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. 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. The anti TNF agents have shown significant clinical effects in reducing the signs and symptoms in patients with rheumatoid arthritis (RA) and in slowing and possibly arresting joint damage in a large number of patients. They are also used in other inflammatory diseases including psoriasis, spondylarthropathies, Wegener?s granulomatosus and inflammatory bowel disease. 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. 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. Growth retardation is a common problem in children with chronic inflammation and is well documented in JRA. The cause is believed to be multifactorial including steroid use, nutrition and direct modulation of the GH axis by inflammatory cytokines for which some evidence exists in animal models. The aforementioned study in children with active JRA has one component for which parents may consent separately to obtain frequents blood samples (q20min) for a GH/IGF evaluation. We also measure hourly blood samples for the proinflammatory cytokines TNF, IL-6 and IL-8. 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. Although the pathogenesis of the loss of lean body mass is poorly understood, increases in the pro-inflammatory cytokines TNF and IL-1, prostaglandins, glucocorticoids, catecholamines and decreases in several anabolic hormones including GH, IGF-1 an insulin likely play a role in this process. We hypothesize that low GH levels or decreases in IGF-1 are related to cachexia. GH and IGF-1 are important anabolic hormones that increase muscle and bone mass and decrease body fat. Therefore augmenting GH and IGF-1 may also be of value in the treatment of RA, however this will not be tested with this proposal. Suppression of the GH axis is associated with a reduced life expectancy related to increases in cardiovascular events and cerebrovascular accidents. We propose to study 18 premenopausal women with early (<3years, untreated, active) RA and 6 healthy, age and body mass index (BMI)-matched female control subjects to determine the extend of hormonal abnormalities in the RA patients. 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. 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 w
| 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 |
