Rheumatology

The Division serves as the coordinating center for an international group of over 70 pediatric rheumatology centers dedicated to performing clinical trials in children with Juvenile Idiopathic Arthritis (JIA) called The Pediatric Rheumatology Collaborative Study Group (PRCSG). Daniel Lovell, MD, MPH serves as the chairman of this group and beginning in 2007 Hermine Brunner, MD, MSc began serving as the Scientific Director. For the prior 30 years Edward Giannini, MSc, DrPH, also a member of our Division had served in that role. In 2007, a double-blind randomized controlled trial that had been performed by members of the PRCSG served as the basis for appreciation of pediataric specific dosing issues and safetyh concerns for a frequently used biologic therapy, inflixximab, for the treatment of children with severe, treatment resistant polyarticular JIA.  Dr. Giannini has served for the past 7 years of the recently completed study entitled “Etanercept Registry in Juvenile Idiopathic Arthritis”. This study enrolled 601 patients who were followed for up to 3 years to determine the longer-term safety of etanercept, a TNF inhibitor. The resulting database constitutes the largest safety database in existence of any biologic in children with arthritis. Division members serve as the overall study coordinating center for an innovative NIH funded randomized, placebo controlled trial of combination therapy in new onset JIA to induce remission (NIH/NIAMS RO1 “Early Aggressive Therapy in Juvenile Idiopathic Arthritis”) and an FDA funded investigator initiated randomized trial in patients with Familial Mediterranean Fever. Division investigators serve as principal investigators on a study determining the long term safety of etanercept in children with JIA and are leading in the development of trials of biologic agents blocking interleukin1 and interleukin 6 in children with Systemic JIA.  

Publications.  Lovell DJ, Reiff A, Ilowite NT, Wallace CA, Chon Y, Lin SL, Baumgartner SW, Giannini EH; Pediatric Rheumatology Collaborative Study Group. Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum. 2008 May;58(5):1496-504.

Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, Wouters C, Silverman ED, Balogh Z, Henrickson M, Apaz MT, Baildam E, Fasth A, Gerloni V, Lahdenne P, Prieur AM, Ravelli A, Saurenmann RK, Gamir ML, Wulffraat N, Marodi L, Petty RE, Joos R, Zulian F, McCurdy D, Myones BL, Nagy K, Reuman P, Szer I, Travers S, Beutler A, Keenan G, Clark J, Visvanathan S, Fasanmade A, Raychaudhuri A, Mendelsohn A, Martini A, and  Giannini EH. 2007. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 56:3096-3106.

The CCHMC Division of Rheumatology has engaged in several externally funded research projects in SLE. Dr. Brunner serves at the overall study PI for several multi-center studies, including a FDA-funded Phase I/II trial to test the safety of triptorelin to protect from ovarian damage due to chemotherapy for SLE; two multinational studies to discover and test novel biomarkers for SLE renal disease (Alliance for Lupus Research, Department of Defense. This research has identified and validated the usefulness of Neutrophil Gelatinase Associated Lipocalin (NGAL) as specific biomarker of lupus nephritis activity, with initial evidence suggesting that is predictive of the future course of and response to lupus nephritis therapy. Additionally, a lupus nephritis proteomic signature has been delineated and a discrete lupus nephritis panel is being tested at present. In collaboration with the National Rehabilitation Hospital, the CCHMC Lupus Center assessed the usefulness of computer-based cognitive testing to better diagnose cognitive dysfunction with SLE (Lupus Foundation) using the Pediatric Neurocognitive Assessment Metrics (Ped-ANAM). Based on this research the Ped-ANAM could well be the first clinical screening tool for neurocognitive dysfunction of children with SLE, leading to validation studies of the Ped-ANAM that are supported by a P60 Rheumatology Center Grant. Together with the CCHMC Pediatric Neuroimaging Center, The CCHMC Lupus Center performed the first functional magnetic imaging study in children with SLE, supporting that neurocognitive dysfunction in SLE is likely due to white matter disease and that even patient with apparently normal cognition show abnormalities on functional imaging (Arthritis Foundation). ). The CCHMC Lupus Center is developing at present clinical trials outcome measures for children with SLE (NIAMS U01). The group has been selected by NIAMS to develop an electronic clinical trial data management system and a National Pediatric Lupus Registry (NIAMS U01). Supported by NIH NIAMS P30 and P60 center grants awarded to the CCHMC Division of Rheumatology as well as a Lupus Foundation grant, measures of patient adherence (compliance) were validated and the impact of SLE-associated cognitive dysfunction on quality of life was explored and risk factors of non-adherence in SLE explored. The results of this study led to a CCHMC Health Service grant to explore interventions to decrease visit and medication adherence using motivational interviewing and text messaging in children and young adults with SLE. Studies initiated within the last year include pharmacogenomic and pharmacodynamic studies to develop the evidence-based dosing regimens of steroids and mycophenolate mofetil for children with SLE. Over past year, nine UC and CCHMC rheumatology as well as nephrology fellows have chosen to conduct their research projects with the CCHMC Lupus Research Group. Similar to the pediatric cancer model, the majority of patients with SLE followed at CCHMC participate in at least 1 of these research studies.

1.  S Koneru, M Shishov, A Ware, Y Farhey, AB Mongey, JL Houk, and HI Brunner. Effectively Measuring Adherence to Medications For Systemic Lupus Erythematosus In A Clinical Setting. Arthritis Rheum 2007, 57: 1000-1006.

2. Mikdashi (Co-Chair), JM Esdaile (Co-Chair), GS Alarcón (Co-Chair), L Crofford, BJ Fessler, L Schanberg, H Brunner, V Gall, JR Kalden, MD Lockshin, MH Liang, N Roberts Jr and M Schneider; for the Ad Hoc Committee on Lupus Response Criteria: Cognition Sub-committee: Proposed response criteria for neurocognitive impairment in systemic lupus erythematosus clinical trials. Lupus (2007) 16, 418–425.

3. HI Brunner, NM Ruth, A German, S Nelson, MH Passo, T Roebuck-Spencer, J Ying, D Ris. Initial validation of the pediatric automated neuropsychological assessment metrics for childhood-onset systemic lupus erythematosus. Arthritis Rheum 2007, 57: 1174-1182.

4. M Suzuki, K Wiers, S Nelson, C Rutherford, P Devarjan, HI Brunner: Identification of urinary proteomic signature for nephritis in children. Pediatr Nephrol. 2007 Dec; 22(12):2047-2057.

5. M DiFrancesco, S Holland, D Ris C Adler, M DeBello, M Altaye, HI Brunner. Functional magnetic resonance imaging of cognitive function in childhood-onset systemic lupus erythematosus: a pilot study. Arthritis Rheum. 2007 Dec;56 (12):4151-63.

6. M Suzuki, KM Wiers, M Klein-Gitelman, KA Haines, J Olson, KB Onel, K O’Neil, MH Passo, NG Singer, L Tucker, J Ying, P Devarajan, HI Brunner. Neutrophil Gelatinase Associated Lipocalin as a Biomarker of Disease Activity In Pediatric Lupus Nephritis; Pediatr Nephrol. Pediatr Nephrol. 2008 Mar;23(3):403-12

7. HI Brunner, DD Gladman, D Ibañez, MD Urowitz, ED Silverman: Difference in disease features between childhood-onset and adult systemic lupus erythematosus (SLE). Arthritis Rheum 2008; 58 (2): 556–562. 

8. S Koneru, L Kochrala, GC Higgins, A Ware, MH Passo, YD Farhey, AB Mongey, TB Graham, JL Houk, and HI Brunner. Adherence to medications in systemic lupus erythematosus. Journal of Clinical Rheumatology; 2008: 14(4):195-201.

A central focus of the laboratory research efforts of the Division for many years has been to better understand the role of genes and their expression patterns in the subtypes of JIA. The genetic features of JIA are complex and it is clear that some susceptibility polymorphisms are unique to JIA or its subtypes while other polymorphisms influence the risk to a number of autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and multiple sclerosis). Thus, progress in other autoimmune disease results in the identification of candidate genes is being leveraged for testing in JIA. At the same time, the unique features of JIA require new well-powered genetic association analyses. Genome-wide single nucleotide polymorphism (SNP) association analysis comparing oligoarticular and polyarticular JIA, high-resolution HLA genotyping, and subtype specific measurements of gene expression represent three large-scale discovery-based approaches being used in our laboratory. These approaches have accelerated the understanding of the genetic traits contributing to JIA and the molecular profiles that are potentially relevant to diagnosis, outcome and therapeutic response. Genome-wide association analysis has resulted in the identification of a genetic variant near Krüppel-like factor 13 (KLF13) which is thus far uniquely associated with oligoarticular JIA. We have confirmed this finding in an independent European cohort. KLF13 is a member of a family of transcription factors and a positive regulator of CCL5 (commonly known as RANTES). This is of interest since CCL5 is a ligand for CCR5 which is commonly expressed on T cells in inflamed JIA joints. In addition, genetic association with JIA has been confirmed for variation in the genes PTPN22, PTPN2, IL7R, IL2Ra and STAT4, all of which have reported associations in other autoimmune diseases. Merging the data from the genome-wide SNP studies and high resolution HLA typing will lead to a new understanding in JIA of the HLA region at the haplotype level.

In complementary gene expression studies, several unique or overlapping patterns have been identified in peripheral blood samples from patients with JIA compared with controls. Analyzing these expression patterns indicated involvement of the IL-10 signaling pathway for all subtypes of JIA studied (ERA, oligoarticular, polyarticular, systemic). Other pathways identified provide support for the concept that systemic JIA is an autoinflammatory disease while the remaining JIA subtypes are autoimmune diseases. Further analysis of the differentially expressed genes relative to disease subtype suggests that the current JIA classification scheme may not be optimal. Through the discovery of genetic associations and the associated pathways important mechanistic information with respect to JIA subtypes and the similarities of JIA to other autoimmune diseases will be established.

Fall N, Barnes M, Thornton S, Luyrink L, Olson J, Ilowite NT, Gottlieb, BS, Griffin, TB, Sherry, DD, Thompson, SD, Glass, DN, Colbert, RA, Grom, AA. Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum 2007;56(11):3793-804.

Prahalad S, Bohnsack JF, Whiting A, Clifford B, Jorde LB, Guthery SL, Thompson SD, Glass DN, Bamshad MJ. 2008 Lack of association of functional CTLA4 polymorphisms with juvenile idiopathic arthritis. Arthritis Rheum 2007; 58(7):2147-2152.