Dr. Pachman's translational and collaborative team studies juvenile dermatomyositis (JDM), an often chronic pediatric systemic vasculopathy of unknown etiology. JDM is associated with inflammation in the skin, as well as in the proximal musculature – resulting in extensive weakness. The goal of their studies is to discover biomarkers of disease activity to guide the utilization and/or creation of more effective therapies. Dr. Pachman’s laboratory has identified genetic and environmental factors that not only play a role in the onset of symptoms, but also govern the child's outcome. For example, the TNF-α-308 promoter A polymorphism is associated with a prolonged disease course requiring immunosuppressive therapy for at least three years. Increased production of the protein, TNF-α, by JDM children with the A allele is seen throughout the disease course, in contrast to serum levels of IFN-α activity, which are usually elevated early in the disease. Gene expression micro array studies of untreated children's diagnostic muscle biopsies disclosed a strong dysregulation of IFN-α induced genes in JDM, similar to an anti-viral immune model, which also shares some features of the IFN-α signature characteristic of systemic lupus erythematosus (SLE). This chronic inflammatory setting promotes the development of often debilitating pathologic calcifications, which have been clearly defined as dystrophic in nature, displaying an increased mineral/matrix ratio, and extensive integrin involvement.
Other epidemiological factors may modify the child's disease course. Specifically, a period of untreated active disease greater than two months is associated with genes controlling vascular remodeling, which appear to differ from genes expressed by muscle from children not fully responsive to therapy. Epigenetic and miRNA studies of the diagnostic muscle biopsies indicate further critical differences when appropriate treatment is delayed, in addition the child's gender skews gene-gene interactions. The search for clinically useful biomarkers of immune activation identified CD3-negative natural killer cells, as well as von Willebrand factor antigen, released from damaged endothelial cells. Endothelial damage is also reflected in loss of nailfold capillary end row loops – the laboratory developed a method to measure changes over time – and are associated, not only with disease chronicity, but lack of absorption of prednisone (when given by mouth). Finally, site specificity is also under investigation: the pathophysiology of the cutaneous inflammation differs from that of muscle – mast cells are increased in both lesional and non-lesional skin in untreated children and scarce in their paired muscle samples and controls.
Dr. Pachman is the Principle Investigator and Director of the Cure JM Foundation’s "Program of Excellence in Myositis Research" and has cared for over 400 children with JDM and other forms of inflammatory myopathy. The patient derived material has been obtained with consent for genetic research and includes diagnostic muscle and skin biopsies, sequential sera, peripheral blood lymphocytes, lymphocyte culture supernatant fluid, and samples of dystrophic calcifications. This repository is keyed to a sequential, coded, specific myositis database containing over a 1,000 variables/child. In summary, this collaborative and intensive research effort broadens the clinical, genetic and immunological characterization of the child with JDM, which helps to guide current therapy and may lead to the consideration of novel targeted interventions.
- Christen-Zaech S; Seshadri R, Sundberg J, Paller AS, Pachman LM. Persistent Association of Nailfold Capillaroscopy Changes and Skin Involvement Over Thirty-Six Months With Duration of Untreated Disease in Patients With Juvenile Dermatomyositis. Arthritis Rheum 58:571-576, 2008. PMID: 18240225.
- Rouster-Stevens KA, Pachman LM. Autoantibody to signal recognition particle in African-American girls. J Rheumatol 35:927-929, 2008.
- Rouster-Stevens KA, Gursahaney A, Ngai K-L, Daru JA, Pachman LM. Pharmacokinetic study of oral prednisolone compared with intravenous methylprednisolone in patients with juvenile dermatomyositis. Arthritis Rheum (Arthritis Care Res) 59: 222-266, 2008.
- Chen Y-W, Shi R, Geraci N, Shrestha S, Gordish-Dressman H, Pachman LM. Duration of chronic inflammation alters gene expression in muscle from untreated girls with juvenile dermatomyositis. BMC Immunology, Jul 31;9:43, 2008.
- Seshadri R, Feldman B, Ilowite N, Cawkwell GD, Pachman LM. The role of aggressive corticosteroid therapy in Juvenile Dermatomyositis: A Propensity score Analysis. Arthritis Care Res 59:989-995, 2008. PMID: 18576304.
- Urganus AL, Zhao Y-D, Pachman LM. Juvenile dermatomyositis calcifications selectively displayed markers of bone formation. Arthritis Rheum. 2009 Apr 15;61(4):501-8.
- Niewold TB, Kariuki SN, Morgan GA, Shrestha S, Pachman LM. Elevated serum interferon-alpha activity in juvenile dermatomyositis: Associations with disease activity at diagnosis and after thirty-six months of therapy. Arthritis Rheum. 2009 Jun;60(6):1815-24.
- Zhao Y-D, Urganus A, Spevak L, Shrestha S, Doty SB, Boskey AL, Pachman LM. Characterization of Dystrophic Calcification Induced in Mice by Cardiotoxin. Calcif Tissue Int. 2009 Sep;85(3):267-75. Epub 2009 Aug 20.
- Rider LG, Lachenbruch P, Monroe J, Ravelli A, Cabalar I, Feldman B, Villalba M, Myones B, Pachman LM, Rennebohm R, Reed A, Miller F. Damage Extent and Predictors in Adult and Juvenile Dermatomyositis and Polymyositis Using the Myositis Damage Index. Arthritis Rheum. 2009 Nov:60(11):3425-35.
- Huber AM, Giannini EH, Bowyer SL, Kim S, Lang B, Lindsley CB, Pachman LM, Pilkington C, Reed AM, Rennebohm RM, Rider LG, Wallace CA, Feldman BM. Protocols for the Treatment of Moderately Severe Juvenile Dermatomyositis: Results of a Children’s Arthritis and Rheumatology Research Alliance Consensus Conference. Arthritis Care Res (Hoboken). 2010 Feb;62(2):219-25.
- Rider L, Koziol D, Giannini E, Jain M, Smith M, Whitney-Mahoney K, Wright S, Lindsley C, Pachman LM, Villalba M, Lovell D, Bowyer S, Plotz P, Miller F. Validation of Manual Muscle Testing and a Subset of Eight Muscles (MMT8) for Adult and Juvenile Idiopathic Inflammatory Myopathies. Arthritis Rheum. 2010 Apr:62(4):465-72.
- Ibarra M, Zhao Y-D, Boskey AL, Chou PM, Pachman LM. Characterization of calcification in circumscribed myositis ossificans by Fourier Transform Infrared Spectroscopic Imaging (FTIRI). J Rheumatol. 2010 Apr;37(4):876.
- Ostrowski R, Sullivan C, Seshadri R, Morgan GA, Pachman LM. Normal Nailfold End Row Loops are Associated with a Shorter Duration of Untreated Disease in Children with Juvenile Dermatomyositis. Arthritis Rheum. 2010 May;62(5):1533-8.
- Ruperto N, Pistorio A, Ravelli A, Pilkington C, Oliveira S, Wulffraat N, Meiorin S, Garay S, Cuttica R, Hofer M, Quartier P, Melo-Gomes J, Reed A, Wierzbowska M, Feldman B, Harjacek M, Huppertz H, Nielson S, Flato B, Lahdenne P, Michels H, Murray KJ, Punaro L, Rennebohm R, Russo R, Balogh Z, Rooney M, Pachman LM, Wallace C, Hashkes P, Lovell DJ, Giannini EH, Martini A, for the Paediatric Rheumatology International Trials Organisation (PRINTO), The Pediatric Rheumatology International Trials Organization Criteria for the Evaluation of Response to Therapy in Juvenile Dermatomyositis. Prospective Validation of the Definition of Improvement. Arthritis Care Res (Hoboken). 2010 Jun 25. [Epub ahead of print].
- Niewold TB, Kariuki SN, Morgan, GA, Shrestha S, Pachman LM. Gene-Gene-Gender Interaction between Cytokine Gene Polymorphisms Revealed by Serum IFN-α Phenotype in Juvenile Dermatomyositis. J Pediatr. 2010 Jun 3. [Epub ahead of print].
- Shrestha S, Wershil B, Sarwark JF, Philipp T, Pachman LM. Lesional and Non Lesional Skin from Untreated Juvenile Dermatomyositis (JDM) Displays Increased Mast Cells and Mature Plasmacytoid Dendritic Cells. Arthritis Rheum, 2010 Apr 21. [Epub ahead of print].
- Rouster-Stevens K, Morgan G, Wang D, Pachman LM. Mycophenolate Mofetil, a Possible Therapeutic Agent for Children with Juvenile Dermatomyositis. Arthritis Care Res (Hoboken). 2010 Jun 2. [Epub ahead of print].
- Vega P, Ibarra M, Prestridge A, Pachman LM. Autoantibody to PL12 (anti-alanyl-tRNA synthetase) in an African American girl with juvenile dermatomyositis and resolution of interstitial lung disease. J Rheumatol, 2010, submitted.
- Characterization of the IFN-α/β 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.)
- Gene expression profiles in muscle biopsy material from untreated children with JDM compared with other inflammatory myopathies. The purpose of this study is to identify the impact of specific 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)
- 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 and x-ray diffraction (laboratory of S. Stock, PhD, nanotechnology). The impact of the inflammatory response and changes in vascular function on the process of calcification will also be investigated. (C. Chuu, A. Veiss, S. Stock, L.M. Pachman).
- The Pharmacokinetics of Prednisolone in Children with JDM: The purpose of this study is to determine the impact of vasculitis on the bioavailability of prednisolone as measured over an 8 hour time course. (K. Rouster-Stevens, C. Chuu).
- Outcomes of JDM: This study will describe the association of family history of autoimmune disease as well as various genetic markers (e.g.TNFα-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. One cohort of patients will have fasting bloods assessed for levels of glucose, insulin and lipids. (Epidemiology team).
The research team is composed of two interlocking arms, Epidemiology and Immunobiology.
M. Klein-Gitelman, MD, MPH, Health economics (Immunology/Rheumatology)
James Sinacore, PhD, Loyola University, Biostatistical analysis
Sheela Shrestha, MS
Maria Amoruso, MPH
Gabrielle Morgan, MA
Erin Kim, BA
Peter Hendrickson, BS