1) Background: A number of inflammatory arthritic conditions present in adults and children and can be associated with significant long term disability. In adults, rheumatoid arthritis (RA)a chronic, autoimmune mediated, inflammatory arthritis that occurs in approximately 0.5-1% of the general population, affects women 2.5 time more commonly than men. Patients with RA present with an additive symmetric polyarthritis, typically involving the wrists, and small hand joints. Synovial inflammation and bone erosion are the hallmark of this disease and lead to joint destruction, irreversible joint deformities and disability. The etiology and pathogenesis of this disease is not well understood and reliable diagnostic and prognostic factors are often insufficient to predict the outcome early in the course of the disease. In children, juvenile idiopathic arthritis (JIA) or juvenile rheumatoid arthritis (JRA) is the most common childhood rheumatic disease and ranges from 9.2 to 13.9 per 100,000 children. The disease can be divided clinically into 3 different subsets depending on disease presentation: 1. pauciarticular, involving < 4 joints at presentation, 2. polyarticular involving >4 joints and 3. systemic JRA, presenting with systemic features such as fever, evanescent rash, generalized lymphadenopathy, hepato/splenomegaly or serositis. Persistent synovial inflammation in the joint can lead to joint destruction, growth abnormalities, early disability and premature mortality. Once thought to be a disease of children that remits, it is now known that between 50-60% of patients continue to have persistent arthritis into adulthood. Disabilities are more common than previously expected. This research in adults with RA and children with JIA is designed to understand clinical aspects and the underlying pathogenesis of the disease, in the context of interventions targeting specific inflammatory cytokines. Understanding pathogenic mechanisms in clinical responders and non-responders to anti-cytokine therapy may allow us to subset patient populations based on individual differences in immune regulation and eventually guide us towards a rational approach of designing individualized treatment regimens. I have focused my studies on investigating a number of clinical, imaging and laboratory measures that should allow us to evaluate the impact of an anti-TNF intervention on the immunopathogenic mechanisms in adults with RA and children with JRA. Several clinical treatment protocols were initiated to explore a number of clinical questions: 2) OBJECTIVE OF PRESENT STUDIES a. To evaluate the use of MRI and CT as sensitive imaging modalities to address questions concerning the pathophysiology of bone destruction and remodeling b. To evaluate the impact of anti-TNF therapy on immunopathogenic mechanisms c. To evaluate endocrine and metabolic responses to targeted interventions. d. To evaluate the clinical benefit of a Chinese root extract (Tripterygium wilfordii Hook F) in patients with rheumatoid arthritis I. Active Treatment Protocols: a. MRI imaging trial using infliximab in patients with active erosive rheumatoid arthritis. This study explores two imaging modalities of bone, magnetic resonance imaging (MRI) and computertomography (CT) of the wrist in following bone destruction on and off anti TNF therapy. b. Evaluation of the function of regulatory T cells in patients with active rheumatoid arthritis before and after treatment with the TNF inhibitor Infliximab. Regulatory T cell function is compromised in a number of patients with inflammatory conditions. In collaboration with Dr Xavier Valencia we are addressing the question if regulatory T cell function can be restored by blocking TNF in patients with active RA before and after treatment with infliximab. c. In this study we examine if effective treatment with infliximab in children with treatment refractory JIA will improve their GH secretion and growth. d. This study evaluates the growth hormone axis in premenopausal woman with active RA. This study is conducted in collaboration with the National Center for Complementary and Alternative Medicine (NCCAM) e. Evaluation of the clinical benefit of the Chinese root extract (Tripterygium wilfordii Hook F) in patients with active RA. Tripterygium wilfordii Hook F (TwHF) is a traditional medicinal plant that has been used in China for many years to treat inflammatory conditions including RA. This study tests if TwHF is superior to Sulfasalazine in improving the signs and symptoms in subjects with RA. 3) RESULTS DURING THE PAST YEAR AND ONGOING INITIATIVES The following results have come from the ongoing studies: a. Recruitment for the MRI and JIA studies has been discontinued. We continue to use MRI and CT to visualize bony abnormalities of the wrist in patients with early RA. Jeff Duryea developed a semi-automated segmentation tool to outline carpal bones on the CT images. We validated this method using a phantom hand model and are now int he process to determine the size of lesion changes that can be captured with this method. in addition a software was generated to overlay consecutive images and determine the volume and areas of change. b. We recruited 12 patients and have evidence that regulatory T cell function is abnormal in patients with active RA that can be corrected by treating patients with the TNF inhibitor infliximab. c. Recruitment into the JRA study has been discontinued. We can document definite benefit from treatment with infliximab however the sample size is too small and heterogeneous to determine GH secretion chnages with tretment with infliximab. Ananlysis of the bone mineral densitiy evalution is still ongoing d. Eight patients with RA and 10 healthy age and BMI matched control subjects have been enrolled into the GH study. An interim analysis showed a significnat difference in GH secretion, diminished IGF-1 and IGFBP-3 levels in women with RA compared to healthy age and body mass index matched controls. d. The TwHF protocol completed recruitment of 121 subjects. An interim analysis was conducted and showed a significant difference in ACR 20 responses between the two treatment arms indicating that our assumptions regarding differences in treatment effects that found the basis for the power calculations were correct. 4) CONCLUSIONS AND SIGNIFICANCE a. Rheumatoid arthritis and JRA are chronic inflammatory diseases. However the effects of new exiting treatments targeting the inflammatory cytokine, TNF- alpha, on alleviating signs and symptoms of the disease as well as retarding bone damage have recently been established in large multi-center trials. Our studies will help to define the impact of anti-TNF blockade on bone destruction and remodeling using very sensitive imaging modalities such as MRI and CT. b. Regulatory T cells downregulate immune responses and may be important in regulating disease activity in patients with RA. This research is aimed to understand the role and impact of regulatory T cell function in RA patients. c and d. Patients with RA or JRA develop metabolic changes early during their course of disease including loss of bone mineral density (osteopenia), loss of muscle mass (sarcopenia) and an increased cardio-vascular risk. The studies evaluating the immune-endocrine function may help us to understand whether inflammation induced changes in GH secretion can mediate metabolic changes such as osteopenia, sarcopenia and are associated with an increased cardiovascular risk. e. Evaluation of TwHF will allow us to assess a novel drug with mechanisms blocking inflammation that are different from TNF blockade. This drug may be an important adjunct in the treatment armamentarium of drugs to treat inflammation and prevent disease progression in patients with rheumatoid arthritis.
| Yao, Lawrence; Magalnick, Michael; Wilson, Mildred et al. (2006) Periarticular bone findings in rheumatoid arthritis: T2-weighted versus contrast-enhanced T1-weighted MRI. AJR Am J Roentgenol 187:358-63 |
| Goldbach-Mansky, Raphaela; Lipsky, Peter E (2003) New concepts in the treatment of rheumatoid arthritis. Annu Rev Med 54:197-216 |
| Goldbach-Mansky, Raphaela; Woodburn, James; Yao, Lawrence et al. (2003) Magnetic resonance imaging in the evaluation of bone damage in rheumatoid arthritis: a more precise image or just a more expensive one? Arthritis Rheum 48:585-9 |
