Showing papers in "Arthritis & Rheumatism in 1993"

The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials.

Abstract: Objective. To develop a set of disease activity measures for use in rheumatoid arthritis (RA) clinical trials, as well as to recommend specific methods for assessing each outcome measure. This is not intended to be a restrictive list, but rather, a core set of measures that should be included in all trials. Methods. We evaluated disease activity measures commonly used in RA trials, to determine which measures best met each of 5 types of validity: construct, face, content, criterion, and discriminant. The evaluation consisted of an initial structured review of the literature on the validity of measures, with an analysis of data obtained from clinical trials to fill in gaps in this literature. A committee of experts in clinical trials, health services research, and biostatistics reviewed the validity data. A nominal group process method was used to reach consensus on a core set of disease activity measures. This set was then reviewed and finalized at an international conference on outcome measures for RA clinical trials. The committee also selected specific ways to assess each outcome. Results. The core set of disease activity measures consists of a tender joint count, swollen joint count, patient's assessment of pain, patient's and physician's global assessments of disease activity, patient's assessment of physical function, and laboratory evaluation of 1 acute-phase reactant. Together, these measures sample the broad range of improvement in RA (have content validity), and all are at least moderately sensitive to change (have discriminant validity). Many of them predict other important long-term outcomes in RA, including physical disability, radiographic damage, and death. Other disease activity measures frequently used in clinical trials were not chosen for any one of several reasons, including insensitivity to change or duplication of information provided by one of the core measures (e.g., tender joint score and tender joint count) The committee also proposes specific ways of measuring each outcome. Conclusion. We propose a core set of outcome measures for RA clinical trials. We hope this will decrease the number of outcomes assessed and standardize outcomes assessments. Further, we hope that these measures will be found useful in long-term studies.

Preliminary criteria for the classification of Sjögren's syndrome. Results of a prospective concerted action supported by the European Community.

Abstract: Objective. Different sets of diagnostic criteria have been proposed for Sjogren's syndrome (SS), but none have been validated with a large series of patients or in a multicenter study. We conducted the present study involving 26 centers from 12 countries (11 in Europe, plus Israel), with the goals of reaching a consensus on the diagnostic procedures for SS and defining classification criteria to be used in epidemiologic surveys and adopted by the scientific community. Methods. The study protocol was subdivided into two parts. For part I, questionnaires regarding both ocular and oral involvement were developed; they included 13 questions and 7 questions, respectively. For part II a limited set of diagnostic tests was selected, and the exact procedure to be followed in performing these tests was defined. Part I of the study ipcluded 240 patients with primary SS and 240 age- and sex-matched controls. Two hundred forty-six patients with primary SS, 201 with secondary SS, 113 with connective tissue diseases but without associated SS, and 133 control patients were studied in part II. Results. The study resulted in (a) the validation of a simple 6-item questionnaire for determination of dry eyes and dry mouth, which showed good discriminant power between patients and controls, to be used in the initial screening for sicca syndrome; and (b) the definition of a new set of criteria for the classification of SS. The sensitivity and specificity of the criteria in correctly identifying patients with either the primary or the secondary variant of SS were also determined. Conclusion. Using the findings of this prospective multicenter European study, general agreement can be reached on the diagnostic procedures to be used for patients with SS. Final validation of the preliminary classification criteria for SS is underway.

Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha

Abstract: OBJECTIVE: To evaluate the safety and efficacy of a chimeric monoclonal antibody to tumor necrosis factor alpha (TNF alpha) in the treatment of patients with rheumatoid arthritis (RA). METHODS: Twenty patients with active RA were treated with 20 mg/kg of anti-TNF alpha in an open phase I/II trial lasting 8 weeks. RESULTS: The treatment was well tolerated, with no serious adverse events. Significant improvements were seen in the Ritchie Articular Index, which fell from a median of 28 at study entry to a median of 6 by week 6 (P < 0.001), the swollen joint count, which fell from 18 to 5 (P < 0.001) over the same period, and in the other major clinical assessments. Serum C-reactive protein levels fell from a median of 39.5 mg/liter at study entry to 8 mg/liter at week 6 (P < 0.001), and significant decreases were also seen in serum amyloid A and interleukin-6 levels. CONCLUSION: Treatment with anti-TNF alpha was safe and well tolerated and resulted in significant clinical and laboratory improvements. These preliminary results support the hypothesis that TNF alpha is an important regulator in RA, and suggest that it may be a useful new therapeutic target in this disease.

Evidence suggesting that health education for self-management in patients with chronic arthritis has sustained health benefits while reducing health care costs.

Abstract: Objective. To determine the effects of the Arthritis Self-Management Program 4 years after participation in it. Methods. Valid self-administered instruments were used to measure health status, psychological states, and health service utilization. Results. Pain had declined a mean of 20% and visits to physicians 40%, while physical disability had increased 9%. Comparison groups did not show similar changes. Estimated 4-year savings were $648 per rheumatoid arthritis patient and $189 per osteoarthritis patient. Conclusion. Health education in chronic arthritis may add significant and sustained benefits to conventional therapy while reducing costs.

The structure of aggrecan fragments in human synovial fluid : Evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis

Abstract: Objective. To determine the proteolytic fragmentation patterns and N-terminal sequence of aggrecan fragments in human synovial fluid from patients with inflammatory arthritides, joint injury, or osteoarthritis (OA). Methods. Knee synovial fluid was obtained from patients with joint injury, OA, acute pyrophosphate arthritis (pseudogout), reactive arthritis, psoriatic arthritis, or juvenile rheumatoid arthritis. Chondroitin sulfate-substituted aggrecan fragments present in the fluid were purified by cesium chloride gradient centrifugation and enzymatically deglycosylated. Core protein species were determined by N-terminal analysis and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with electroblotting and detection with monoclonal antibody 3B3. Results. Samples from patients with joint injury, OA, and inflammatory joint disease all showed a similar 3-band pattern, with core sizes of approximately 200 kd, 170 kd, and 135 kd. In all samples, diffuse immunereactive products were also seen, with an apparent size of >250 kd. N-terminal analysis of core preparations of all samples showed a consistent single predominant sequence, beginning at alanine 374 of the human aggrecan core protein. Conclusion. The aggrecan fragments present in joint fluids from patients with various inflammatory arthritides, joint injury, or OA result from a predominant cleavage of the human aggrecan core protein at the glutamate 373-alanine 374 bond within the interglobular domain, between the G1 and G2 domains. The consistent pattern of fragments seen on SDS-PAGE and the single predominant N-terminal sequence suggest a common degradative mechanism of aggrecan in these different joint conditions. The identity of the proteolytic agent (aggrecanase), however, remains unknown. These results appear to have important implications with regard to the development of therapies to protect cartilage from degradation in patients with joint disease. (Less)

Metalloproteinases, tissue inhibitor, and proteoglycan fragments in knee synovial fluid in human osteoarthritis

Abstract: Objective. To determine the concentrations of human stromelysin-1, collagenase, tissue inhibitor of metalloproteinases (TIMP), and proteoglycan fragments in knee synovial fluid in patients with injury to the meniscus or anterior cruciate ligament, posttraumatic osteoarthritis, primary osteoarthritis, or pyrophosphate arthritis. Methods. Synovial fluid samples were collected from patients with knee disease diagnosed arthroscopically and radiologically. Concentrations of stromelysin-1, collagenase, and TIMP-1 were determined by sandwich immunoassay, using monoclonal and polyclonal antibodies. Fragments of cartilage proteoglycan containing the chondroitin sulfate-binding region were determined by immunoassay with a polyclonal antibody. Results. Average concentrations of metalloproteinases, TIMP, and proteoglycan fragments in joint fluid were significantly elevated in patients from all disease groups as compared with volunteers with healthy knees (reference group). Stromelysin concentrations in disease groups averaged 15-45 times that of the reference group. The molar ratios between stromelysin and collagenase varied between 10 and 150. The molar ratio between total stromelysin and free TIMP was 0.5 in the reference group and between 1.6 and 5.3 in the disease groups. Conclusion. Stromelysin concentration in joint fluid is a parameter that distinguishes diseased joints from healthy joints, with a sensitivity of 84% and a specificity of 90%. The high concentrations of metalloproteinase relative to TIMP in joint fluid from patients with the conditions studied may be associated with cartilage matrix degradation in these arthritides. (Less)

Quality of life issues in women with vertebral fractures due to osteoporosis.

Abstract: Objective. To learn about the physical, emotional, and social limitations experienced by postmenopausal women who have back pain due to vertebral fractures resulting from osteoporosis. Methods. We conducted a cross-sectional survey of female patients with persistent pain due to vertebral fractures. Results. Respondents had a mean (±SD) bone density of 0.87 ± 0.13 gm/cm2 and a mean (±SD) of 2.48 ± 2.18 fractures. Disability was identified in pain, movement, activities of daily living, and emotion. There was a poor correlation between quality of life and findings on radiography or densitometry. Conclusion. To evaluate the effects of osteoporosis on a patient's functional status, direct questioning is required.

Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis.

Abstract: Objective. To explore the role of proinflammatory cytokines in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), two clinically related syndromes characterized by an intense acute-phase reaction. In particular, to determine plasma concentrations of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) and to correlate changes in plasma IL-6 levels with clinical symptoms during corticosteroid therapy. Methods. IL-6 and TNFα concentrations were determined in plasma samples from patients with untreated PMR or GCA, and plasma IL-6 levels were monitored in patients receiving long-term therapy (14 months) with corticosteroids. To identify IL-6–producing cells, the polymerase chain reaction was used to detect IL-6 messenger RNA. In vitro production of IL-6 and IL-2 by peripheral blood mononuclear cells (PBMC) from treated and untreated patients was quantified using IL-6– and IL-2–specific bioassay systems. Results. IL-6 concentrations were increased in PMR and GCA patients, whereas TNFα concentrations were similar to those in normal donors. Administration of corticosteroids rapidly reduced the levels of circulating IL-6 but did not correct the underlying mechanism inducing the increased IL-6 production. In individual patients, changes in plasma IL-6 levels and clinical manifestations during prolonged therapy were closely correlated. Short-term withdrawal of corticosteroids, even after several months of treatment, was followed by an immediate increase in plasma IL-6 concentrations. To identify the cellular source of plasma IL-6, PBMC from treated and untreated patients with PMR or GCA were analyzed for their ability to secrete IL-6 and the T cell–specific cytokine IL-2. Polyclonal T cell stimulation caused a rapid release of IL-6, which was shown to be derived exclusively from CD14+ cells. Conclusion. Increased production of IL-6, but not TNFα, is a characteristic finding in patients with PMR or GCA. Corticosteroids rapidly suppress IL-6 production but do not correct the underlying mechanism inducing the increased IL-6 production. The close correlation of plasma IL-6 concentrations with clinical symptoms suggests a direct contribution of this cytokine to the disease manifestations and presents the possibility that monitoring IL-6 levels would be useful in making decisions on adjustment of corticosteroid dosage in individual patients.

Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with wegener's granulomatosis

Abstract: One hundred and six patients with Wegener’s granulomatosis (WG) were studied for the presence of antineutrophil cytoplasmic antibodies (ANCA). In 53 patients serial ANCA determinations were obtained. C-ANCA positivity was a sensitive (88%) marker of active WG. However, changes in serial titers were temporally concordant with a change in disease status in only 55% of patients. Furthermore, a rise in c-ANCA titer preceded clinical exacerbation of disease in only 24% of patients who had been in remission or had low grade, smoldering disease. A rise in c-ANCA titer alone should not be considered a priori evidence of impending relapse, and does not justify modification of immunosuppressive therapy.

A longitudinal study of subchondral plate and trabecular bone in cruciate-deficient dogs with osteoarthritis followed up for 54 months

Abstract: Objective. To evaluate the sequence of changes in articular cartilage, trabecular bone, and subchondral plate in dogs with osteoarthritis (OA), 3 months, 18 months, and 54 months after anterior cruciate ligament transection (ACLT). Methods. Specimens of the medial tibial plateau were analyzed with microscopic computed tomography (micro-CT) at a resolution of 60 μm, and biochemical and morphologic changes in the femoral articular cartilage were assessed. Results. At 3 months and 18 months after ACLT, the articular cartilage in the unstable knee showed histologic changes typical of early OA and increased water content and uronic acid concentration; by 54 months, full-thickness ulceration had developed. Micro-CT analysis showed a loss of trabecular bone in the unstable knee, compared with the contralateral knee, at all time points. At both 18 and 54 months, the differences in trabecular thickness and surface-to-volume ratio were greater than at 3 months. Although the mean subchondral plate thickness, especially in the medial aspect of the medial tibial plateau, was greater in the OA knee than in the contralateral knee 18 months and 54 months after ACLT, these differences were not statistically significant; however, the difference was significantly greater at 54 months than at 3 months. Conclusion. Thickening of the subchondral bone is not required for the development of cartilage changes of OA in this model. The bony changes that develop after ACLT, however, could result in abnormal transmission of stress to the overlying cartilage and thereby contribute to the progression of cartilage degeneration.

The adhesion molecules of inflammation.

Abstract: BRUCE N. CRONSTEIN and GERALD WEISSMANN Inflammation is characterized by the accumula- tion of leukocytes and other mesenchymal cells at sites of injury or infection. When inflammation results from invasion by a microorganism, the inflammatory re- sponse is designed to localize, destroy, and eliminate the offending organism. However, persistent inflam- mation in the absence of an identifiable irritant or microorganism is often as destructive to the host as any invader; it is, of course, the hallmark of such inflammatory diseases as rheumatoid arthritis. The recent explosion of information on the molecules which govern the emigration of leukocytes from blood vessels and their accumulation at loci of inflammation has completely changed our understand- ing of inflammation and may lead to new strategies in the treatment of acute and chronic inflammation. We describe here current ideas as to the pathogenesis of inflammation, the biochemistry and function of the adhesive molecules involved in inflammation, and what we know of their role in rheumatic disease. We also indicate how drugs presently used to treat these diseases affect adhesion molecules.

Pressure pain threshold in pain-free subjects, in patients with chronic regional pain syndromes, and in patients with fibromyalgia syndrome.

Abstract: Objective. We hypothesized that change in pain threshold to pressure reflects a generalized change in the pain system affecting both tender and control points. Methods. We assessed 18 tender points and 4 control points using an algometer in 60 patients with generalized fibromyalgia/fibrositis syndrome, 60 patients with localized chronic pain syndromes, and in 60 pain-free subjects. Results. A significant correlation was found between myalgia scores at tender points and control points in these subjects. Conclusion. These results suggest that there is a diffuse change in pain modulation in fibromyalgia, as hypothesized, but the tender point is still clinically useful.

Bone mineral density and knee osteoarthritis in elderly men and women : the Framingham study

Abstract: Objective. To examine the possible inverse relationship between osteoporosis and osteoarthritis (OA) by evaluating the association between bone mineral density (BMD) and knee OA in the Framingham Study cohort. Methods. Of the 1,154 Framingham Study cohort subjects in whom BMD measurements were obtained at biennial examination 20, 932 (81%) had had knee OA assessed during the Framingham Knee OA Study 4 years earlier. BMD of the proximal femur and radius was measured by densitometry. Knee OA was assessed from a weight-bearing anteroposterior radiograph and graded on a scale of 0 (no OA) to 4 (severe OA). Osteophytes and joint space narrowing were also evaluated separately. Linear regression was used to test the association of BMD with knee OA, with osteophytes, and with joint space narrowing, after adjustment for age, body mass index, and mean number of cigarettes smoked per day. Results. The subjects included 572 women and 360 men with an age range of 63–91 years (mean 71 years). Of these, 351 had no OA, 269 had grade 1 OA, 170 had grade 2 OA, 93 had grade 3 OA, and 49 had grade 4 OA. Mean femoral BMD at the 3 proximal femur sites was 5–9% higher in men and women with either grade 1, grade 2, or grade 3 knee OA, compared with those with no knee OA (P < 0.0001). Mean femoral BMD in those with grade 4 OA was not higher than in those with no OA. Radius BMD was not associated with knee OA in subjects of either sex. Women with osteophytes had higher BMD compared with women with no osteophytes. Mean BMD did not differ across levels of joint space narrowing. Conclusion. We conclude that, among women, femoral BMD is higher in those with osteophytosis of the knee, and BMD is not necessarily associated with joint space narrowing.

Comparison of naproxen and acetaminophen in a two‐year study of treatment of osteoarthritis of the knee

Abstract: Objective. To compare the relative safety and efficacy of naproxen and acetaminophen in the treatment of osteoarthritis (OA) of the knee. The major outcome measures were radiographic progression and withdrawal from the trial due to lack of efficacy. Methods. One hundred seventy-eight patients with OA of the knee were enrolled in a 2-year prospective, controlled, double-blind multicenter trial and were randomly assigned to receive acetaminophen (ACT) or naproxen (NPX) treatment. Results. After 6 weeks of treatment, modest improvement in pain on motion and in physician's global assessment was seen in both the ACT and the NPX groups, and the NPX group also had modest improvement in pain at rest and in 50-foot walk time. Sixty-two patients completed the 2-year study. Among these patients, radiographic progression was similar in the 2 treatment groups. Withdrawal from the trial due to lack of drug efficacy was slightly more frequent among patients in the ACT group (22% versus 16%), but withdrawal due to adverse drug effects was slightly more common in the NPX group (23% versus 18%). Conclusion. The efficacy of ACT treatment and NPX treatment was similar, although it was slightly better for NPX. The toxicity rate was slightly lower with ACT. However, the high rate of withdrawal in both treatment groups suggests that neither is satisfactory for the treatment of OA.

Reduced synovial membrane macrophage numbers, elam-1 expression, and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis

Abstract: Objective. To define the immunohistologic features of the synovial membrane (SM) of patients with psoriatic arthritis (PA) and to compare them with those of an age- and disease-duration–matched population of patients with rheumatoid arthritis (RA). Methods. Synovial membrane needle biopsy was performed on 15 PA patients with knee involvement (8 had asymmetric oligoarthritis and 7 had symmetric polyarthritis) and on 15 RA controls. Specimens were stained with monoclonal antibodies against T cells (CD3, CD8, CD4, CD45RO), B cells (CD20), macrophages (Mac387, CD14), and cells bearing class II antigens (DAKO-DR). Vascular endothelium was examined using a polyclonal antibody to Factor VIII–related antigen, and adhesion molecule expression was examined using antibodies 1.3B6, 6.5B5, and 1.4C3, which identify endothelial leukocyte adhesion molecule 1 (ELAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1), respectively. Results. There was significantly less lining layer hyperplasia, fewer macrophages, and a greater number of blood vessels in PA SM than in RA SM. ELAM-1 expression was less intense in PA than in RA SM, while there was no difference in expression of ICAM-1 and VCAM-1. Numbers of B cells, T cells, and T cell subsets (predominantly CD4, CD45RO T cells) were similar in both groups of patients. Conclusion. Our findings demonstrate important differences in the immunohistologic features of PA and RA SM. The PA SM is more vascular, ELAM-1 expression is less intense, and fewer macrophages invade the stroma and migrate to the lining layer than in RA SM. However, the lymphocytic infiltrate in the SM of both groups is similar.

A randomized, controlled trial of arthroscopic surgery versus closed-needle joint lavage for patients with osteoarthritis of the knee.

Abstract: Objective. To compare arthroscopic surgery and closed-needle joint lavage for patients with non—end-stage osteoarthritis (OA) of the knee under controlled, experimental conditions. Methods. Thirty-two subjects who met specific clinical, radiologic, medical, and rehabilitation criteria were randomized to receive arthroscopic surgery (n = 18) or joint lavage (n = 14). Outcome measures evaluated at baseline and at 3 and 12 months of followup included 3 standard clinical parameters, self-reported pain and functional status (by the Arthritis Impact Measurement Scales), 50-foot walk time, 2 global scales, and direct and indirect medical costs. Results. At 3 months of followup, there were no significant between-group differences in pain, self-reported and observed functional status, and patient and “blinded” physician global assessments. The arthroscopic procedure cost $3,840 more than did closedneedle joint lavage. After 1 year, there were no between-group differences in medication costs, utilization of medical services, or indirect costs related to employment or use of household help. After 1 year, 44% of subjects who underwent arthroscopy reported improvement and 58% of subjects who underwent joint lavage improved. Patients with tears of the anterior two-thirds of the medial meniscus or any lateral meniscus tear had a higher probability of improvement (by “blinded” physician assessment) after arthroscopic surgery (0.63) than did patients with other intraarticular pathology (0.20). Conclusion. The search for and removal of soft tissue abnormalities via arthroscopic surgery does not appear justified for all patients with non—end-stage OA of the knee who fail to respond to conservative therapy, but it may be beneficial for certain subgroups.

Lupus and pregnancy studies

Abstract: Objective. To examine factors prior to pregnancy in patients with systemic lupus erythematosus (SLE) that are prognostic for the occurrence of active disease during and shortly after pregnancy. Methods. Case–control study of pregnant SLE patients and nonpregnant SLE controls, using logistic regression analyses to assess the role of prepregnancy disease activity as a prognostic factor for flare during pregnancy or the postpartum followup period. Results. Lupus flares occurred frequently and in similar percentages of pregnant SLE patients and control SLE patients. Active lupus at study entry, both in control and in pregnant patients, was not predictive of flare. Inactive lupus at onset was not protective against flare in controls but was protective in pregnant lupus patients. Conclusion. Inactive disease at the onset of pregnancy in SLE provides optimum protection against the occurrence of flare during pregnancy.

The effect of an interleukin-1 receptor antagonist protein on type ii collagen–induced arthritis and antigen-induced arthritis in mice

Abstract: Objective. To investigate the anti-arthritic effect of recombinant human interleukin-1 receptor antagonist protein (IRAP) in two experimental models of arthritis. Methods. Recombinant IRAP was administered daily to mice with type II collagen–induced arthritis (CIA) or with antigen-induced arthritis (AIA) provoked by methylated bovine serum albumin (mBSA). Disease incidence and severity were assessed by a clinical index and histologic features. Serum antibody to type II collagen, spleen cell proliferation to mBSA, and anti-IRAP antibodies were measured as indices of immune function. Results. IRAP reduced the incidence and delayed the onset of CIA and suppressed the antibody response to type II collagen. In contrast, IRAP did not affect the pathogenesis of AIA and had no effect on either humoral or cellular immune responses to mBSA in arthritic mice. Conclusion. These observations suggest that interleukin-1 may play a prominent role in the development of some, but not all, forms of arthritis.

The spectrum of vasculitis in human immunodeficiency virus-infected patients. A clinicopathologic evaluation.

Abstract: Objective. To delineate the different types of inflammatory vascular diseases (IVD) occurring in patients with human immunodeficiency virus (HIV) infection. Methods. Muscle, nerve, or skin biopsy specimens from 148 symptomatic HIV-infected individuals were reviewed, and subgroups of vasculitis were identified using the American College of Rheumatology (ACR) 1990 clinicopathologic criteria for the classification of vasculitis. Results. IVD was documented in 34 patients (23%) and included necrotizing arteritis (3 patients), non-necrotizing arteritis (1 patient), neutrophilic IVD (7 patients), mononuclear IVD (17 patients), and other small vessel inflammatory changes (6 patients). According to the ACR criteria, 11 patients could be classified as having a distinct category of vasculitis, including polyarteritis nodosa (4 patients), Henoch-Schonlein purpura (1 patient), and drug-induced hypersensitivity vasculitis (6 patients), and 23 were classified in the group ‘other vasculitis, type unspecified.’ One patient had hepatitis B virus surface antigenemia, 2 had cryoglobulinemia, and 2 were coinfected by human T lymphotropic virus type I. Cytomegalovirus inclusions and antigens were found in endothelial cells in 1 patient. HIV antigens and genome were detected in perivascular cells of 2 of the 3 patients with necrotizing arteritis; in 1, HIV-like particles were seen by electron microscopy. Immune deposits were found in small vessel walls in 5 skin biopsy samples showing small vessel vasculitis and in the muscle of the 3 patients with necrotizing arteritis. Conclusion. A wide range of inflammatory vascular diseases may occur in HIV-infected individuals. Vascular inflammation appears multifactorial and may result from HIV-induced immunologic abnormalities and exposure to a variety of xenoantigens, such as HIV itself, other infectious agents, and drugs.

Adhesion molecule expression in human synovial tissue

Abstract: OBJECTIVE We have previously shown that E-selectin is expressed on endothelium in rheumatoid arthritis (RA) synovial tissues, and hence may be important in recruitment of leukocytes into the inflamed joint. In the present study, we determined whether other cellular adhesion molecules, including selectins and members of the integrin and immunoglobulin supergene families, are expressed in frozen synovium. METHODS We employed immunohistochemical staining to determine the distribution of CD31 (PECAM), CD44 (hyaluronate receptor), CD62 (P-selectin), Leu-8 (L-selectin), and the integrin subunits alpha 5 (VLA-5), alpha 6 (VLA-6), beta 1 (VLA 1-6), and beta 3 (vitro-nectin receptor), in synovial tissue from 9 RA and 9 osteoarthritis (OA) patients, and from 3 normal (NL) subjects. RESULTS P-selectin was expressed on vascular endothelium in all synovial tissues examined. L-selectin and alpha 5-integrin, while expressed on a variety of cell types, were not differentially expressed on RA synovial tissues. Integrin subunits alpha 6 and beta 1 were down-regulated on some RA synovial tissue components. In contrast, CD31 was expressed to a greater extent on RA than on OA lining cells and macrophages (P < 0.05). CD44 was expressed to a greater extent on RA or OA macrophages, lining cells, and fibroblasts compared with NL (P < 0.05). Integrin subunit beta 3 was strongly expressed on RA synovial blood vessels compared with NL (P < 0.05). CONCLUSION The expression of integrins VLA 1-6, and selectins P and L is not up-regulated in RA synovial tissues. CD31 and CD44 are up-regulated on RA macrophages and lining cells, CD44 on RA fibroblasts, and beta 3-integrin on RA blood vessels. The up-regulation of CD31, CD44, and beta 3-integrin in RA synovial tissues may help tip the balance of adhesive interactions toward passage and retention of leukocytes in the inflamed joint.

Cancer in systemic sclerosis.

Abstract: Objective. To determine whether the frequency of cancer is increased among patients with systemic sclerosis (SSc). Methods. A retrospective chart review of 248 patients who were followed up prospectively was conducted. Results. Cancers developed in 18 patients (7.3%) during 2,001 patient-years at risk. The most frequent types were cancers of the lung (7 patients) and breast (5 patients). Older age at diagnosis of SSc was a significant risk factor for cancer. Lung cancer was associated with the presence of pulmonary fibrosis. The age-standardized incidence rate for all cancers (7.9/1,000) was 2.1 times the overall rate in the Ontario population (P > 0.0001). Conclusion. The frequency of cancer is increased in patients with SSc.

Integrin-mediated attachment of articular chondrocytes to extracellular matrix proteins.

Abstract: Objective To investigate the interactions between chondrocytes and their extracellular matrix (ECM). An attachment assay was used to determine the extent of integrin-mediated attachment of chondrocytes to a variety of ECM proteins and the effect of monolayer culturing on attachment activity. Methods Bovine and human articular cartilage chondrocytes were grown in high-density monolayer cultures for 3-21 days and used in the assays. Cell shape and production of 3H-proline-labeled collagen were monitored to assess phenotypic changes with time in culture. Cultured chondrocytes were incubated in wells coated with purified proteins, with and without specific inhibitors of integrin-mediated attachment, and cell attachment was determined. Results Compared with bovine serum albumin, chondrocytes showed significant attachment to fibronectin, matrix Gla protein (MGP), osteopontin, bone sialoprotein II (BSP II), vitronectin, and types II and VI collagen. A synthetic peptide containing the integrin-recognition sequence Arg-Gly-Asp inhibited attachment to all the proteins tested, except types II and VI collagen. A monoclonal antibody (MAb) to the beta 1-integrin subunit inhibited attachment to fibronectin, MGP, and type II collagen, and a MAb to the beta 3-integrin subunit inhibited attachment to BSP II and osteopontin. An increase in cell attachment was seen with time in culture, and this increase was followed by a change in the chondrocytes to flattened, type I collagen-producing cells. Conclusion Chondrocytes can attach to a variety of cartilage and bone proteins; this attachment is mediated via integrins, including members of both the beta 1 and beta 3 subunit families. The modulation of the chondrocyte phenotype during monolayer culture may be related to activation or increased expression of integrins.

Generalized osteoarthritis associated with increased insulin‐like growth factor types i and ii and transforming growth factor β in cortical bone from the iliac crest. possible mechanism of increased bone density and protection against osteoporosis

Abstract: OBJECTIVE To investigate whether growth factors stored in bone might explain the increased bone density and resistance to osteoporosis in generalized osteoarthritis. METHODS Levels of insulin-like growth factor (IGF) types I and II and transforming growth factor beta (TGF beta) were measured in extracts of cortical bone from the iliac crest obtained at necropsy from subjects with or without osteoarthritis of the hands. RESULTS Concentrations of IGF-I, IGF-II, and TGF beta were significantly higher in extracts of bone powder from subjects in the osteoarthritis group than in extracts from subjects in the control group. CONCLUSION The results suggest that the increased bone density and resistance to osteoporosis in patients with osteoarthritis may be associated with increased skeletal concentrations of IGF-I, IGF-II, and TGF beta and may reflect a generally increased biosynthetic activity of osteoblasts in these patients.

The effect of rheumatoid arthritis and steroid therapy on bone density in postmenopausal women

Abstract: Objective. To assess bone mineral density (BMD) in postmenopausal women with rheumatoid arthritis (RA) and the relative effects of disease activity, disability, and past and current use of corticosteroids. Methods. One hundred ninety-five postmenopausal patients with RA were compared with 597 postmenopausal control subjects. Bone density was measured at the lumbar spine and the proximal femur using dual x-ray absorptiometry. Patients were divided into 3 groups according to corticosteroid use, i.e., never users (61%), current users (21%), and ex-users (18%). Results. Compared with controls, the never users had no difference in BMD at the lumbar spine, but a 6.9% reduction at the femur (95% confidence interval [95% CI] 3.4–10.3%). In current users (mean daily prednisolone dosage 6.9 mg), BMD was reduced by 6.5% at the spine (95% CI 0–13.0%) and by 7.4% at the hip (95% CI 1.2–13.6%) compared with never users, after adjustment for age, weight, duration of menopause, and functional disability. Mean BMD was similar in the ex-user and never user groups. Results were confirmed in 54 patients who had whole-body BMD measurements. There were inverse correlations between BMD and Health Assessment Questionnaire scores (femoral BMD r = –0.23, P < 0.01; whole-body BMD r = –0.40, P < 0.01) and between BMD and cumulative steroid dose (femoral BMD r = –0.32, P < 0.01; whole-body BMD r = –0.72, P < 0.01). Conclusion. Osteoporosis in postmenopausal women with RA is more evident at the hip than the spine, and the most important determinants of bone loss are disability and cumulative corticosteroid dose. Low-dose steroids cannot be used with complacency, but recovery after discontinuation of use may be possible.

Identification of mothers at risk for congenital heart block and other neonatal lupus syndromes in their children. Comparison of enzyme-linked immunosorbent assay and immunoblot for measurement of anti-SS-A/Ro and anti-SS-B/La antibodies.

Abstract: Objective. To identify the fine specificity patterns of maternal anti–SS-A/Ro and anti–SS-B/La antibodies that are associated with the birth of a child with transient or permanent manifestations of neonatal lupus syndromes, and to suggest a predictor algorithm for use in counseling. Methods. Sera were obtained from 4 groups of mothers: 57 whose children had congenital heart block, 12 whose children had transient dermatologic or hepatic manifestations of neonatal lupus but no detectable cardiac involvement, 152 with systemic lupus erythematosus and related autoimmune diseases, who gave birth to healthy infants, and 30 with autoimmune diseases whose pregnancy resulted in miscarriage, fetal death, or early postpartum death unrelated to neonatal lupus. Antibodies to SS-A/Ro and SS-B/La were assessed by enzymelinked immunosorbent assay (ELISA) and by sodium dodecyl sulfate (SDS)-immunoblot. Results. Anti–SS-A/Ro antibodies were identified by ELISA in 100%, 91%, 47%, and 43% of the mothers of infants with heart block, with transient neonatal lupus, healthy infants, and fetal death, respectively. High titers of anti–SS-A/Ro antibodies were present more often in mothers of children with cardiac disease or transient neonatal lupus than in either of the other 2 groups. Maternal antibodies to SS-B/La were detected by ELISA in 76% of the heart block group, 73% of the cutaneous neonatal lupus group, 15% of the group with healthy children, and 7% of the fetal death group. On SDS-immunoblot, sera from 91% of the heart block group mothers who had antibodies to SS-A/Ro but not to SS-B/La recognized at least 1 SS-A/Ro antigen, with significantly greater reactivity against the 52-kd component. In contrast, only 62% of the anti–SS-A/Ro positive, anti–SS-B/La negative responders in the healthy group recognized the 52-kd and/or the 60-kd component. Although there was no profile of anti–SS-A/Ro response unique to the mothers of children with heart block or cutaneous manifestations of neonatal lupus, only 1% of the healthy infants were born to mothers with antibodies directed to both the 52-kd SS-A/Ro and 48-kd SS-B/La antigens and not to the 60-kd SS-A/Ro antigen. Conclusion. Women with antibodies to both SS-A/Ro and SS-B/La have an increased risk of giving birth to children with neonatal lupus, especially if the anti-SS-A/ Ro response identifies the 52-kd component on SDS-immunoblot. Women whose sera contain only anti-SS-A/Ro antibodies in low titer and only recognize determinants that are altered by conditions of SDS-immunoblot have a low risk for giving birth to a child with neonatal lupus. Specific antibody profiles do not distinguish among the manifestations of the neonatal lupus syndromes.

Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis

Abstract: Objective. To assess the risk of serious liver disease in patients with rheumatoid arthritis (RA) taking methotrexate (MTX). Methods. We surveyed members of the American College of Rheumatology to determine previous use of MTX in the treatment of rheumatoid arthritis and to identify cases of cirrhosis and liver failure. Cases were confirmed by review of pathology specimens, findings from diagnostic testing, and clinical presentations. A case—control study was then conducted to ascertain prognostic factors. Case and control medical records were reviewed for information on MTX therapy as well as other possible determinants of serious liver disease. Results. Twenty-four cases of cirrhosis and liver failure were identified, giving a 5-year cumulative incidence of ˜ 1/1,000 treated patients. Six of the 24 patients had died: 4 died of the initial liver disease, 1 of hepatic complications of another illness, and 1 of unrelated causes. Two patients continue to have active liver disease. Late age at first use of MTX and duration of therapy with MTX were independent predictors of serious liver disease. Conclusion. Serious liver disease is an uncommon, age- and dose-related complication of low-dose MTX therapy for RA.

Effect of piroxicam on gait in patients with osteoarthritis of the knee

Abstract: Objective. To determine whether the use of a nonsteroidal antiinflammatory drug (NSAID) in patients with painful osteoarthritis (OA) of the knee would result in alterations in specific biomechanical parameters of gait. Methods. Eighteen patients with symptomatic knee OA and varus knee deformity underwent initial clinical evaluation for pain and activities of daily living, and assessment of parameters of gait utilizing a well-described computerized system. All patients were then treated with piroxicam at 20 mg once daily, and clinical and gait analyses were repeated after 4 weeks. Results. Fifteen of the 18 patients studied had a significant increase in the knee adduction moment after treatment. In the group as a whole there was a significant increase in knee adduction moment (mean percent body weight times height [%BWTH] 4.11 pretreatment versus 4.57 after 4 weeks of treatment; P < 0.01) and maximum quadriceps moment (mean %BWTH 2.13 pretreatment, 2.62 posttreatment; P < 0.01), as well as changes in other gait parameters that might be expected to be altered as a result of relief of pain. Sixteen of 18 patients experienced symptomatic relief, with a significant reduction in pain in the group as a whole after 4 weeks (P < 0.001). Conclusion. NSAID treatment in patients with knee OA results in a reduction in symptomatic pain and an increase in loading of the knee. Whether the increased loading is due to the analgesic effects of the treatment is unknown, but if so, the development of agents capable of relieving pain while reducing loads at the knee may be desirable.

Correlation between serum levels of soluble tumor necrosis factor receptor and disease activity in systemic lupus erythematosus

Abstract: Objective. To determine the value of measurement of serum soluble tumor necrosis factor receptor (sTNFR), compared with established parameters such as anti–double-stranded DNA, in monitoring systemic lupus erythematosus (SLE) disease activity, and to determine whether serum sTNFR are bioactive and can effectively inhibit TNF bioactivity. Methods. Fifty-three consecutive ambulatory or hospitalized SLE patients and 140 consecutive healthy subjects were enrolled in a prospective cohort study. Serum levels of sTNFR were measured by a unique 2-sided capture enzyme-linked immunosorbent assay using mouse monoclonal antibodies and rabbit antisera against the sTNFR. Results. The mean ± SD concentrations of both the p55 (type I) and p75 (type II) soluble receptors were significantly higher in a group of 46 SLE patients than in controls: 1.89 ± 0.89 ng/ml versus 0.77 ± 0.19 ng/ml and 7.25 ± 3.89 ng/ml versus 3.02 ± 0.57 ng/ml, respectively (P < 0.0001 for both). The incidence and the extent of the increase among the healthy subjects and these patients (as well as in 7 additional patients on whom sequential studies were performed) correlated with disease activity more than did the occurrence of serum anti-DNA antibodies (correlation coefficients with disease activity 0.81 and 0.85 for p55 and p75 sTNFR, respectively, and 0.51 for anti-DNA antibodies). The increase in sTNFR levels seems to reflect, largely, enhanced formation, and only to a minor extent, reduced clearance due to impairment of renal function. Sera of the SLE patients had a marked inhibitory effect on the in vitro cytocidal activity of TNF, and this was shown to result entirely from their higher sTNFR receptor concentration. Conclusion. An increase in serum levels of sTNFR may become a useful marker for SLE activity since it shows a stronger correlation than do any other laboratory or clinical parameters employed presently in the daily clinical setting. At the concentrations attained in the serum of SLE patients, sTNFR effectively inhibit the bioactivity of TNF and may thus be a significant determinant of the intensity of the manifestations of SLE.