A 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) is a chronic, autoimmune mediated, inflammatory arthritis that occurs in approximately 0.5-1% of the general population and affects women 2.5 time more commonly than men. RA affects over 2 million patients in the US and the annual cost per million patients with RA, ranges third after Alzheimer's disease and stroke. Patients with rheumatoid arthritis 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. JIA represents a spectrum of chronic, autoimmune mediated, inflammatory diseases of unknown etiology affecting girls 2.5-4 times more commonly than boys. 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, and psychosocial morbidity is substantial. The focus of research in adults with RA and children with JIA is centered to understand clinical aspects and the underlying pathogenesis of the disease, in the context of interventions targeting specific inflammatory cytokines. The development of targeted therapeutic agents, such as the FDA approved anti-TNF agents, etanercept and infliximab make it possible to focus on specific pathways that may be critically involved in disease expression and progression. Despite their impressive clinical effects, anti-TNF agents do not induce remission and unsatisfactory clinical responses are seen in 30-40% of patients with RA and polyarticular juvenile rheumatoid arthritis (JRA). It is currently not understood whether the lack of a consistent response in all patients is because of insufficient TNF blockade in the clinical non-responders or because of differences in the predominant cytokine pathway activated in different disease subsets. Understanding pathogenic mechanisms in clinical responders and non-responders 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 a 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. Infliximab dose escalation trial in patients with therapy resistant JRA Some children respond well others poorly to anti-TNF therapy. In this study we will examine if a stepwise increase in the dose of infliximab in children with treatment refractory JRA will improve their response to this treatment. c. Evaluation of the growth hormone axis in patients with early untreated rheumatoid arthritis. Cachexia is a common problem in many disease states, including patients with RA and is associated with a poorer outcome and higher mortality. d. Evaluation of the clinical benefit of the Chinese root extract (Tripterygium wilfordii Hook F) in patients with active rheumatoid arthritis. 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 we will be testing if a standardized plant extract from the roots of 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 treatment trials continue to actively recruit patients the NOMID study recently started to recruit patients. The following results have come from the ongoing studies: 1. We continued to use MRI and CT to visualize bony abnormalities of the wrist in patients with early RA. To reduce inter-rater variability in evaluating these images we improved visualization and used automated tools to assess the degree of bone damage. We are using a semi-automated segmentation tool to outline areas of bony abnormalities on MRI and CT and 3D reconstruction techniques. Volumetric measurements of the reconstructed CT lesions and MRI lesions indicate that the MRI lesions are larger than the corresponding lesion on CT. However, the size difference between imaging modalities of the corresponding lesions varied. Some lesions on the CT have no corresponding abnormality on the MRI and vice versa, indicating that both imaging modalities may visualize different pathophysiologic processes. Animal studies to identify the pathophysiologic correlate of these imaging abnormalities haveben started. 2. Automated subtractions of pre an post gadolinium enhancement images have been generated and are used to evaluate changes before and after treatment. 3. Evaluation of validated MRI measures in the context of a treatment intervention suggest, that the disappearance of bone marrow changes in the context of a treatment intervention may be associated with stabilization of bone damage however these evaluations are ongoing. 4) CONCLUSIONS AND SIGNIFICANCE Rheumatoid arthritis and JRA are both chronic inflammatory diseases that are associated with the development of disabilities and large costs. 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. These treatment modalities do not lead to a cure of the disease and thus require long-term chronic administration. Long-term side effects from these treatments are currently not known. Our studies will help to define the impact of anti-TNF blockade on our understanding of bone destruction and remodeling using very sensitive imaging modalities such as MRI and CT. We will further explore if characteristic baseline cytokine patterns allow us to predict responses to therapy.
| 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 |
