Daniel G. Malone

Rheumatoid Arthritis: Evolving Concepts of Pathogenesis and Treatment

Rheumatoid arthritis is a chronic inflammatory synovitis that primarily involves peripheral diarthrodial joints. Immunohistologic analysis of diseased synovium has shown a spectrum of abnormalities that resemble various stages of a cell-mediated, or delayed-type, immune reaction. The infiltrating mononuclear cells produce various factors that modulate adjacent tissues and appear to produce the characteristic destructive features of the disorder. Our understanding of the mechanisms of action of various therapeutic modes also indicates that the disease is primarily mediated by activated mononuclear cells. All effective therapies have been shown to affect either mononuclear cell function or the rates of production or elimination of these cells. The disorder likely represents the pathologic expression of a genetically controlled host immune response to an undefined causative stimulus. The stimulus could be an infectious agent(s), a product(s) derived from an infectious agent(s), a constituent(s) of synovial or connective tissue, or a combination of these.

Role of the thymus in streptococcal cell wall-induced arthritis and hepatic granuloma formation. Comparative studies of pathology and cell wall distribution in athymic and euthymic rats.

Systemic administration of an aqueous suspension of group A streptococcal cell wall fragments to susceptible rats induces acute and chronic polyarthritis, as well as noncaseating hepatic granulomas. To gain insight into the role of the thymus in the pathogenesis of this experimental model, pathologic responses and cell wall tissue distribution were compared in congenitally athymic rats (rnu/rnu) and their euthymic littermates (NIH/rnu). Within 24 h, both rat strains developed acute arthritis, characterized by polymorphonuclear leukocytic exudate in the synovium and joint spaces. This acute process was maximal at day 3 and gradually subsided. Beginning 2-3 wk after injection, the euthymic, but not the athymic, rats developed the typical exacerbation of arthritis, characterized by synovial cell hyperplasia with villus formation and T helper/inducer lymphocyte-rich mononuclear cell infiltration. This process eventually resulted in marginal erosions and destruction of periarticular bone and cartilage. Parallel development of acute and chronic hepatic lesions was observed. Bacterial cell wall antigen distribution and persistence were similar in the athymic and euthymic rats. Cell wall antigens were demonstrated in the cytoplasm of cells within subchondral bone marrow, synovium, liver, and spleen, coincident with the development of the acute lesions, and persisted in these sites, although in decreasing amounts, for the duration of the experiment. Our findings provide evidence that the acute and chronic phases of the experimental model are mechanistically distinct. The thymus and functional thymus derived-lymphocytes appear not to be required for the development of the acute exudative disease but are essential for the development of chronic proliferative and erosive disease. Induction of disease is dependent upon cell wall dissemination to and persistence in the affected tissues.

Patient variables impact lumbar spine dual energy X-ray absorptiometry precision

IntroductionChanges in bone mineral density are used to monitor osteoporosis therapy. To determine whether a change in bone mass is clinically significant, the precision of bone mineral density measurements must be known.MethodsWe therefore measured the impact of vertebral body exclusion on dual energy X-ray absorptiometry (DXA) precision. At one university and one Veterans Affairs DXA center, three radiology technologists each scanned 30 participants twice, with repositioning between scans, to estimate DXA precision. Three International Society for Clinical Densitometry-certified physicians reviewed all lumbar spinal scans to note the presence of focal structural defects. We calculated precision for subsets of vertebrae, and for virtual samples of patients with and without physician-identified vertebral focal structural defects. We graphed the reciprocal of least significant change versus bone area to determine the dependence of precision on interpreted scan area.ResultsWithin each sample, greater interpretable bone area improved precision. The contribution of interpreted bone area to precision differed among the samples, ranging from 57 to 94%. Greater population bone mineral density heterogeneity and presence of focal structural defects each decreased precision.ConclusionAll bone densitometry centers must determine precision using a sample representative of their served populations. Failure to do so may lead to incorrect determination of least significant change. Population heterogeneity, vertebral body exclusion and presence of focal structural defects each decreases precision.

Mast cell activation in human synovium explants by calcium ionophore A23187, compound 48/80, and rabbit IgG anti-human IgE, but not morphine sulfate

To investigate human synovial mast cell physiology, we developed a model in which mast cells in human synovial explant cultures were activated by immunologic or non-immunologic mechanisms. Small (3 mm) cubes of synovial membrane were incubated with or without secretagogue for 30, 45 or 60 min, and supernatant histamine concentrations were quantified. We measured significant histamine release with compound 48/80 at concentrations ≥1 mg/ml, and with calcium ionophore A23187 at ≥5 μg/ml. Rabbit IgG anti-human IgE induced significant histamine release at all concentrations tested, maximum at 78 μg/ml. Morphine sulfate produced no histamine release from synovial explants, in contrast to its significant stimulation of histamine release from neonatal foreskin explants in our explant system. We confirmed synovial mast cell degranulation by electron microscopy, and showed that it corresponded with measurable histamine release. Furthermore, histamine release was not due to secretagogue-induced cytotoxicity, as assessed by supernatant lactate dehydrogenase levels and by ultrastructural analysis. Since morphine sulfate induces mast cell degranulation and histamine release in adult and neonatal human skin, our data show that although synovial and dermal mast cells have a similar granule enzyme profile and electron microscopic morphology, they differ in functional responses. These observations support recent data that among similar human mast cell subtypes there are physiologic differences. Finally, our explant model will be useful in studies of mast cell involvement in arthritis.

Musculoskeletal ultrasound training and competency assessment program for rheumatology fellows

The purpose of this study was to establish standards for musculoskeletal ultrasound competency through knowledge and skills testing using criterion‐referenced methods.

Musculoskeletal Ultrasound Objective Structured Clinical Examination: An Assessment of the Test

To determine the reliability and validity of an objective structured clinical examination (OSCE) for musculoskeletal ultrasound (MSUS).

Droperidol-fentanyl inhibits mast cell histamine release in rat synovium, but not skin, after immunologic activation: Evidence for mast cell heterogeneity

The characteristics of mast cell heterogeneity include differences in mast cell staining, cellular structure, content of proteoglycans and vasoactive amines, and in vitro responses to secretagogues. We have found that the anesthetic agent, droperidol-fentanyl, significantly decreased rat synovial vascular permeability after selective synovial mast cell degranulation. In contrast, there was no effect on skin mast cell-induced vascular permeability. To address the possibility that this difference in response represents mast cell heterogeneity and uniqueness of synovial mast cells, we investigated the effects of three different anesthetic agents on synovial mast cells. In these studies we examined whether (1) the drugs affect synovial mast cells and (2) whether the drugs affect synovial mast cells differently from mast cells in skin. Our data indicate that, compared to inhaled methoxyflurane and ethyl ether, subcutaneous droperidol-fentanyl had a significant inhibitory effect on synovial, but not skin, mast cell-mediated vascular permeability, which was associated with a significant inhibition of synovial mast cell histamine release. Thus, the permeability differences were not due only to effects on histamine receptors. Our data suggest the possibility that there are significant functional differences between synovial and skin mast cells, a phenomenon that may have important therapeutic implications for treatment of mast cell-mediated synovial inflammation.

Poster 65: Ultrasound-guided Tenotomy and Hydrodissection of the Flexor Retinaculum in Carpal Tunnel Syndrome (CTS)

program. Main Outcome Measures: Rehabilitation length of stay (LOS), FIM® instrument scores, mobility (walking distance, transfers, stairs), discharge location, mortality. Results: The rehabilitation LOS was not different between the non-obese and obese patients (10.9 5.1 vs 11.2 5.9 days, respectively). Total FIM scores were not different at admission and by discharge (95.3 14.6 vs 96.2 points at discharge, respectively). At admission, 13.9% and 24.5% of obese and non-obese patients were able to walk 150 feet independently; by discharge, the percentages increased to 68.1% and 78.9%, respectively. At follow-up, walking independence declined in both groups. Similar proportions of patients in both groups obtained complete independence or supervision only for stair climb and transfers. These functional improvements were maintained out to month 6. A total of 84.7% and 84.1% of non-obese and obese patients were discharged to home. Only 1 non-obese patient had died before follow-up. Conclusions: Obesity does not hinder functional improvements made during inpatient rehabilitation and out to 6 months of follow-up in patients with cardiac disease related exacerbations. FIM is a trademark of Uniform Data System for Medical Rehabilitation, a division of UB Foundation Activities, Inc.