Potential risk factors for undifferentiated connective tissue disease among women: implanted medical devices.

A case-control study was conducted among 205 women in Michigan and Ohio who were diagnosed with undifferentiated connective tissue disease (UCTD) to investigate the significance of self-reported past exposures to implanted silicone-containing or non-silicone-containing medical devices. The 205 UCTD cases were compared with 2,095 controls who were sampled by random digit dialing. When silicone-containing devices, including shunts and catheters, were analyzed collectively, a significant association was observed (odds ratio (OR) = 2.81, 95% confidence interval (CI): 1.34, 5.89). The odds ratio for exposure to breast implants was increased, but not significantly (OR = 2.22, 95% CI: 0.65, 7.57). Among the non-silicone-containing devices, artificial joints (OR = 5.01, 95% CI: 1.60, 15.71) and orthopedic metallic fixation devices (OR = 1.95, 95% CI: 1.05, 3.60) were associated with UCTD. The estimations of risk associated with implanted medical devices in UCTD cases were explored in a comparison with 660 scleroderma patients who were ascertained concurrently in Michigan and Ohio. In general, the associations that were observed with non-silicone-containing devices, and more specifically with the fixation devices, persisted in the comparison of UCTD cases with scleroderma patients. The studies conducted among populations in Michigan and Ohio are intended to stimulate new hypotheses, innovative approaches, and the fostering of understanding of the environmental determinants of autoimmune disease.

Petroleum distillate solvents as risk factors for undifferentiated connective tissue disease (UCTD).

Occupational solvent exposure may increase the risk of connective tissue disease (CTD). The objective of this case-control study was to investigate the relation between undifferentiated connective tissue disease (UCTD) and solvent exposure in Michigan and Ohio. Women were considered to have UCTD if they did not meet the American College of Rheumatology classification criteria for any CTD but had at least two documented signs, symptoms, or laboratory abnormalities suggestive of a CTD. Detailed information on solvent exposure was ascertained from 205 cases, diagnosed between 1980 and 1992, and 2,095 population-based controls. Age-adjusted odds ratios (OR) and 95 percent confidence intervals (CI) were calculated for all exposures. Among 16 self-reported occupational activities with potential solvent exposure, furniture refinishing (OR = 9.73, 95 percent CI 1.48-63.90), perfume, cosmetic, or drug manufacturing (OR = 7.71, 95 percent CI 2.24-26.56), rubber product manufacturing (OR = 4.70, 95 percent CI 1.75-12.61), work in a medical diagnostic or pathology laboratory (OR = 4.52, 95 percent CI 2.27-8.97), and painting or paint manufacturing (OR = 2.87, 95 percent CI 1.06-7.76) were significantly associated with UCTD. After expert review of self-reported exposure to ten specific solvents, paint thinners or removers (OR = 2.73, 95 percent CI 1.80-4.16) and mineral spirits (OR = 1.81, 95 percent CI 1.09-3.02) were associated with UCTD. These results suggest that exposure to petroleum distillates increases the risk of developing UCTD.

Molecular lysis of synovial lining cells by in vivo herpes simplex virus-thymidine kinase gene transfer.

Herpes simples virus thymidine kinase (HSV-TK) expression plasmid DNA was injected into the joint space of rabbits with antigen-induced arthritis (AIA). Purified plasmid DNA was able to mediate transfection of synovial lining cells and transient overexpression of HSV-TK in the context of active synovial inflammation. The pharmacodynamic distribution of intraarticular expression plasmid DNA was confined to the joint space. Arthritic rabbits treated with intraarticular expression plasmid DNA followed by intravenous ganciclovir (GCV, 5 mg/kg) twice daily for 3 days showed histologic evidence of synovial lining layer cytolysis when articular tissues were examined 21 days posttreatment. There was also a reduction in joint swelling in the TK-treated knees. No untoward clinical effects were observed in the rabbits and no evidence of cytolytic damage specific to the TK-GCV gene therapy was observed either in the articular cartilage or bone. The application of TK-GCV intraarticular gene therapy using purified expression plasmid DNA for the induction of synovial cytolysis may be applicable to the treatment of human inflammatory arthritis.

Racial differences in scleroderma among women in Michigan.

OBJECTIVE: To examine racial differences in disease onset, extent, manifestations, and survival among women with scleroderma. METHODS: A retrospective cohort study of women with scleroderma, diagnosed in Michigan between 1980 and 1991, was conducted. Clinical, laboratory, and demographic data were abstracted from the patients' medical records. RESULTS: A total of 514 women with scleroderma were identified: 117 (23%) were black and 397 (77%) were white. Among black women, the mean age at diagnosis was lower (44.5 years versus 51.5 years; P < 0.001) and diffuse disease was more common (49.6% versus 24.9%; P < 0.001) than among white women. The overall incidence of scleroderma was 14.1 per million per year: 22.5 per million per year in black women versus 12.8 per million per year in white women (P < 0.001). Pericarditis (P = 0.009), pulmonary hypertension (P < 0.001), pleural effusions (P = 0.01), myositis (P = 0.02), and an erythrocyte sedimentation rate >40 mm/hour (P < 0.001) were more frequent among black women, while white women were more likely to have digital infarctions (P < 0.001). Survival at 7 years from diagnosis was 72.5% among black women and 77.6% among white women. Age-adjusted survival was significantly reduced among black women (P = 0.033), most likely because of increased diffuse involvement. Survival among those with renal or pulmonary involvement was also significantly reduced. CONCLUSION: Black women with scleroderma were significantly more likely than white women to develop diffuse disease, be diagnosed at a younger age, have a higher incidence of inflammatory features, and have a worse age-adjusted survival rate.

Ultrasonic characterization of in vitro osteoarthritic articular cartilage with validation by confocal microscopy.

The majority of adults over the age of 65 y develop osteoarthritis (OA), a joint disease characterized by degeneration of articular cartilage and subchondral sclerosis. Early in the disease, the articular cartilage surface begins to change histologically from a smooth to a rough or fibrillated appearance. A prerequisite for any chondroprotective pharmacological intervention is detection of OA in its preclinical phase. Current diagnostic imaging modalities, such as radiographs or (nuclear) magnetic resonance imaging, either cannot directly image the cartilage surface or lack sufficient resolution to detect surface fibrillations. We have developed an ultrasonic technique that can be used to characterize these surface fibrillations directly. We present our in vitro results with validation by laser-based confocal microscopic imaging.

The epidemiology of scleroderma among women: assessment of risk from exposure to silicone and silica.

OBJECTIVE: To investigate the relationship between exposure to silicone (including breast implants) and silica and the development of scleroderma (systemic sclerosis, SSc) among women. METHODS: A population based case-control study was conducted among women in Michigan. 274 confirmed cases of SSc diagnosed between 1985 and 1991 were identified by contacting rheumatologists, hospitals, and a scleroderma support group. These cases and 1184 controls were interviewed by telephone to ascertain past exposures to silicone or silica. RESULTS: Silicone in the form of breast implants was not associated with significantly increased risk of SSc (adjusted odds ratio, 1.30; 95% confidence interval, 0.27 to 6.23). Among 20 other potential silicone exposure surveyed, self-reported exposure to silicone based glues, sealants, and caulks, manufacture or repair of windows or windshields, repairing or frequently using photocopy machines, consumption of simethicone-containing antacids, and implanted medication delivery pumps were significantly associated with SSc. However, blinded assessment of all job and hobby descriptions in terms of their potential for silicone exposure failed to support the first 3 associations, antacid consumption may have been confounded by esophageal dysmotility before the diagnosis of SSc, and other silicone containing device categories (pacemakers, central nervous system shunts, other shunts and catheters) were not significantly associated with SSc. Surgically implanted metallic fixation devices were associated with significantly reduced risk for SSc. No association was detected between SSc and silica dust exposure. CONCLUSION: Consistent with other studies, we found no increased risk of SSc among women with silicone breast implants, equivocal evidence of risk from other silicone exposures, and no evidence of risk from silica exposure.

The use of trained patient educators with rheumatoid arthritis to teach medical students.

OBJECTIVE: To assess whether patients with rheumatoid arthritis (RA) trained as educators can enhance the integration of clinical and basic science education among second-year medical students during their rheumatology sequence. METHODS: Twenty patients with RA and strong communication skills were extensively trained to teach students how to perform the whole-body joint examination. Each arthritis educator taught three 2-hour small group sessions and participated in a concluding 2-hour panel discussion with the entire class. Changes in student knowledge and attitudes were assessed in a pre-post evaluation design. RESULTS: There were statistically and educationally significant gains in knowledge, confidence, and attitudes related to psychosocial aspects of arthritis in each of the 2 years the program was implemented. One-year followup data indicated substantial retention of these gains. CONCLUSIONS: Patients trained in arthritis education can effectively teach fundamental musculoskeletal examination skills and encourage the development of sensitivity to the impact of chronic arthritis on the daily life of other patients.

Power Doppler sonography of synovitis: assessment of therapeutic response--preliminary observations.

Power Doppler sonography was used in eight symptomatic knees in seven patients with arthritis before and after joint aspiration and intraarticular administration of steroids. A qualitative decrease in synovial perfusion was observed in all eight knees, and symptoms improved in seven of the eight cases. These preliminary data suggest a role for power Doppler sonography in assessment of serial changes in synovial inflammation.

Pulmonary inflammation induced by incomplete or inactivated adenoviral particles.

One of the major obstacles to pulmonary-directed gene therapy using adenoviral vectors is the induction of inflammation. We investigated whether the adenoviral particles that constitute the initial inoculum can serve as an inflammatory stimulus, independent of their ability to express genes that they contain. Viral particles were prepared that are defective in gene expression by (i) isolating particles that have incomplete genomes by selecting those that have buoyant densities on CsCl density gradients lighter than complete viruses; and (ii) cross-linking viral DNA by exposure to ultraviolet light in the presence of 8-methoxypsoralen. The defective particles retained their icosahedral appearance when viewed by electron microscopy but lost their plaque-forming ability on 293 cells. High doses of intact, incomplete, or inactivated viral particles were instilled intratracheally into CBA/J mice, and after 6 days the amount of inflammation was quantified by counting inflammatory cells contained within lung tissue. We found that the inflammatory responses induced by the incomplete or inactivated viral vectors were quantitatively similar to those caused by intact, competent viral vectors. We conclude that high doses of adenoviral vectors that are used for gene therapy can induce pulmonary inflammation, independent of expressing the genes they contain.

Ultraviolet light and 8-methoxypsoralen inhibit expression of endothelial adhesion molecules.

OBJECTIVE: Having previously found that treating small areas of synovitis within the knees of patients with rheumatoid arthritis (RA) with 8-methoxypsoralen (8-MOP) and laser-derived ultraviolet A (PUVA) resulted in decreases in adhesion molecule expression, we sought to determine the effect of PUVA on expression of vascular cellular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selection by human umbilical vein endothelial cells (HUVEC). METHODS: Expression of VCAM-1, ICAM-1, and E-selectin on the surface of HUVEC was measured using specific antibodies and flow cytometry or a fluorescence plate reader, following treatment of cells with 8-MOP and UVA, before and after tumor necrosis factor (TNF) stimulation. RESULTS: PUVA led to significant dose dependent decreases in the expression of VCAM-1 and E-selectin that had been induced with TNF before PUVA treatment. Pretreatment with PUVA was also able to prevent subsequent TNF induction of VCAM-1 expression. TNF-induced ICAM-1 expression was not decreased by PUVA, however, and pretreatment only partially decreased ICAM-1 expression. CONCLUSION: The in vivo effects of PUVA may be explained, in part, by down regulation of adhesion molecule expression. The relative resistance of ICAM-1 to PUVA suggests some specificity to the effect on adhesion molecule expression.

A pilot study of the effect of oral 8-methoxypsoralen and intraarticular ultraviolet light on rheumatoid synovitis.

OBJECTIVE: To determine the feasibility and safety of combining oral 8-methoxypsoralen (8-MOP) and intraarticular ultraviolet A band light (UVA) to treat rheumatoid synovitis, and to demonstrate a favorable biological effect. METHODS: Six patients with rheumatoid arthritis (RA) and clinically evident knee synovitis were given a single oral dose of 8-MOP (0.6 mg/kg) followed by arthroscopy with a UVA laser equipped small arthroscope. Nine tissue samples treated with UVA doses ranging from 4 to 52 J/cm2 were examined by light microscopy and by immunohistochemistry for vascular cell adhesion molecule 1 (VACM-1), intracellular adhesion molecule 1 (ICAM-1), E-selectin and HLA-DR expression. RESULTS: No reduction in inflammation was evident on light microscopy, nor was there any evidence of tissue injury on gross inspection or light microscopy. At 28 and 52 J/cm2, VCAM-1, ICAM-1 and E-selectin staining were reduced in the posttreatment synovial biopsies. No local or systemic complications were observed by Day 30 in any patient. CONCLUSION: This treatment modality appears to be feasible and safe and may potentially be useful in the treatment of the synovitis associated with RA.

Quantitative assessment of surface roughness using backscattered ultrasound: the effects of finite surface curvature.

We have previously described a technique to quantify surface fibrillatory changes in osteoarthritic articular cartilage. In that study, the angular distribution of the scattered acoustic field from an insonifying source directly related to the distribution of surface fibrillatory changes. In the current study, we demonstrate a more sensitive method to quantify surface roughness, the effect of global surface curvature in estimating surface roughness and the utility of using focused transducers in circumventing this potential problem for in vivo work. Phantoms composed of acrylic rods with and without sandpaper grit (about 15 to 72 microns, mean particle size) applied to the surface were scanned. A more robust angular scattering technique to measure the angle dependent data was employed, in which the integrated squared pressure amplitude over a finite time window (mean power) was measured as a function of incident acoustic angle for varying surface roughnesses and radii of curvature. We show that the potential dynamic range for making roughness discriminations diminishes with decreasing radius of curvature of the acrylic rod phantoms using an unfocused transducer. This effect is minimized with use of a focused transducer. Roughness effects are most evident at sufficiently large angles where incoherent scattering dominates. We conclude that the roughness of cylindrically curved surfaces can be quantitatively assessed using a focused ultrasound beam at sufficiently large incident angles, given that the focal spot size is sufficiently smaller than the radius of curvature of the surface.

Medical student use of history and physical information in diagnostic reasoning.

Clinical data gathering is central to clinical competence. Although research has demonstrated the value to experienced clinicians of information obtained from the history, little is known of how medical students use this information. In the present study, two case simulations (in rheumatoid arthritis and systemic lupus erythematosis) were developed to assess medical student information gathering and utilization. The results indicate that most of the students were already considering the correct diagnosis as a possibility after the presenting complaint and patient description. However, the medical history exerted the strongest influence on transforming the correct diagnosis from just another diagnostic possibility into the favored diagnostic candidate. Students who failed to list the correct diagnosis in the differential diagnosis after obtaining the history were significantly less likely to reach the correct diagnosis at the end of the case. These results confirm the critical importance of the history in medical problem solving.

Quantitative assessment of cartilage surface roughness in osteoarthritis using high frequency ultrasound.

Osteoarthritis (OA) is a common disease which affects nearly 50% of people over age 60. Histologic evaluation suggests that fibrillations approximately 20-150 microns are among the earliest changes in the articular cartilage. We propose a technique to quantify these surface fibrillatory changes in osteoarthritic articular cartilage by considering the angular distribution of the envelope-detected backscattered pressure field from an incident 30-MHz focused transducer. The angular distribution of the scattered acoustic field from an inosonifying source will directly relate to the distribution of surface fibrillatory changes. Data are presented for three different grades (400, 500 and 600 grit) of commercially available emory paper and three samples of osteoarthritic femoral head articular cartilage, which were visually assessed as having smooth, intermediate and rough surfaces, respectively. Our preliminary results indicate a probable monotonic relationship between articular cartilage roughening and the degree of broadening in the angle-dependent pressure amplitude. When applied to the emory paper, the technique indicates sensitivity to differences as small as approximately 5-10 microns in mean roughness. This procedure may provide an extremely sensitive and reproducible means of quantifying and following the cartilage changes observed in early osteoarthritis.

Mononeuritis multiplex: the yield of evaluations for occult rheumatic diseases.

We identified 35 patients who had electrodiagnostic evidence of mononeuritis multiplex and did not have diabetes or multiple nerve compressions. Their charts were reviewed to determine the etiologies of the mononeuritis multiplex and to determine how often the laboratory examination revealed a rheumatic disease in patients whose initial history and physical examination did not suggest that a rheumatic disease was present. In 11/35 (31%; CI = 17-49) a disorder capable of causing mononeuritis multiplex was diagnosed before the symptoms of mononeuritis multiplex began. Ten had a rheumatic disease; 1 had lymphoma. Nine of the other patients were suspected, on the basis of the history and physical examination, of having new onset of a rheumatic disease. Subsequent laboratory evaluation showed that 5/9 (56%; CI = 21-86) had a rheumatic disease, and 4/9 (44%; CI = 14-79) were unknowns. In 15/35 (43%; CI = 26-61) patients with mononeuritis multiplex, no rheumatic disease was suspected on the basis of the initial history and physical examination. The subsequent laboratory examination revealed an underlying rheumatic disease in 0/15 (0%; CI = 0-18). Mean clinical follow-up of 16 +/- 16 months in the patients with mononeuritis multiplex of unknown cause also failed to identify a rheumatic disease. Overall 19/35 (54%; CI = 37-71) did not have a rheumatic disease or any other known cause. Of the 14 patients with mononeuritis multiplex associated with a rheumatic disease, 5/14 (36%; CI = 13-15) had systemic lupus erythematosus; an additional patient had both lupus and the CREST syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for IL-2 independent proliferation in human T cells.

Previous models of human T cell proliferation have assumed IL-2 to be largely responsible for the clonal expansion observed after TCR complex (CD3/Ti)-mediated stimulation. By using mAb to the CD3 component of CD3/Ti as well as mAb to other nonpolymorphic T cell surface molecules, we demonstrate T cell proliferation in the absence of detectable IL-2 and define some of the conditions necessary for IL-2 production in vitro. PBL cultured with soluble OKT3 alone or OKT3 plus PMA proliferated nearly equally, but IL-2 was detectable only in the supernatants in the latter condition. RNA blot analyses at 8, 16, and 36 h consistently showed high levels of IL-2 transcripts in the OKT3 + PMA stimulated cells. In contrast, when stimulated with OKT3 alone IL-2 transcripts were barely detectable at the 8-h time point only. Anti-Tac only partially inhibited proliferation induced by either OKT3 or OKT3 + PMA, but consistently prevented it when PBL were stimulated by PMA plus exogenous human rIL-2. Cyclosporin A (CsA) was added in varying doses to PBL cultured in the presence of OKT3 + PMA. At 0.05 microgram/ml, proliferation was only partially inhibited, whereas IL-2 was undetectable. To examine the possibility that IL-4 could account for the observed proliferative response, CsA was added to PBL cultured with either OKT3 alone or OKT3 and PMA. Although IL-4 transcript levels were detectable in the presence of OKT3 alone or OKT3 + PMA, CsA at 0.05 microgram/ml allowed proliferation to occur in the absence of detectable IL-2 as well as IL-2 and IL-4 transcripts. Finally, T cell-enriched PBL were shown to proliferate and also to produce substantial quantities of IL-2 in response to immobilized OKT3 + either OKT11 or 9.3. These results strongly suggest the existence of an IL-2 and IL-4 independent pathway of human T cell proliferation and demonstrate that IL-2 production may result only when a closely defined set of stimuli are present.

Quantitation of T-macrophage binding avidity with and without antigen using a novel centrifugation assay.

The T cell-macrophage interaction, necessary for T cell activation, has nonspecific and specific components. Nonspecific T-macrophage interactions are mediated by surface glycoproteins such as LFA 1, 2 and 3, while specific interactions are mediated by the T3-Ti complex on the T cell and antigen plus Ia molecules on the macrophage. To determine the relative contributions of specific antigen to the total avidity of T-macrophage binding we adapted a novel assay capable of providing quantitative estimations of the avidity of cell-cell interactions. Using this assay we determined the avidity of a cloned CD4+ antigen specific T cell line for autologous macrophages with and without antigen. The presence of specific antigen increased binding avidity by approximately 25%. This assay should prove useful in further characterizing the avidity of T-macrophage interactions.