Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
A Pilot Study of Gene Expression (GE) Profiles in Juvenile Dermatomyositis (JDM) Responders and Non-Responders: Diagnostic and Follow-Up Muscle Biopsy (MBx) Data.
Pachman1, Lauren M., Chen2, Yi-Wen, Hendrickson1, Peter, Shrestha1, Sheela, Morgan1, Gabrielle, Sredni1, Simone
Previous data documented that both the TNF-a-308 A allele and a long duration of untreated disease (DUD) before diagnosis contributed to the lack of response of JDM children to therapy. Studies of untreated juvenile dermatomyositis (JDM) muscle biopsies (MBx) had documented a marked increased in IFN-a induced genes (Tezak, JI, 2000). It is not known if there are differences in the GE profiles in the untreated muscle biopsy of responders (R) vs non-responders (NR) at the diagnosis of JDM, or if this dysregulation persists once the children have been classified as having responded by clinical standards to immunosuppressive therapy. Finally, there is no information about the genetic status after a course of therapy that may have improved the muscle symptoms, despite other evidence of active disease.
To compare the GE profiles in the diagnostic muscle biopsies in untreated children at diagnosis of JDM and after immunosuppressive therapy.
Materials and Methods:
Seven children with definite/probable JDM were recruited for this study, along with four healthy age-, race-, and gender-matched controls undergoing orthopedic surgery. All JDM were initially untreated at the time of the diagnostic MBx, mean age 7.43 ±4.21 yrs, 3/7 female; six Caucasian and one Hispanic. Four of the children responded to therapy and were off all medication at the time of follow-up needle MBx, two of the NR still required medication, and one was non-compliant. RNA was extracted and hybridized to Affymetrix U133A arrays (at diagnostic) and U133Aplus2 arrays (post-treatment). Data was normalized and filtered to exclude the controls and probes with maximum expression less than a log scale of 6 across all samples. The GE of R was compared to the NR using two-sample t-tests. Evaluation of gene functions and networks utilized Ingenuity Pathway Analysis software (Ingenuity Systems, Redwood City, CA).
The NR were older at the time of the diagnostic MBx: mean age of 9.6 ± 5.7 yrs with a longer DUD of 14.0 ±1.24 mos vs mean age of 5.8 ±2.5 yrs and DUD of 3.3 ±1.4 mos for the R. At needle follow-up biopsy, R were mean age of 10.7 ±1.8 yrs vs 17.7 ±7.4 yrs for NR.
A significant number of genes were found to be differentially expressed in R compared with NR. Skeletal-muscular and cardiovascular system development and function were within the main networks represented. Of importance, at diagnostic MBx several apoptosis related genes were significantly up regulated in R compared with NR, including CASP1 (FC 2.3; p=0.03) and CASP7 (FC 1.8; p=0.02). After treatment, the NOS1 gene that is usually expressed in skeletal muscle and is regulated by IL1B and TNF was over-expressed in non-responders compared with responders (FC 3.7; p=0.02).
The results of this preliminary analysis point to specific genetic mechanisms involved with non-responsiveness to treatment in JDM patients. GE studies involving larger cohorts will clarify these mechanisms and allow the identification at diagnosis of patients that may not respond to treatment and may benefit from more aggressive or alternative therapy.
Supported by NIH/NIAMS R01 AR48289 and Cure JM Foundation (LMP).
To cite this abstract, please use the following information:
Pachman, Lauren M., Chen, Yi-Wen, Hendrickson, Peter, Shrestha, Sheela, Morgan, Gabrielle, Sredni, Simone; A Pilot Study of Gene Expression (GE) Profiles in Juvenile Dermatomyositis (JDM) Responders and Non-Responders: Diagnostic and Follow-Up Muscle Biopsy (MBx) Data. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :242