.
Lutz M, Fedczyna T, Huwiler KG, Lechman TS, Crawford S and Pachman LM. Increased plasma thrombospondin-1 (TSP-1) levels are associated with the TNFa-308A allele in children with juvenile dermatomyositis (JDM). Clin Immunol, 103:250-263, 2002.
Mendez E, Lipton R, Dyer A, Ramsey-Goldman R, Roettcher P, Bowyer S, and Pachman LM. U.S. Incidence of JDM 1995-98: Results from the NIAMS Registry. Arthritis Care Res, 49: 300-305, 2003.
Smith RL, Sundberg J, Shamiyah E, Dyer A, Pachman LM. Skin Involvement in Juvenile Dermatomyositis (JDM) is Associated with Loss of End Row Nailfold Capillary (NFC) Loops. J Rheumatol 31: 1644-1649, 2004.
Stock, SR, Ignatiev K, Lee,PL, Abbott,K, Pachman, LM. Pathological calcification in Juvenile Dermatomyositis (JDM): MicroCT and synchrotron x-ray diffraction reveal hydroxyapatite with varied microstructures Calcified Tissue Res 45: 248-256, 2004.
Pachman LM, Lipton R, Ramsey-Goldman R, Shamiyeh E, Abbott K, Mendez EP, Dyer A, Mc Curdy D, Vogler L, Reed A, Cawkwell G, Zemel L, Sandborg C, Rivas-Chacon R, Hom C, Ilowite N, Gedalia A, Gitlin J, Borzy M. History of infection before the onset of Juvenile Dermatomyositis (JDM): results from the National Institute of Arthritis Muscle and Skin Diseases (NIAMS) Research Registry. Arthritis Rheum 53: 166-172, 2005.
Zhao P, Caretti G, Mitchell S, McKeehan WL, BoskeyAL, Pachman LM, Sartorelli V, Hoffman EP. Fgfr4 is required for effective muscle regeneration in viv delineation of a MyoD-Tead2-Fgfr4 transcriptional pathway. J Biol Chem 281: 429-438, 2006.
Pachman LM, Abbott K, Sinecore JM, Amoruso L, Dyer A, Lipton R, Ilowite N, Cawkwell G, White A, Rivas-Chacon R, Kumura Y, Ray L and Ramsey-Goldman, R. Duration of illness is an important variable for untreated children with juvenile dermatomyositis (J Pediatrics, in press, 2006).