1) Background Several forms of inflammatory arthritis present in adults and children. 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, being even more expensive than chronic heart disease, diabetes, and depression. 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. Juvenile rheumatoid arthritis (JRA) is the most common childhood rheumatic disease and ranges from 9.2 to 13.9 per 100,000 children. JRA 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, although not major, are more common than previously expected, and psychosocial morbidity is substantial. The focus of research in adults with RA and children with JRA is centered to understand clinical aspects and the underlying pathogenesis of the disease, in the context of interventions targeting inflammatory cytokines. TNF-a is a potent pro-inflammatory cytokine that has recently been shown to be an important therapeutic target in patients with methotrexate resistant rheumatoid arthritis. Data from the several anti-TNF trials have suggested that administration of the soluble TNF receptor molecule, etanercept, or the anti-TNF-a antibody, infliximab, concomitantly with methotrexate therapy resulted in a highly significant anti-erosive effect in patients who had an incomplete response to methotrexate therapy alone. Addition of infliximab to existing methotrexate therapy resulted in an almost complete inhibition of progression of erosions and joint space narrowing. An important role of anti-TNF therapy in the control of disease in patients with polyarticular JRA and systemic onset JRA has also recently been established. We are currently examining the effects of chronic TNF blockade on bone destruction, immune function and metabolic abnormalities. Objectives of each intervention trial are outlined below. 2) OBJECTIVE OF PRESENT STUDIES 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. We will evaluate the use of surrogate markers of bone and cartilage degradation in following bone destruction and healing on TNF therapy. Metabolic abnormalities are associated with inflammatory states as occurs with RA and are associated with chronic changes such as cachexia and an increase in cardiovascular morbiditiy. We plan to measure the degree of hormonal and other metabolic abnormalities and explore the role of anti-TNF therapy in reversing some of these effects. 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. We will examine the change of inflammatory mediators in responders and non-responders and the hormonal changes that lead to the growth retardation that often complicates the course of their disease. II. Natural History Protocol: We have evaluated patients for treatment protocol eligibility and consulted on patients referred to us for clinical questions. We continued to investigate the following issues: a. We previously explored the role of serum Granzyme B, a serine kinase, in predicting more severe disease subsets of patients with recent onset of an inflammatory arthritis, we now examine the expression of granzyme B in the synovial tissue to better understand its association with bone destruction. b. Children with JRA and ongoing joint inflammation, even if only limited to few joints, experience physical and psychosocial disabilities. We are attempting to determine the degree of disability in patients with JRA using standard tests to assess gait, fine motor skills and questionnaires to evaluate the impact of the disease on activities of daily living and on psychosocial behavior. 3) RESULTS DURING THE PAST YEAR AND ONGOING INITIATIVES The two treatment trial were initiated during the past year and we are actively recruiting for both trials. The following results have come from the ongoing studies: 1. An antibody glucosephosphate isomerase has recently been shown to cause a destructive arthritis in mice. We explored its role in patients with recent onset of arthritis and found that it is elevated in patients with at spectrum of arthritis but not specifically in patients that have more destructive disease and is therefore not a marker for disease severity. 2. We focused our initial evaluation of patients entered into the treatment trial on comparing MRI bony abnormalities of the wrist to the corresponding CT lesions. In patients with early RA, considerable mismatch in detecting carpal bone changes between the two imaging modalities indicates the need to better understand the underlying processes imaged by these two modalities. Furthermore, the large inter-observer variability in scoring indicates a need for standardized scoring procedures when evaluating imaging modalities. 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 are expensive, 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 infliximab on our understanding of bone remodeling using very sensitive imaging modalities such as MRI and CT. Comorbidities, mainly cardiovascular disease in adults and growth retardation in children, are associated with metabolic derangements that derive from chronic exposure to an excess of inflammatory cytokines. In patients with RA these are associated with increased mortality. A better understanding of the role of anti-TNF therapy on reversing these side effects and modulating the immune function will crucially impact on our risk and benefit
| 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 |
