Showing papers in "Arthritis & Rheumatism in 2001"

Multipotent mesenchymal stem cells from adult human synovial membrane

Abstract: Objective To characterize mesenchymal stem cells (MSCs) from human synovial membrane (SM). Methods Cell populations were enzymatically released from the SM obtained from knee joints of adult human donors and were expanded in monolayer with serial passages at confluence. Cell clones were obtained by limiting dilution. At different passages, SM-derived cells were subjected to in vitro assays to investigate their multilineage potential. Upon treatments, phenotypes of cell cultures were analyzed by histo- and immunohistochemistry and by semiquantitative reverse transcription–polymerase chain reaction for the expression of lineage-related marker genes. Results SM-derived cells could be expanded extensively in monolayer, with limited senescence. Under appropriate culture conditions, SM-derived cells were induced to differentiate to the chondrocyte, osteocyte, and adipocyte lineages. Sporadic myogenesis was also observed. Five independent cell clones displayed multilineage potential. Interestingly, only 1 clone was myogenic. Donor age, cell passaging, and cryopreservation did not affect the multilineage potential of SM-derived cells. In contrast, normal dermal fibroblasts under the same culture conditions did not display this potential. Conclusion Our study demonstrates that human multipotent MSCs can be isolated from the SM of knee joints. These cells have the ability to proliferate extensively in culture, and they maintain their multilineage differentiation potential in vitro, establishing their progenitor cell nature. SM-derived MSCs may play a role in the regenerative response during arthritic diseases and are promising candidates for developing novel cell-based therapeutic approaches for postnatal skeletal tissue repair.

High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors

Abstract: Objective. To compare the incidence of cardiovascular (CV) events in persons with rheumatoid arthritis (RA) with that in people from the general population, adjusting for traditional CV risk factors. Methods. Two hundred thirty-six consecutive patients with RA were assessed for the 1-year occurrence of 1) CV-related hospitalizations, including myocardial infarction, stroke or other arterial occlusive events, or arterial revascularization procedures, or 2) CV deaths. Both outcomes were ascertained by medical records or death certificates. For comparison, we used CV events that occurred during an 8-year period among participants in an epidemiologic study of atherosclerosis and CV disease who were ages 25–65 years at study entry. We calculated the age- and sex-stratified incidence rate ratio (IRR) of CV events between the 2 cohorts and used Poisson regression to adjust for age, sex, smoking status, diabetes mellitus, hypercholesterolemia, systolic blood pressure, and body mass index. Results. Of the 236 RA patients, 234 were observed for 252 patient-years, during which 15 CV events occurred. Of these, 7 incident events occurred during the 204 patient-years contributed by patients ages 25–65 years, for an incidence of 3.43 per 100 patient-years. In the comparison cohort, 4,635 community-dwelling persons were followed up for 33,881 person-years, during which 200 new events occurred, for an incidence of 0.59 per 100 person-years. The age- and sex-adjusted IRR of incident CV events associated with RA was 3.96 (95% confidence interval [95% CI] 1.86–8.43). After adjusting for CV risk factors using Poisson regression, the IRR decreased slightly, to 3.17 (95% CI 1.33–6.36). Conclusion. The increased incidence of CV events in RA patients is independent of traditional CV risk factors. This suggests that additional mechanisms are responsible for CV disease in RA. Physicians who provide care to individuals with RA should be aware of their increased risk of CV events and implement appropriate diagnostic and therapeutic measures.

Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus.

Abstract: Objective The frequency of coronary heart disease (CHD) and stroke are increased in systemic lupus erythematosus (SLE), but the extent of the increase is uncertain. We sought to determine to what extent the increase could not be explained by common risk factors. Methods The participants at two SLE registries were assessed retrospectively for the baseline level of the Framingham study risk factors and for the presence of vascular outcomes: nonfatal myocardial infarction (MI), death due to CHD, overall CHD (nonfatal MI, death due to CHD, angina pectoris, and congestive heart failure due to CHD), and stroke. For each patient, the probability of the given outcome was estimated based on the individual's risk profile and the Framingham multiple logistic regression model, corrected for observed followup. Ninety-five percent confidence intervals (95% CIs) were estimated by bootstrap techniques. Results Of 296 SLE patients, 33 with a vascular event prior to baseline were excluded. Of the 263 remaining patients, 34 had CHD events (17 nonfatal MIs, 12 CHD deaths) and 16 had strokes over a mean followup period of 8.6 years. After controlling for common risk factors at baseline, the increase in relative risk for these outcomes was 10.1 for nonfatal MI (95% CI 5.8–15.6), 17.0 for death due to CHD (95% CI 8.1–29.7), 7.5 for overall CHD (95% CI 5.1–10.4), and 7.9 for stroke (95% CI 4.0–13.6). Conclusion There is a substantial and statistically significant increase in CHD and stroke in SLE that cannot be fully explained by traditional Framingham risk factors alone.

Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets

Abstract: Osteoarthritis (OA) is a well-known disease that is part of the aging process and also one of the most common diseases among mammals. Although this musculoskeletal disorder has been described in mammals of many ages, having been reported in Egyptian mummies and in dinosaurs, its exact etiology is far from being fully understood. With the graying of the world population, it is of the utmost importance to find out more about the pathogenesis of the disease and thus allow the discovery of new treatments to stop or prevent its progression. A number of risk factors have lately been identified (1). Mechanical factors, among others, are likely to play a very important role in the initiation of the disease process. Endogenous factors such as type II collagen mutation or dysplastic conditions are also known to be involved in initiating the OA process (2). There is now strong evidence that the structural changes globally observed in OA are due to a combination of factors, ranging from the mechanical to the biochemical (3,4). The disease process affects not only the cartilage, but also the entire joint structure, including the synovial membrane, subchondral bone, ligaments, and periarticular muscles. In OA synovium, the inflammatory changes that take place include synovial hypertrophy and hyperplasia with an increased number of lining cells, and also an infiltration of the sublining tissue with a mixed population of inflammatory cells. In patients with severe disease, the extent of inflammation can sometimes reach that observed in rheumatoid arthritis (RA) patients at the clinical stage (5,6). Some degree of synovitis has also been reported in even the early stages of the disease (7). Synovial inflammation is clearly reflected in many of the signs and symptoms of OA, including joint swelling and effusion, stiffness, and sometimes redness, particularly at the level of the proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints.

Elevated serum B lymphocyte stimulator levels in patients with systemic immune–based rheumatic diseases

Abstract: Objective To determine whether serum levels of B lymphocyte stimulator (BLyS) are elevated in patients with systemic immune–based rheumatic diseases and correlate with serum Ig levels and/or autoantibody titers. Methods Sera from 185 patients with various systemic immune–based rheumatic diseases (95 with systemic lupus erythematosus [SLE], 67 with rheumatoid arthritis [RA], 23 with other diagnoses) were assayed for BLyS and Ig. In 7 patients who required arthrocentesis of a swollen knee, coincident serum and synovial fluid samples were assayed for BLyS. Medical charts were retrospectively reviewed for elevated autoantibody titers and proteinuria within a 1-month period before or after collection of sera for BLyS and Ig determination. Sera concurrently collected from 48 normal healthy subjects served as controls. Results Serum BLyS levels were elevated in 38 of 185 patients (21%) and correlated significantly with serum IgG levels. Serum BLyS levels did not correlate with the patients' age, sex, race, or medications, but correlated positively with anti–double-stranded DNA antibody titers among SLE patients and with rheumatoid factor titers among seropositive RA patients. In contrast, serum BLyS levels correlated inversely with nephrotic-range proteinuria among SLE patients. In every case tested, BLyS levels in clinically inflamed synovial fluids were greater than those in simultaneously obtained sera. Conclusion BLyS may be an important factor in driving polyclonal hypergammaglobulinemia and elevated autoantibody titers in patients with systemic immune–based rheumatic diseases. Local production of BLyS in the joints may contribute to joint pathology. Patients with elevated serum BLyS levels may be ideal candidates for therapeutic targeting of BLyS.

Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides.

Abstract: Objective. To review the occurrence of neurologic events suggestive of demyelination during anti-tumor necrosis factor a (anti-TNFa) therapy for inflammatory arthritides. Methods. The Adverse Events Reporting System of the Food and Drug Administration (FDA) was queried following a report of a patient with refractory rheumatoid arthritis who developed confusion and difficulty with walking after receiving etanercept for 4 months. Results. Nineteen patients with similar neurologic events were identified from the FDA database, 17 following etanercept administration and 2 following infliximab administration for inflammatory arthritis. All neurologic events were temporally related to anti-TNFa therapy, with partial or complete resolution on discontinuation. One patient exhibited a positive rechallenge phenomenon. Conclusion. Further surveillance and studies are required to better define risk factors for and frequency of adverse events and their relationship to anti-TNFa therapies. Until more long-term safety data are available, consideration should be given to avoiding anti-TNFa therapy in patients with preexisting multiple sclerosis and to discontinuing anti-TNFa therapy immediately when new neurologic signs and symptoms occur, pending an appropriate evaluation.

Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: Associations with degenerative changes

Abstract: Objective To examine by immunohistochemistry the relative distributions of 6 matrix metalloproteinases (MMPs 1, 2, 3, 8, 9, and 13) and the 2 proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) in osteoarthritic (OA) cartilage compared with normal, age-matched articular cartilage. Methods Articular cartilage samples were obtained from the tibial plateau of OA knees removed at arthroplasty and from normal, nonarthritic, knees obtained at autopsy. Specimens were promptly fixed in Carnoy's fixative, processed, embedded in paraffin, sectioned, and examined by immunohistochemistry for MMP and cytokine production. In addition, human articular chondrocytes (HAC) were treated in vitro with either IL-1β, TNFα, or phorbol myristate acetate (PMA) to assess their potential to produce each of the MMPs, as determined by Western blotting and gelatin zymography. Results Immunodetection of the collagenases (MMPs 1, 8, and 13) and stromelysin 1 (MMP-3) was demonstrated in a proportion of chondrocytes in the superficial zone of almost all of the OA specimens that had degenerative matrix changes. The gelatinases (MMPs 2 and 9) were also demonstrated by immunohistochemistry but were not so prominent. IL-1β– and TNFα-positive chondrocytes were also observed in a proportion of cells in the superficial zones of OA specimens. Much less immunostaining for MMPs and cytokines was observed in the deep zone of all OA specimens, where the cartilage matrix and chondrocyte morphology appeared normal. In contrast, full-thickness normal cartilage specimens showed virtually no immunostaining for these MMPs or cytokines. Confirmation that chondrocytes can produce these 6 MMPs was obtained from HAC cultures treated with either IL-1β, TNFα, or PMA; conditioned medium from activated HAC contained all the MMPs demonstrated by immunohistochemistry. Dual immunolocalization studies of OA cartilage specimens demonstrated the coexpression of IL-1 with MMP-8 by individual chondrocytes in situ. Conclusion These results indicate that the superficial zone of OA cartilage specimens, which is characterized by fibrillations, chondrocyte clusters, and degenerative matrix changes, contains a variable proportion of cells that immunostain for IL-1β, TNFα, and 6 different MMPs. These observations support the concept that cytokine–MMP associations reflect a modified chondrocyte phenotype and an intrinsic process of cartilage degradation in OA.

Smallest detectable and minimal clinically important differences of rehabilitation intervention with their implications for required sample sizes using WOMAC and SF-36 quality of life measurement instruments in patients with osteoarthritis of the lower extremities.

Abstract: Objective To discuss the concepts of the minimal clinically important difference (MCID) and the smallest detectable difference (SDD) and to examine their relation to required sample sizes for future studies using concrete data of the condition-specific Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the generic Medical Outcomes Study 36-Item Short Form (SF-36) in patients with osteoarthritis of the lower extremities undergoing a comprehensive inpatient rehabilitation intervention. Methods SDD and MCID were determined in a prospective study of 122 patients before a comprehensive inpatient rehabilitation intervention and at the 3-month followup. MCID was assessed by the transition method. Required SDD and sample sizes were determined by applying normal approximation and taking into account the calculation of power. Results In the WOMAC sections the SDD and MCID ranged from 0.51 to 1.33 points (scale 0 to 10), and in the SF-36 sections the SDD and MCID ranged from 2.0 to 7.8 points (scale 0 to 100). Both questionnaires showed 2 moderately responsive sections that led to required sample sizes of 40 to 325 per treatment arm for a clinical study with unpaired data or total for paired followup data. Conclusion In rehabilitation intervention, effects larger than 12% of baseline score (6% of maximal score) can be attained and detected as MCID by the transition method in both the WOMAC and the SF-36. Effects of this size lead to reasonable sample sizes for future studies lying below n = 300. The same holds true for moderately responsive questionnaire sections with effect sizes higher than 0.25. When designing studies, assumed effects below the MCID may be detectable but are clinically meaningless.

Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis.

Abstract: Objective To develop criteria for symptomatic improvement in patients with ankylosing spondylitis (AS), using outcome domain data from placebo-controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs). Methods Patient data from 5 short-term, randomized, controlled trials were used to assess equivalence, reliability, and responsiveness of multiple items in the 5 outcome domains for AS treatment: physical function, pain, spinal mobility, patient global assessment, and inflammation. At least one measure per domain was responsive (standardized response mean of >0.5), except for the spinal mobility domain, which was omitted from the criteria. We developed and tested candidate improvement criteria in a random two-thirds subset from the 3 largest trials and used the remaining one-third for validation. These 3 largest trials included 923 patients (631 receiving NSAIDs, 292 in placebo groups). We selected the multiple domain definition that best distinguished NSAID treatment from placebo by chi-square test and that had a placebo response rate of ≤25%. Results Candidate definitions were changes in single domains and in multiple measure indices, as well as combinations of improvements in multiple domains. Worsening in a domain was defined as a change for the worse of ≥20% and a net change for the worse of ≥10 units on a scale of 0–100. Partial remission (for comparison purposes) was defined as an end-of-trial value of <20/100 in each of the 4 domains. Among 20 candidate criteria, change of ≥20% and ≥10 units in each of 3 domains and absence of worsening in the fourth discriminated best in the development subset (51% of patients improved with NSAIDs, 25% with placebo; χ2 = 36.4, P < 0.001). Results were confirmed in the validation subset. Almost all patients satisfying the definition of partial disease remission at the end of the trial had also improved by this criterion. Among all 923 patients, improvement rates using this criterion were 49% for NSAID-treated patients and 24% for placebo-treated patients. Conclusion Although further validation using data from new trials is still needed, we conclude that we have developed a clinically valid, easy-to-use measure of short-term improvement in AS.

Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial.

Abstract: OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis.

Abstract: Objective To investigate the relationship between functional capacity, disease activity, and joint destruction over the course of rheumatoid arthritis (RA). Methods The followup data on 378 patients with early RA (duration <1 year), included in an open, prospective study since 1985 at the Department of Rheumatology of the University Medical Center Nijmegen, were used. Functional capacity, disease activity, and joint destruction were assessed using the Health Assessment Questionnaire disability index (HAQ DI), the Disease Activity Score (DAS), and a modification of the sharp radiographic damage score, respectively. Multiple linear regression was used to model the data collected at 0, 3, 6, and 9 years after study start, to investigate which variables influenced functional capacity during the disease course. A general linear mixed model for longitudinal data, which included the variables identified as significant in the multiple linear regression models and several interaction terms between the variables, was run. Results On average, the functional capacity of the patients, as measured by the HAQ DI, worsened over the course of the disease after an initial improvement. After an initial reduction in the extent of disease activity, the mean DAS remained more or less stable over the course of the disease. The mean modified sharp joint damage score worsened over the course of the disease, with a slower progression rate later in the disease. In the multiple linear regression at 0, 3, and 6 years after study start, disease activity was found to be an important factor influencing functional capacity, and at 6 and 9 years, joint damage had an important effect on functional capacity. Furthermore, at 6 and 9 years, there was an interaction effect of joint destruction with disease activity. In the general linear mixed model, disease activity, joint damage, and an interaction effect of disease activity and joint damage were the main factors explaining functional capacity. Conclusion The effect of disease activity and joint destruction on functional capacity changes over the course of the disease. In early RA, functional capacity is most associated with disease activity, and in late disease, with joint damage.

Long‐term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg‐Strauss syndrome: Analysis of four prospective trials including 278 patients

Abstract: Objective To determine the long-term outcome of patients with polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS), to compare the long-term outcome with the overall French population, to evaluate the impact on outcome of the type of vasculitis, prognostic factors, and treatments administered at diagnosis, and to analyze treatment side effects and sequelae. Methods Data from PAN, MPA, and CSS patients (n = 278) who were enrolled between 1980 and 1993 were collected in 1996 and 1997 and analyzed. Two prognostic scoring systems, the Five-Factors Score (FFS) and the Birmingham Vasculitis Activity Score (BVAS), were used to evaluate all patients at the time of diagnosis. Results The mean (±SD) followup of the entire population was 88.3 ± 51.9 months (range 3 days to 192 months). Of the 85 deaths recorded, at least 41 were due to progressive vasculitis or its consequences. Death rates reflected disease severity, as assessed by the FFS (P = 0.004) and the BVAS (P < 0.0002), and the 2 scores were correlated (r = 0.69). Relapses, rarer in hepatitis B virus (HBV)–related PAN (7.9%) than in MPA (34.5%) (P = 0.004), occurred in 56 patients (20.1%) and did not reflect disease severity. Survival curves were similar for the subpopulation of 215 patients with CSS, MPA, and non–HBV-related PAN who were given first-line corticosteroids (CS) with or without cyclophosphamide (CYC). However, CS with CYC therapy significantly prolonged survival for patients with FFS scores ≥2 (P = 0.041). Relapse rates were similar regardless of the treatment regimen; only patients treated with CS alone had uncontrolled disease. CYC was associated with a greater frequency of side effects (P < 0.00001). Conclusion Rates of mortality due to PAN (related or unrelated to HBV), MPA, and CSS reflected disease severity and were higher than the mortality rate in the general population (P < 0.0004). Rates of relapse, more common in MPA than HBV-related PAN patients, did not reflect disease severity. Survival rates were better among the more severely ill patients who had received first-line CYC. Based on these findings, we recommend that the intensity of the initial treatment be consistent with the severity of the disease. The use of the FFS and BVAS scores improved the ability to evaluate the therapeutic response.

Effects of a ginger extract on knee pain in patients with osteoarthritis.

Abstract: Objective. To evaluate the efficacy and safety of a standardized and highly concentrated extract of 2 ginger species, Zingiber officinale and Alpinia galanga (EV.EXT 77), in patients with osteoarthritis (OA) of the knee. Methods. Two hundred sixty-one patients with OA of the knee and moderate-to-severe pain were enrolled in a randomized, double-blind, placebocontrolled, multicenter, parallel-group, 6-week study. After washout, patients received ginger extract or placebo twice daily, with acetaminophen allowed as rescue medication. The primary efficacy variable was the proportion of responders experiencing a reduction in “knee pain on standing,” using an intent-to-treat analysis. A responder was defined by a reduction in pain of >15 mm on a visual analog scale. Results. In the 247 evaluable patients, the percentage of responders experiencing a reduction in knee pain on standing was superior in the ginger extract group compared with the control group (63% versus 50%; P 5 0.048). Analysis of the secondary efficacy variables revealed a consistently greater response in the ginger extract group compared with the control group, when analyzing mean values: reduction in knee pain on standing (24.5 mm versus 16.4 mm; P 5 0.005), reduction in knee pain after walking 50 feet (15.1 mm versus 8.7 mm; P 5 0.016), and reduction in the Western Ontario and McMaster Universities osteoarthritis composite index (12.9 mm versus 9.0 mm; P 5 0.087). Change in global status and reduction in intake of rescue medication were numerically greater in the ginger extract group. Change in quality of life was equal in the 2 groups. Patients receiving ginger extract experienced more gastrointestinal (GI) adverse events than did the placebo group (59 patients versus 21 patients). GI adverse events were mostly mild. Conclusion. A highly purified and standardized ginger extract had a statistically significant effect on reducing symptoms of OA of the knee. This effect was moderate. There was a good safety profile, with mostly mild GI adverse events in the ginger extract group.

Correlation of power Doppler sonography with vascularity of the synovial tissue of the knee joint in patients with osteoarthritis and rheumatoid arthritis

Abstract: Objective To examine the significance of power Doppler sonography (PDS) in the diagnosis of synovial hypertrophy of the knee joint by verifying and comparing the PDS findings with histopathologic findings of synovial membrane vascularity. Methods The knee joints of 23 patients who were undergoing arthroplasty of the knee joint because of osteoarthritis or rheumatoid arthritis were examined with ultrasound before arthroplasty. The vascularity of the synovial membrane was classified semiquantitatively using PDS. A sample of synovial tissue was obtained during the arthroplasty, and the vascularity of the synovial tissue was evaluated by immunohistochemistry (factor VIII) and was graded qualitatively by a pathologist who was unaware of the PDS findings. The visual qualitative grading by the examiner was controlled by analyzing PDS images and histologic samples using a digital image evaluation system. Results The correlation between the qualitative PDS results and the qualitative grading of the vascularity by the pathologist was 0.89 by Spearman's ρ (P < 0.01). The Pearson correlation coefficient between the digital analysis of the PDS images and the digital analysis of the tissue sections was 0.81 (P < 0.01). Digital image analysis and qualitative grading by the examiner had a correlation of 0.89 by Spearman's ρ (P < 0.01) for the PDS images. The correlation between the qualitative estimation of vascularity by the pathologist and the digital image analysis was 0.88 by Spearman's ρ (P < 0.01). Conclusion In the present study, PDS proved to be a reliable diagnostic method for qualitative grading of the vascularity of the synovial tissue. In clinical practice, PDS allows further differentiation of the hypertrophic synovium.

Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: A prospective study of 100 women

Abstract: To assess the true prevalence of congenital complete heart block (CCHB) in infants of anti-Ro/SSA-positive women known to have connective tissue disease (CTD) and, secondarily, to evaluate the prevalence of other electrocardiographic abnormalities in these newborns at birth.

A disease-specific activity index for Wegener's granulomatosis: Modification of the Birmingham Vasculitis Activity Score

Abstract: Objective To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegener's granulomatosis (WG). Methods Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting = 1 point) or major (e.g., alveolar hemorrhage = 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG. Results We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physician's global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearman's rank correlation coefficient between the BVAS/WG and the PGA was r = 0.81 (95% confidence interval 0.73–0.87). The interobserver reliability using intraclass (within-case) correlation coefficients in the 2 simulation exercises was r = 0.93 for the BVAS/WG and r = 0.88 for the PGA in the first and r = 0.91 for the BVAS/WG and r = 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r = 0.73 (95% confidence interval 0.43–0.83). Conclusion The BVAS/WG is a valid, disease-specific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good inter- and intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.

Power doppler ultrasonography for assessment of synovitis in the metacarpophalangeal joints of patients with rheumatoid arthritis: A comparison with dynamic magnetic resonance imaging

Abstract: Objective To evaluate the effectiveness of power Doppler ultrasonography (PDUS) for assessing inflammatory activity in the metacarpophalangeal (MCP) joints of patients with rheumatoid arthritis (RA), using dynamic magnetic resonance imaging (MRI) as a reference method. Methods PDUS and dynamic MRI were performed on 54 MCP joints of 15 patients with active RA and on 12 MCP joints of 3 healthy controls. PDUS was performed with a LOGIQ 500 unit by means of a 7–-13-MHz linear array transducer. Later the same day, MRI was performed with a 1.0T MR unit. A series of 24 coronal T1-weighted images of the second through the fifth MCP joints was obtained, with intravenous injection of gadolinium diethylenetriaminepentaacetic acid after the fourth image (dynamic MRI). From the MR images, the rate of early synovial enhancement (RESE; defined as the relative enhancement per second during the first 55 seconds postinjection) was calculated and compared with the flow signal on PDUS, which was scored as present or absent. Results In RA patients, flow signal on PDUS was detected in 17 of 54 MCP joints examined. Postcontrast MR images revealed an RESE of ≥1.0%/second in 18 of 54 RA MCP joints. PDUS showed no flow in 47 of 48 MCP joints with an RESE of <1.0%/second and revealed flow in 16 of 18 MCP joints with an RESE of ≥1.0%/second. Using dynamic MRI as a reference, PDUS had a sensitivity of 88.8% and a specificity of 97.9%. Conclusion PDUS was reliable for assessing inflammatory activity in the MCP joints of RA patients, using dynamic MRI as the standard. PDUS and clinical assessment of joint swelling/tenderness were only weakly correlated.

Activated human T cells directly induce osteoclastogenesis from human monocytes: possible role of T cells in bone destruction in rheumatoid arthritis patients.

Abstract: Objective To elucidate the direct role of human T cells in the induction of osteoclastogenesis in rheumatoid arthritis (RA), by studying human monocytes and the pathogenetic roles of receptor activator of nuclear factor κB ligand (RANKL), RANK, and osteoprotegerin (OPG). Methods Synovial tissue obtained at total knee replacement was stained immunohistologically using anti-RANKL, CD3, and CD4 antibodies. Synovial fluid was obtained from patients with RA, osteoarthritis (OA), gout, or trauma. Concentrations of the soluble form of RANKL (sRANKL) and OPG in the synovial fluid were measured by enzyme-linked immunosorbent assay. Activated T cells from peripheral blood mononuclear cells (PBMC) of healthy volunteers were cultured with human monocytes from PBMC. Results Immunostaining of the synovial tissue of RA patients demonstrated that RANKL-positive cells were detected in a subset of fibroblast-like synoviocytes and infiltrating mononuclear cells. Double immunostaining revealed that RANKL-positive cells were detected in a subset of CD3+ cells and CD4+ cells. An increased concentration of sRANKL and a decreased concentration of OPG were detected in synovial fluid from RA patients. The ratio of the concentration of sRANKL to that of OPG was significantly higher in synovial fluid of RA patients than in synovial fluid of patients with OA or gout. The activated T cells expressing RANKL induced osteoclastogenesis from autologous peripheral monocytes. The role of RANKL in this osteoclastogenetic process was confirmed by dose-dependent inhibition by OPG. Conclusion The present study is the first to demonstrate osteoclastogenesis using human-derived T cells and monocytes. In addition, the present findings suggest that excess production of RANKL by activated T cells increases the level of sRANKL in synovial fluid and may contribute to osteoclastic bone resorption in RA patients.

Comparison of the prevalence of knee osteoarthritis between the elderly Chinese population in Beijing and whites in the United States: The Beijing osteoarthritis study

Abstract: Objective To estimate the prevalence of radiographic and symptomatic knee osteoarthritis (OA) in a population-based sample of elderly subjects in Beijing, China and compare it with that reported in the Framingham (Massachusetts) OA Study. Methods We recruited a sample of persons age ≥60, using door-to-door enumeration in randomly selected neighborhoods in Beijing. Subjects completed a home interview including questions on knee symptoms and a hospital examination including knee radiographs obtained during weight bearing. The protocol was identical to that used in the Framingham OA Study. A reader read intermingled Beijing and Framingham Study films to ensure high reliability. We defined a subject as having radiographic knee OA when the Kellgren/Lawrence grade was ≥2 in at least 1 knee. Symptomatic knee OA was recorded as present when knee pain was reported and the symptomatic knee had radiographic OA. We estimated the prevalence of these entities in elderly subjects in Beijing and compared it with OA prevalence in Framingham, using an age-standardized prevalence ratio. Results Of 2,180 age-eligible Beijing subjects contacted, knee radiographs were obtained in 1,787 (82.0%). The prevalence of radiographic knee OA was 42.8% in women and 21.5% in men. Symptomatic knee OA occurred in 15.0% of women and 5.6% of men. Compared with women of the same age in Framingham, women in Beijing had a higher prevalence of radiographic knee OA (prevalence ratio 1.45, 95% confidence interval 1.31–1.60) and of symptomatic knee OA (prevalence ratio 1.43, 95% confidence interval 1.16–1.75). The prevalence of knee OA in Chinese men was similar to that in their white US counterparts (for radiographic OA, prevalence ratio 0.90; for symptomatic OA, prevalence ratio 1.02). Conclusion Using identical methods and definitions to evaluate the prevalence of OA across populations, we found, surprisingly, that older Chinese women have a higher prevalence of knee OA than women in Framingham, Massachusetts. The prevalence in men was comparable. Possible explanations for these differences range from genetic differences to heavy physical activity among Chinese.

Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study

Abstract: OBJECTIVE: To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial. METHODS: Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX. RESULTS: Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively). CONCLUSION: Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.

A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma

Abstract: Objective. Early diffuse scleroderma (systemic sclerosis; SSc) has no proven treatment. This study was undertaken to examine the efficacy of methotrexate (MTX) in improving the skin and other disease parameters in early diffuse SSc. Methods. Seventy-one patients with diffuse SSc of <3 years' duration were enrolled in a multicenter, randomized, placebo-controlled, double-blind trial. Thirty-five patients were treated with MTX and 36 with placebo. Treatment was administered for 12 months. The primary outcome measures were skin score (as determined with 2 different indices) and physician global assessment. Results. At baseline, there were no statistically significant differences in skin scores, carbon monoxide diffusing capacity (DLco), physician global assessment, or other secondary outcome measurements between the 2 treatment groups. At study completion, results slightly favored the MTX group (mean SEM modified Rodnan skin score 21.4 +/- 2.8 in the MTX group versus 26.3 +/- 2.1 in the placebo group [P < 0.17]; UCLA skin score. 8.8 +/- 1.2 in the MTX group versus 11.0 +/- 0.9 in the placebo group [P < 0.15]; DLco in the MTX group 75.7 +/- 4.6 versus 61.8 +/- 3.4 in the placebo group [P < 0.2]). In addition, physician global assessment results favored MTX (P < 0.035), whereas patient global assessment did not differ significantly between groups. When between-group differences for changes in scores from baseline to 12 months were examined using intent-to-treat methodology, MTX appeared to have a favorable effect on skin scores (modified Rodnan score -4.3 in the MTX group versus 1.8 in the placebo group [P < 0.009]; UCLA score -1.2 in the MTX group versus 1.2 in the placebo group [P < 0.02]), but differences in the degree of change in the DLco and physician global assessment were not significant. For the UCLA skin score, these differences in results were not statistically significant after adjustment for baseline differences in sex distribution and steroid use. Dropout rates were similar in the 2 groups. Conclusion. Although results of this trial demonstrated a trend in favor of MTX versus placebo in the treatment of early diffuse SSc, the between-group differences were small and the power to rule out false-negative results was only 50%. Our findings do not provide evidence that MTX is significantly effective in the treatment of early diffuse SSc.

Systemic lupus erythematosus in adults is associated with previous Epstein‐Barr virus exposure

Abstract: Objective The possible molecular mimicry of the Epstein-Barr virus (EBV) peptide PPPGRRP by the peptide PPPGMRPP from Sm B'/B of the human spliceosome is consistent with the possibility that EBV infection is related to the origin of systemic lupus erythematosus (SLE) in some patients. Association of EBV exposure with SLE was therefore tested for and subsequently found in children and adolescents (odds ratio [OR] 49.9, 95% confidence interval [95% CI] 9.3-1,025, P 10, 95% CI 2.53-infinity, P Methods We selected 196 antinuclear antibody-positive adult SLE patients (age > or =20 years) and 2 age-, race-, and sex-matched controls per patient. SLE patients and matched controls were tested for evidence of previous infection with EBV, cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), or varicella-zoster virus (VZV) by standardized enzyme-linked immunosorbent assays. Results Of the 196 lupus patients tested, all but 1 had been exposed to EBV, while 22 of the 392 controls did not have antibodies consistent with previous EBV exposure (OR 9.35, 95% CI 1.45-infinity, P = 0.014). No differences were observed between SLE patients and controls in the seroconversion rate against CMV, HSV-2, or VZV. Conclusion These new data from adults, along with the many suggestive features of EBV infection, are consistent with the contribution of this infection to the etiology of SLE.

Response of Wegener's granulomatosis to anti-CD20 chimeric monoclonal antibody therapy

Abstract: We report on the successful, compassionate use of the anti-CD20 chimeric monoclonal antibody rituximab in a patient with chronic, relapsing cytoplasmic antineutrophil cytoplasmic antibody (cANCA)-associated Wegener's granulomatosis (WG). The patient initially responded to treatment with glucocorticoids and cyclophosphamide. However, bone marrow toxicity during cyclophosphamide treatment of a relapse precluded its further use. Azathioprine and mycophenolate mofetil treatment had failed to maintain remission of the WG, and methotrexate was contraindicated. Because the patient's 5-year course was characterized by close correlation of cANCA levels with disease activity, selective elimination of cANCA was deemed a treatment option for his latest relapse. He was given 4 infusions of 375 mg/M2 of rituximab and high-dose glucocorticoids. Complete remission was associated with the disappearance of B lymphocytes and cANCA. Glucocorticoid treatment was then discontinued. After 11 months, the cANCA recurred, and rituximab therapy was repeated, without glucocorticoids. At 8 months after the second course of rituximab (18 months after the first course), the patient's WG has remained in complete remission. Elimination of B cells by rituximab therapy may prove to be an effective and safe new treatment modality for ANCA-associated vasculitis and possibly other autoimmune diseases. This modality warrants closer examination in a carefully conducted clinical trial.

Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease.

Abstract: Objective To evaluate the clinical usefulness of tumor necrosis factor (TNF) inhibitors in patients with inflammatory eye disease that is resistant to conventional immunosuppressive therapies Methods Sixteen patients (4 males and 12 females aged 7 to 78 years) who received etanercept (n = 14) or infliximab (n = 2) for either inflammatory eye disease or associated joint disease were studied retrospectively to determine the effect of these medications on their ocular inflammation Results Nine cases of uveitis and 7 cases of scleritis were treated Systemic diagnoses included rheumatoid arthritis (n = 8), juvenile rheumatoid arthritis (n = 3), ankylosing spondylitis (n = 1), and psoriatic spondylarthropathy (n = 1) Three patients had uveitis without associated systemic disease Although 12 of 12 patients with active articular inflammation (100%) experienced improvement in joint disease, only 6 of 16 with ocular inflammation (38%) experienced improvement in eye disease Five patients developed inflammatory eye disease for the first time while taking a TNF inhibitor No patient discontinued treatment because of adverse drug effects Conclusion TNF inhibitors are well tolerated immunosuppressive medications that may benefit certain subgroups of patients with inflammatory eye disease, but they appear to be more effective in controlling associated inflammatory arthritis

Prospective evaluation of magnetic resonance imaging and physical examination findings in patients with greater trochanteric pain syndrome

Abstract: Objective This study examined patients with greater trochanteric pain syndrome (GTPS) to determine the prevalence of gluteus medius pathology by utilizing magnetic resonance imaging (MRI), and to evaluate the presence of Trendelenburg's sign, pain on resisted hip abduction, and pain on resisted hip internal rotation as predictors of a gluteus medius tear in this group of patients. Methods Twenty-four subjects with clinical features consistent with GTPS were recruited. A standard physical assessment was performed at study entry, including assessment of the 3 specific physical signs. Following this initial assessment, MRI of the affected hip was performed. A 1.5T whole body MRI system was utilized, with T1 and T2 fast spin-echo sequences performed in the coronal and axial planes. All MR images were reviewed in random order by a single radiologist. In 12 patients, the 3 physical signs were assessed at study entry and at 2 months by the same observer and the intraobserver reliability for each of the signs was calculated. Results All subjects were women (median age 58 years, range 36–75 years). The median duration of symptoms was 12 months (range 12–60 months). MRI findings were as follows: 11 patients (45.8%) had a gluteus medius tear, 15 patients (62.5%) had gluteus medius tendinitis (pure tendinitis in 9 patients and tendinitis with a tear in 6 patients), 2 patients had trochanteric bursal distension, and 1 patient had avascular necrosis of the femoral head. Trendelenburg's sign was the most accurate of the 3 physical signs in predicting a tendon tear, with a sensitivity of 72.7% and a specificity of 76.9%. Moreover, Trendelenburg's sign was the most reliable measure, with a calculated intraobserver kappa of 0.676 (95% confidence interval 0.270–1.08). Conclusion The results support the hypothesis that gluteus medius tendon pathology is important in defining GTPS. In this series, trochanteric bursal distension was uncommon and did not occur in the absence of gluteus medius pathology. The physical findings suggest that Trendelenburg's sign is the most sensitive and specific physical sign for the detection of gluteus medius tears, with an acceptable intraobserver reliability. Further delineation with MRI, especially in patients with a positive Trendelenburg's sign, is recommended prior to any consideration of surgery in this group of patients. Finally, with the pathology of this condition defined, the challenge will be to devise and assess, by randomized controlled trial, an appropriate treatment strategy for this group of patients.

The relationship of health-related quality of life to prevalent and incident vertebral fractures in postmenopausal women with osteoporosis: results from the Multiple Outcomes of Raloxifene Evaluation Study.

Abstract: Objective To examine the effect of both prevalent and incident vertebral fractures on health-related quality of life (HRQOL) in postmenopausal women with osteoporosis and to characterize the effect of prevalent vertebral fractures on HRQOL with respect to number, location, severity, and adjacency. Methods Participants were a subset of women (n = 1,395, mean age 68.5 years) from the Multiple Outcomes of Raloxifene Evaluation trial who had low bone mineral density and/or prevalent vertebral fractures. Vertebral fractures were measured by radiography at baseline, 2 years, and 3 years. HRQOL was assessed using the Osteoporosis Assessment Questionnaire (OPAQ), a validated disease-targeted instrument, at baseline and annually for 3 years. Results Both prevalent and incident radiographic vertebral fractures were associated with decreased HRQOL. At baseline, women with a prevalent vertebral fracture had significantly lower OPAQ scores on physical function, emotional status, clinical symptoms, and overall HRQOL compared with women without a prevalent fracture (all P < 0.01). HRQOL scores were lower with each subsequent fracture. The effect of prevalent vertebral fracture was dependent on the location within the spine and was strongest in the lumbar region (L1–L4). Incident vertebral fractures significantly decreased OPAQ scores on physical function, emotional status, clinical symptoms, and overall HRQOL (all P < 0.001). Conclusion Our findings demonstrate the importance of treating postmenopausal women who have prevalent vertebral fractures to prevent further decreases in HRQOL associated with subsequent incident vertebral fracture.

Human periosteum‐derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age

Abstract: Objective To assess the in vitro chondrogenic potential of adult human periosteum-derived cells (PDCs) with regard to the number of cell passages and the age of the donor. Methods Cells were enzymatically released from the periosteum of the proximal tibia obtained from adult human donors and expanded in monolayer. PDCs were harvested at multiple passages for total RNA extraction and semiquantitative reverse transcription–polymerase chain reaction (RT-PCR) gene expression analysis. For the chondrogenesis assay, cells were plated in micromass and treated with transforming growth factor β1 (TGFβ1) in a chemically defined medium. At different time points, micromasses were either harvested for RT-PCR analysis for cartilage and bone markers or fixed, paraffin-embedded, and stained for cartilage matrix, and immunostained for type II collagen. Results At the first 2 passages, human PDCs from young donors formed chondrogenic nodules. This spontaneous chondrogenic activity was lost upon passaging, and it was not observed in donors older than 30 years. Using a panel of marker genes, PDCs were shown to be phenotypically stable during cell expansion. Regardless of donor age or cell passage, chondrogenesis could be induced consistently by combining micromass culture and TGFβ1 treatment. Histochemical and immunohistochemical analyses demonstrated the hyaline-like cartilage phenotype of the tissue generated in vitro. Other TGFβ superfamily members, such as growth differentiation factor 5/cartilage-derived morphogenetic protein 1, and bone morphogenetic proteins 2, 4, and 7, were poorly chondrogenic under the same culture conditions. Conclusion Adult human PDCs have the potential to differentiate toward the chondrocytic lineage in vitro, retaining this property even after extensive subculture. Human PDCs are easily accessible, expandable, and maintain their chondrogenic potential, and are therefore promising progenitor cells for use in the repair of joint surface defects.

Health-related quality of life of patients with psoriatic arthritis: a comparison with patients with rheumatoid arthritis.

Abstract: Objective To compare health-related quality of life (QOL) between patients with psoriatic arthritis (PsA) and patients with rheumatoid arthritis (RA), using the Medical Outcomes Study Short Form health survey (SF-36) and the Health Assessment Questionnaire (HAQ). Methods Both the SF-36 and the HAQ were administered to 107 PsA patients attending the University of Toronto Psoriatic Arthritis Clinic between January 1 and December 31, 1994, and to 43 RA patients attending a University of Toronto–affiliated RA clinic during the same period. Standardized assessments of disease activity and severity were also performed at each clinic visit. Logistic regression analysis was used to compare health-related QOL between PsA and RA. Results Both patient populations experienced lower physical health compared with that of a general population sample. The RA patients demonstrated more active inflammatory disease at the time of assessment than the PsA patients. The PsA patients were younger, and more were men. Logistic regression analyses showed that patients with PsA reported higher levels of vitality than patients with RA, even after adjusting for the observed differences in clinical and demographic characteristics. PsA patients, however, reported more role limitations due to emotional problems and more bodily pain after adjusting for the difference in vitality and other covariates. Conclusions Although both patient populations experienced reduced QOL, there were some meaningful differences in how the 2 conditions affect health-related QOL. Further, it appeared that there may be unique disabilities associated with the psoriasis dimension of PsA.