bluuebunny/crossref_metadata_2025 huggingface dataset:
Reflex sympathetic dystrophy syndrome of the lower limbs in renal transplant patients treated with cyclosporin A
Authors: Muñoz‐Gomez Jose , Collado Antonio , Gratacós Jordi , Llena Joaquin , Campistol J. M. , Andreu Jordi , Lomeña Francisco
Published: February 2007

In a 36‐month period, 240 patients at our institution received kidney transplants from cadaver donors. Cyclosporin A (CsA) was used as the initial immunosuppressive therapy. Seven patients (5 men and 2 women) developed severe pain, periarticular soft tissue swelling with no effusion, and vasomotor changes in affected areas. Although articular mobility was conserved, most of the patients had great difficulty in walking. A patchy osteoporotic pattern was seen radiographically and increased uptake of 99mtechnetium with a periarticular distribution in the clinically affected areas were found. All of these symptoms and radiographic and scintigraphic signs are compatible with definite reflex sympathetic dystrophy syndrome (RSDS). Articular symptoms began within 3 months after kidney transplantation in all patients; all but 1 patient had plasma CsA levels >200 ng/ml at that time. When the dosage of CsA was reduced, there was concomitant improvement in the RSDS, which appeared when the plasma CsA levels declined to <200 ng/ml. The mean duration of the clinical symptoms of RSDS was 8 months. We believe RSDS should be added to the list of complications that may appear in kidney transplant patients who receive CsA treatment.
Treatment of rheumatoid arthritis by extracorporeal photochemotherapy. A pilot study
Authors: Malawista Stephen E. , Trock David H. , Edelson Richard L.
Published: February 2007

In a 6‐month pilot study of 7 patients with rheumatoid arthritis, we tested a treatment involving the extracorporeal photoactivation of biologically inert methoxsalen (8‐methoxypsoralen) by ultraviolet A energy to a form that covalently cross‐links lymphocyte DNA; the injured cells are reinfused into the patient. Prior experimental studies had indicated that this regimen produces an immune reaction against antigens on treated T cells, and a clinical trial in patients with cutaneous T cell lymphoma had been successful. The current study patients were treated monthly, on 2 successive days (or biweekly, later on). Between 12 and 16 weeks of therapy, there appeared to be a breakpoint, after which the joint counts and joint scores of 4 of the patients began to improve. In 3 of the 4 patients, these measures eventually diminished by a mean of 71% and 80% of baseline values, respectively, and there was variable improvement in less direct indicators of clinical response. The joint counts and scores of the fourth patient improved modestly (by 33% and 59% of baselines, respectively) but he required alternative therapy, and those of the remaining 3 study patients did not improve. Mean slopes for the joint counts were significantly different from zero after the apparent breakpoint (but not before), whether one examined the 4 apparent responders (P = 0.01) or the entire group of 7 patients (P = 0.01). After completion of therapy, there was also a delay, of 2–3 months, in the clinical deterioration of those patients who had improved. There was only 1 mechanical adverse effect—a single episode of transient hypotension in 102 treatment sessions–‐and no toxic effects. This preliminary study suggests that extracorporeal photochemotherapy may be effective, at least in the short term, in certain patients with rheumatoid arthritis, with less apparent toxicity than that of any of the drugs currently used for this disorder. It deserves further evaluation.
T cell responses to polypeptide fractions of Borrelia burgdorferi in patients with lyme arthritis
Authors: Yoshinari Natalino H. , Reinhardt Bruce N. , Steere Allen C.
Published: February 2007

Among 6 patients with prolonged episodes of Lyme arthritis, the mean response of peripheral blood lymphocytes (PBL) to all Borrelia burgdorferi antigens (stimulation index [SI] 46) was greater than that among 5 patients with brief attacks of Lyme arthritis (SI 13; P < 0.1), as well as that among 7 control patients with rheumatoid arthritis and among 6 normal control subjects (in both instances SI 3; P < 0.05). In individual patients with brief episodes of Lyme arthritis, PBL had similar low levels of reactivity with the 20‐kd, 31‐kd, 34‐kd, 41‐kd, 55/58‐kd, and 66‐kd spirochetal polypeptides. In individual patients with prolonged arthritis, PBL usually had similar marked responsiveness to the 34‐kd, 41‐kd, 55/58‐kd, and 66‐kd polypeptides, but they had greater reactivity with the 34‐kd outer surface protein B than with the 31‐kd outer surface protein A (P < 0.05). In the 2 patients tested, paired samples of synovial fluid lymphocytes and PBL had a similar pattern of reactivity, but the response was 2–100‐fold greater in synovial fluid lymphocytes. We conclude that patients with prolonged Lyme arthritis have T cell responses to multiple spirochetal polypeptides.
Arthritis in patients infected with human T lymphotropic virus type I. Clinical and immunopathologic features
Authors: Sato Kazuto , Maruyama Ikuro , Maruyama Yoshikazu , Kitajima Isao , Nakajima Yuko , Higaki Megumu , Yamamoto Kazuhiko , Miyasaka Nobuyuki , Osame Mitsuhiro , Nishioka Kusuki
Published: February 2007

Ten patients with chronic inflammatory arthropathy and the human T lymphotropic virus type I (HTLV‐I) are described. These patients showed chronic persistent oligoarthritis, associated with proliferative synovitis, in large joints. The place of birth or residence of these patients was within the area endemic for adult T cell leukemia (ATL) and HTLV‐I. The age at onset of articular symptoms tended to be higher in these patients than in typical rheumatoid arthritis patients. Anti–HTLV‐I antibodies were detected in both sera and synovial fluids from all patients. Western blot analysis revealed antibodies to viral gag proteins (p19, p24, and p28). Atypical lymphocytes with nuclear indentations, consistent with ATL‐like cells, were observed in both synovial fluid and synovial tissue. Furthermore, HTLV‐I proviral DNA was integrated into the DNA of synovial fluid cells and synovial tissue cells. These findings suggest that HTLV‐I might be involved in the pathogenesis of this unique arthropathy.
The clinical and health status of patients with recent‐onset rheumatoid arthritis
Authors: Meenan Robert F. , Kazis Lewis E. , Anthony John M. , Wallin Bruce A.
Published: February 2007

This study was designed to document the clinical and health status of patients with recent‐onset rheumatoid arthritis (RA). Three groups were studied: 108 patients who had had RA for >1 year (established RA group), 313 patients who had had RA for ≤ 1 year (recent‐onset RA group), and 188 healthy friends of the patients with recent‐onset RA (no RA group). Clinical status was measured using tender joint count, erythrocyte sedimentation rate, and overall physician assessment. Health status was measured using the physical, psychological, pain, and arthritis impact scores of the Arthritis Impact Measurement Scales. Scores on all clinical and health status measures indicated substantial disease effects in the group with recent‐onset RA. For most of these measures, effect size analysis indicated that clinical and health status impacts in the recent‐onset RA group were similar in magnitude to those found in the group with more established disease, with scores in both groups being substantially different from those found in the no RA group. These results document the magnitude of the clinical and health status impacts in recent‐onset RA. They lend support to recent arguments advocating aggressive therapy earlier in the course of this frequently disabling disease.
Treatment of de Quervain's tenosynovitis with corticosteroids. A prospective study of the response to local injection
Authors: Anderson Bruce Carl , Manthey Richard , Brouns Matthew C.
Published: February 2007

Fifty‐six cases of De Quervain's tenosynovitis (in 55 patients) were treated with a “long‐acting” corticosteroid, methylprednisolone acetate, and followed prospectively over a 4‐year period. Approximately 90% of these patients were effectively managed either with a single injection (58%) or with multiple injections (33%) of this compound. Seventeen patients experienced recurrence a mean of 11.9 months after the initial injection. Three had minor flares and were not reinjected; the others responded to reinjections. Ten percent of the cases could not be controlled with local injection, and these patients were referred for surgery. Adverse reactions were self‐limited and relatively minor; no tendon ruptures or local infections occurred. We present a discussion of our review of the literature regarding medical therapy and surgical release for this condition. Treatment of De Quervain's tenosynovitis with methylprednisolone acetate injection rapidly controls the signs and symptoms, does not lead to serious adverse reactions, and should be the preferred initial treatment.
Association of HLA–DR4 with a more progressive disease course in patients with rheumatoid arthritis. Results of a followup study
Authors: Van Zeben Derkjen , Hazes Johanna M. W. , Zwinderman Aeilko H. , Cats Arnold , Schreuder Geziena M. T. , D'Amaro Joe , Breedveld Ferdinand C.
Published: February 2007

The association between HLA–DR antigens and rheumatoid arthritis (RA) was investigated in a wellcharacterized cohort of RA patients who were followed from the beginning of the disease (mean followup 6 years). The frequencies of HLA–DR antigens in patients with possible or probable RA (n = 49) were similar to those in controls. In patients with definite RA (n = 134), the frequencies of DR1, DR4, and DRw53 were increased, whereas the frequencies of DR2, DR3, DRw6, DRw13, and DRw52 were decreased, compared with controls. Comparison of HLA–DR frequencies in patients with definite RA subclassified according to the severity of the disease at the end of the followup period revealed a difference only in the frequency of DR4, which was increased in patients with progressive RA (59.2%) compared with those who had mild RA (34.8%). Further analysis showed that, compared with DR4‐negative RA patients, DR4‐positive patients had more swollen joints, higher scores on the Ritchie articular index, the Health Assessment Questionnaire, and the Steinbrocker functional classification, more radiologic abnormalities, and more use of second‐line drugs. Also, the rate of progression of radiologic abnormalities, functional classification, and use of second‐line drugs was higher in DR4‐positive patients. We conclude that DR4 is associated with a more severe disease course, and is a prognostic marker in early RA.
The geri‐aims. Reliability and validity of the arthritis impact measurement scales adapted for elderly respondents
Authors: Hughes Susan L. , Edelman Perry , Chang Rowland W. , Singer Ruth H. , Schuette Patrick
Published: February 2007

We adapted the Arthritis Impact Measurement Scales (AIMS) for use with frail elderly respondents. The new instrument, called the GERI‐AIMS, generates both generic and arthritis‐specific impairment scores, to control for comorbid conditions that are commonly found in an older population. An analysis of scores obtained on 438 elderly persons (mean age 76) indicated that more than half of the total disability measured by the generic GERI‐AIMS scores is related to arthritis. The GERI‐AIMS scales have standardized‐item alpha levels >0.70 and correlate well with clinical measures of arthritis severity. Information gained by using the GERI‐AIMS has important public policy implications, insofar as information on both generic and diseasespecific functional impairment is needed to establish priorities for basic research, epidemiologic, and intervention studies.
Altered interleukin‐2 secretion in patients with primary fibromyalgia syndrome
Authors: Hader Nader , Rimon David , Kinarty Amalia , Lahat Nitza
Published: February 2007

Interleukin‐2 (IL‐2) production was studied in T lymphocytes and isolated CD4+ T lymphocytes from 12 patients with primary fibromyalgia syndrome and 10 healthy volunteers. The dose and time kinetics of IL‐2 production by concanavalin A‐stimulated T cells and CD4+ T cells of fibromyalgia patients differed from findings in controls by 1) a need for a higher concentration of mitogen in order to achieve optimal IL‐2 secretion, and 2) a delay in the peak time of optimal IL‐2 secretion. Unlike normal IL‐2 secretion, which was higher after removal of CD8+ T cells, the pattern and degree of IL‐2 secretion by cells from fibromyalgia patients were not changed following removal of CD8+ T cells. Addition of calcium ionophore in assays using suboptimal concanavalin A concentrations did not correct the reduction in IL‐2 secretion by fibromyalgia patient T cells, but addition of phorbol myristate acetate induced normal secretion of IL‐2. These findings suggest that there is a defect in the IL‐2 pathway, which is related to protein kinase C activation and does not involve impairment of Ca2+ elevation, in patients with fibromyalgia.
Development of a disability measurement tool for juvenile rheumatoid arthritis. The juvenile arthritis functional assessment report for children and their parents
Authors: Howe Steven , Levinson Joseph , Shear Edith , Hartner Sandra , McGirr Gerri , Schulte Marion , Lovell Daniel
Published: February 2007

Two questionnaires were developed for measuring disability due to juvenile rheumatoid arthritis (JRA), one based on patient reports and one on parent reports. These questionnaires were termed the Juvenile Arthritis Functional Assessment Report for Children (JAFAR‐C) and for Parents (JAFAR‐P). The questionnaires were administered to 72 JRA patients ages 7‐18 years and to their parents. Respondents rated the patient's recent ability to perform 23 activities. Patient reports and parent reports were found to correlate highly with each other and with an objective assessment performed by therapists. Questionnaire scores did not correlate significantly with the age of the patient. The JAFAR appears to be a convenient, reliable, and valid measure of disability in patients with JRA.
Ro/SS‐A antigen in human platelets. Different distributions of the isoforms of Ro/SS‐A protein and the Ro/SS‐A–binding RNA
Authors: Itoh Yasuhiko , Reichlin Morris
Published: February 2007

Ro/SS‐A antigen is present in human platelets at a concentration that is approximately one‐twentieth to one‐thirtieth its concentration in lymphocytes, but the distribution of the Ro/SS‐A isoforms is different from that in lymphocytes or red blood cells. The Ro/SS‐A in platelets is largely the 52‐kd form. Moreover, the 52‐kd isoform in platelets is antigenically different from that in lymphocytes. In addition to the varied isoform distribution, a different distribution of the Ro/SS‐A–binding RNA (hY RNA) is seen in platelets. While there are 4 hY RNA (hY1, hY3, hY4, and hY5) in lymphocytes and other nucleated cells, we have found that platelets contain only 2 hY RNA: hY3 and hY4. This hY RNA distribution is also different from that in red blood cells, which contain only hY1 and hY4. The different distributions of the Ro/SS‐A components in lymphocytes, red blood cells, and platelets suggest different functional roles for the various protein and RNA components, as well as the possibility of different tissue‐specific events related to the Ro/SS‐A–autoanti–Ro/SS‐A system.
Transforming growth factor β1 stimulates inorganic pyrophosphate elaboration by porcine cartilage
Authors: Rosenthal Ann K. , Cheung Herman S. , Ryan Lawrence M.
Published: February 2007

The overproduction of inorganic pyrophosphate (PPi) by cartilage is thought to be a key element in the formation of calcium pyrophosphate dihydrate (CPPD) crystals in joints, and the subsequent development of pseudogout or chondrocalcinosis. We report herein that transforming growth factor β1 (TGFβ1), alone and in synergy with epidermal growth factor (EGF) or TGFα, markedly stimulates PPi elaboration by porcine articular cartilage in organ culture and monolayer culture. This effect is not seen with platelet‐derived growth factor, basic fibroblast growth factor, or insulin‐like growth factor types 1 and 2, substances which also affect chondrocyte metabolism or are mitogenic. TGFβ1 produces only a modest increase in nucleoside triphosphate pyrophosphohydrolase (NTPPPH), a chondrocyte ectoenzyme that produces PPi; this implies the existence of other pathways for PPi elaboration. TGFβ1 is present in joint fluid and cartilage. TGFβ1, TGFα, and EGF are the first known physiologic modifiers of cartilage PPi production. They provide a novel model for the study of CPPD crystal formation in cartilage, as well as new insights into the pathogenesis of this common affliction of aging.
Insufficiency fractures of the distal tibia misdiagnosed as cellulitis in three patients with rheumatoid arthritis
Authors: Straaton Karin V. , López‐Méndez Ada , Alarcón Graciela S.
Published: February 2007

We describe 3 patients with rheumatoid arthritis who presented with diffuse pain, swelling, and erythema of the distal aspect of the lower extremity, suggestive of either cellulitis or thrombophlebitis, but were found to have insufficiency fractures of the distal tibia. The value of technetium‐99m diphosphonate bone scintigraphy in the early recognition of these fractures and a possible explanation for the associated inflammatory symptoms are discussed.
Definition, incidence, and clinical description of flare in systemic lupus erythematosus. A prospective cohort study
Authors: Petri Michelle , Genovese Mark , Engle Eric , Hochberg Marc
Published: February 2007

The course of systemic lupus erythematosus (SLE) is characterized by exacerbations (or flares) and remissions of disease activity. As part of an ongoing prospective cohort study, 3 disease activity indices, the physician's global assessment, the Lupus Activity Index, and the University of Toronto SLE Disease Activity Index, have been recorded, at least quarterly since 1987, on 185 SLE patients. We developed a definition of SLE flare and a description of its clinical epidemiology. Disease flare was defined as a change of ≥1.0 in the physician's global assessment of disease activity (measured on a 0–3 scale) from the previous visit or from a visit within the last 93 days. Of the 185 patients, 98 (53%) had ≥1 flare; the total number of flares was 146. The incidence of flare was 0.65 per patient‐year of followup. The median time from the first study visit to a flare was 12 months. Flares were frequently characterized by constitutional symptoms, musculoskeletal involvement, cutaneous involvement, and decreasing levels of C3 and C4. At the time of flare, the mean University of Toronto SLE Disease Activity Index score increased by 3.0 and the mean Lupus Activity Index score (modified to omit the physician's global assessment) increased by 0.26. Overall, 44.8% of the flares prompted a change in treatment. Patients who experienced flares fulfilled more of the SLE criteria at entry and had been followed up for a longer duration after entry into the study, compared with those who did not have flares. By survival analysis, no specific clinical or laboratory variables present at entry were found to predict the time to first flare. These data show that quantification of flare is possible, flare is frequent in patients with SLE of long duration, and the majority of flares involve the so‐called “minor” organ systems.
Methotrexate versus azathioprine in the treatment of rheumatoid arthritis. A forty‐eight–week randomized, double‐blind trial
Authors: Jeurissen Maurice E. C. , Th. Boerbooms Agnes M. , Van De Putte Levinus B. A. , Doesburg Wim H. , Mulder Jan , Rasker Johannes J. , Kruijsen Marijn W. M. , Haverman Joost F. , Van Beusekom Henk J. , Muller Wim Hissink , Franssen Marcel J. A. M. , De Rooy Dirk‐Jan R. A. M.
Published: February 2007

We conducted a double‐blind, randomized trial comparing azathioprine (AZA) and methotrexate (MTX) in the treatment of patients with rheumatoid arthritis in whom parenteral gold and/or D‐penicillamine treatment had been unsuccessful. Patients were randomly assigned to receive either AZA (100 mg daily) or oral MTX (7.5 mg weekly). After 8 weeks, the dosage was increased depending on the clinical improvement. Sixty‐four patients were followed up for 48 weeks (33 AZA, 31 MTX). Comparison of values at week 24 with baseline values revealed significant improvement in 12 of 13 disease variables in the MTX group and in 6 of 13 in the AZA group. Comparison between the 2 treatment groups at 24 weeks, by area‐under‐the‐curve analysis, showed significantly more improvement in the MTX group in terms of the swollen joint count, pain score, erythrocyte sedimentation rate, C‐reactive protein level, hemoglobin level, thrombocyte level, and disease activity score. A significant overall clinical improvement (disease activity score) was found in 7 of 20 patients treated with AZA and 18 of 30 patients treated with MTX after 24 weeks of therapy, and in 6 of 12 AZA‐treated patients and 19 of 25 MTX‐treated patients after 48 weeks. The number of withdrawals due to side effects was significantly higher in the AZA group. After 48 weeks, only 12 patients from the AZA group (36%), but 25 from the MTX group (81%), were still using the initial drug. These results demonstrate MTX to be superior to AZA in the treatment of rheumatoid arthritis, with a more rapid clinical improvement which is sustained after 1 year, accompanied by a lower rate of serious adverse reactions.
Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis
Authors: Weinberg J. Brice , Pippen ANNE M. M. , Greenberg Charles S.
Published: February 2007

Fibrin deposition is a prominent finding in the synovium of patients with rheumatoid arthritis (RA). Macrophages are found in increased numbers in RA synovium, and these cells are known to produce a variety of procoagulant and anticoagulant molecules. Using immunohistologic techniques, the content and distribution of several important components of the coagulation system in the synovium of patients with RA, osteoarthritis (OA), or traumatic joint abnormalities requiring surgery were investigated. Samples from 3 patients from each category were examined in detail. RA synovium (compared with that of patients with OA or joint trauma) had increased numbers of macrophages and increased expression/content of fibrinogen, tissue factor, factor XIII, tissue transglutaminase, cross‐linked fibrin (fibrin D dimer), urokinase‐type plasminogen activator, and α2–plasmin inhibitor. Macrophage content in RA synovium was increased in both the lining cell areas and the interstitial cell areas. Fibrinogen was distributed throughout the tissue in all samples and was greater in RA synovium. In trauma and OA synovia, tissue factor was seen only in association with vessels (endothelial cells), but in RA synovium, it was markedly increased throughout the tissues. While fibrin D dimer was seen in small amounts in synovial lining cell areas of trauma and OA synovia, it was present in increased amounts in the lining cell and interstitial cell areas of RA synovium. Factor XIII and tissue transglutaminase were present in scant amounts in trauma and OA synovia, but there were increased amounts of both (especially tissue transglutaminase) in RA synovium in the vessel, lining cell, and interstitial cell areas. Urokinase and α2–plasmin inhibitor were also markedly increased in RA synovium. These results suggest that in inflamed synovium, there is ongoing extravascular tissue fibrin formation and dissolution that correlates with the degree of inflammation and macrophage content. Extravascular coagulation/fibrinolysis in RA represents a potential target for therapeutic intervention in this disease.
Binding of c‐reactive protein to human neutrophils. Inhibition of respiratory burst activity
Authors: Dobrinich Robert , Spagnuolo Philip J.
Published: February 2007

We investigated the binding of highly purified soluble human C‐reactive protein (CRP) to human neutrophils. Binding of CRP to neutrophils was rapid (50% of maximal binding occurred within 15 seconds), and complete within 5 minutes. Binding was inhibitable by excess unlabeled CRP, and nonspecific binding in the presence of a 200‐fold excess of unlabeled CRP was 10% of total binding. Binding was not affected by other proteins, including albumin, fibroncctin, rabbit IgG, or normal human plasma. Maximal binding required both calcium (0.5 mM) and magnesium (0.24 mM) ions. Calcium phosphorylcholine (10 μg/ml) or sodium citrate (10 μg/ml) completely dissociated bound CRP. Binding was saturable and most consistent with a 2‐site model, demonstrating both a high‐affinity receptor (1.4 × 104 sites/cell Kd 3.7 × 10−8M) and a low‐affinity receptor (4.2 × 105 sites/cell Kd 2.5 × 10−8M). CRP at concentrations of 50 μg/ml inhibited the neutrophil superoxide production induced by phorbol ester. At concentrations of 100 μg/ml or greater, CRP also inhibited superoxide production in a cell‐free xanthine oxidase–acetaldehyde system. These data suggest that CRP can down‐regulate neutrophil oxidative capacity through interaction with receptors on neutrophils as well as by direct antioxidant activity.
Treatment of collagen‐induced arthritis in rats with a monoclonal antibody against the α/β T cell antigen receptor
Authors: Yoshino Shin , Cleland Leslie G. , Mayrhofer Graham
Published: February 2007

A monoclonal antibody (MAb) to the α/β T cell receptor (TCRα/β), R73 MAb, completely blocked the induction of collagen‐induced arthritis (CIA) in rats when the MAb was administered at the time of immunization with type II collagen. When administered after CIA had begun, the progression of the arthritis was suppressed significantly by R73 MAb treatment. The preventive and suppressive effects of R73 MAb on CIA were associated with the depletion of peripheral blood α/β‐positive T cells. These results indicate that α/β‐positive T cells play a role in the progression of existing CIA as well as in its induction.
Cerebral vasculopathy associated with collateralization resembling moya moya phenomenon and with anti‐Ro/SS‐A and anti–La/SS‐B antibodies
Authors: Provost Thomas T. , Moses Howard , Morris Edward L. , Altman Jeremy , Harley John B. , Alexander Elaine , Reichlin Morris
Published: February 2007

We describe a 48‐year‐old, previously healthy, anti–Ro/SS‐A and anti–La/SS‐B antibody positive black woman with negative risk factors for atherosclerosis, who developed mental status and personality changes over a 6–12‐month period, and progressive cortical blindness over a 2‐week period. Angiographic and computed axial tomographic studies of the brain demonstrated multiple large areas of infarction correlating with stenosis and occlusions of the internal carotid and posterior cerebral arteries. Moya moya–like findings were prominent radiographically. Results of angiographic, computed tomographic, and magnetic resonance imaging studies were interpreted as being compatible with large, medium, and small vessel disease, most likely a vasculitis.
Expression of Metalloproteinases and Metalloproteinase Inhibitor in Human Arthritic Synovium
Authors: Spence Mccachren S.
Published: February 2007

The expression of messenger RNA encoding neutral metalloproteinases and the tissue inhibitor of metalloproteinases (TIMP) in human arthritic synovium was evaluated in situ, using RNA probes. Interstitial collagenase and stromelysin were expressed by synovial lining cells in patients with active rheumatoid arthritis (RA). Proteinase messenger RNA was found both in cells expressing mononuclear phagocyte antigens and in cells that were negative for the antigens. TIMP was also expressed predominantly along the synovial lining layer. In highly inflammatory RA, TIMP expression appeared less intense than that of the proteases. In osteoarthritic synovium, TIMP was expressed at easily detectable levels, whereas the expression of collagenase and stromelysin was less prominent. The balance between expression of the metalloproteinases and of the metalloproteinase inhibitor in synovium appears to be altered during inflammation. These results are consistent with the notion that synovium plays different roles in the cartilage damage of RA and of osteoarthritis.
Gene Expression (Collagenase, Tissue Inhibitor of Metalloproteinases, Complement, and HLA–DR) in Rheumatoid Arthritis and Osteoarthritis Synovium. Quantitative Analysis and Effect of Intraarticular Corticosteroids
Authors: Firestein Gary S. , Paine Mary M. , Littman Bruce H.
Published: February 2007

In situ hybridization was used to localize and quantify gene expression in rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. Collagenase, tissue inhibitor of metalloproteinases (TIMP), HLA–DR, and complement (C2 and C3) gene expression was studied in synovial tissue from 23 patients with RA, OA, or other inflammatory arthropathies. Gene expression was highly compartmentalized: Collagenase, TIMP, and C2 messenger RNA (mRNA) were localized primarily to the synovial lining layer; HLA–DR mRNA was prominent in the lining and in some sublining lymphoid aggregates; the C3 probe hybridized only to sublining lymphoid aggregates. Relative mRNA levels were quantified using computer‐assisted image analysis. There was significantly more collagenase, C2, C3, and HLA–DR mRNA in RA compared with OA patients. However, TIMP mRNA levels were similar in RA and OA. Expression of collagenase, TIMP, C2, C3, and HLA–DR genes correlated with the degree of synovial inflammation. The effect of intraarticular corticosteroid injection on synovial tissue gene expression was studied using serial percutaneous synovial biopsy samples from the knees of 3 RA patients. Joints were biopsied, injected with triamcinolone, and rebiopsied 1–2 weeks later. Histologic inflammation scores were lower in posttreatment synovia. Collagenase and TIMP mRNA, although abundant in presteroid samples, were nearly undetectable in post‐steroid tissues. HLA–DR mRNA levels also were significantly decreased. C2 and C3 hybridization significantly decreased in 2 of 3 patients and 1 of 3 patients, respectively. Hence, clinical response to intraarticular steroid therapy was accompanied by histologic improvement and decreased expression of genes that play a role in articular destruction. This study demonstrates the power of quantitative in situ hybridization as a tool for studying drug efficacy and mechanism.
Localization of Tumor Necrosis Factor α in Synovial Tissues and at the Cartilage–Pannus Junction in Patients With Rheumatoid Arthritis
Authors: Chu C. Q. , Field M. , Feldmann M. , Maini R. N.
Published: February 2007

Using immunoaffinity‐purified polyclonal anti‐human recombinant tumor necrosis factor α (TNFα) F(ab′)2 fragments and immunohistochemical techniques, the cells that make TNFα were localized in the inflamed synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Anti‐TNFα antibody–stained cells were demonstrated in 9 of 11 RA and 2 of 4 OA but none of 5 normal synovial membranes examined. In RA, 26–64% of the lining layer cells were positive for TNFα. In the interaggregate area, 10–30% of the cells contained TNFα, often in a perivascular distribution, and up to 19% of the cells in lymphoid aggregates stained for TNFα. Some endothelial cells also stained with these antibodies. In OA tissues, the TNFα‐containing cells were found predominantly in the deeper layer. Cells containing TNFα were also found at the cartilage–pannus junction in all 4 RA specimens examined. Double immunofluorescence analysis demonstrated that most TNFα‐secreting cells in the RA synovial membrane expressed the monocyte/macrophage marker antigens CD11b and CD14, and a few expressed the T cell marker CD3. Our findings provide histologic evidence that TNFα is locally produced in the lining and deeper layers of the synovium by cells of the mónocyte/macrophage lineage, supporting its role in inflammation. Further, our findings demonstrate that TNFα is produced by cells at the cartilage–pannus junction, which could affect chondrocyte metabolism, leading to the cartilage degradation in RA.
Autoantibodies to Human Stress Proteins. A Survey of Various Rheumatic and Other Inflammatory Diseases
Authors: Jarjour Wael N. , Jeffries Brentley D. , Davis John S. , Welch William J. , Mimura Toshihide , Winfield John B.
Published: February 2007

Unselected sera from patients with various rheumatic, inflammatory bowel, and autoimmune skin diseases (n = 268) were examined against human cell lysate by immunoblotting procedures, to determine the prevalence of autoantibodies to stress proteins (heat‐shock proteins) hsp60 (homolog of Escherichia coli groEL and mycobacterial 65K antigens), hsp73, and hsp90. Using standard, sensitive and specific assay conditions, IgG and IgM autoantibodies to these stress proteins were not demonstrable, or were detected infrequently, in sera from control subjects (n = 36) and from patients with rheumatoid arthritis, Sjögren's syndrome, ankylosing spondylitis, Reiter's syndrome, systemic lupus erythematosus, and systemic sclerosis. Autoantibodies to hsp60 were relatively more common (≧20% of sera) in patients with mixed connective tissue disease, polymyositis/dermatomyositis, psoriatic arthritis, inflammatory bowel disease, epidermolysis bullosa acquisita, and bullous pemphigoid. Anti‐hsp73 autoantibodies were detected in 20% or more of the sera from patients with Lyme disease and ulcerative colitis. Taken together, these data extend the spectrum of autoimmune and inflammatory diseases in which humoral anti–stress protein autoreactivity develops. However, the paucity of humoral autoreactivity to stress proteins in patients with systemic lupus erythematosus and rheumatoid arthritis argues against a direct role of anti–stress protein autoantibodies in the pathogenesis of these disorders.
Predominant Role of Neutrophils in the Inactivation of α2‐Macroglobulin in Arthritic Joints
Authors: Abbink J. J. , Kamp A. M. , Nieuwenhuys E. J. , Nuijens J. H. , Swaak A. J. G. , Hack C. E.
Published: February 2007

We studied the state of α2‐macroglobulin (α2M), an important inhibitor of cartilage‐degrading proteinases, in relation to activation of neutrophils in 82 patients with several types of arthritis, including 52 with rheumatoid arthritis and 11 with osteoarthritis. Levels of total inactive α2M (iα2M), which comprises α2M complexed to proteinases and α2M inactivated by oxidation or hydrolysis, were measured with a monoclonal antibody specific for iα2M. In addition, levels of α2M complexed to proteinases were quantitated with specific assays. Neutrophil activation was assessed by measuring elastase–α1‐antitrypsin complexes and lactoferrin. In 83% of the 82 patients tested, the synovial fluid (SF) to plasma ratio of iα2M exceeded 1, indicating an intraarticular generation. Levels of iα2M significantly correlated with neutrophil numbers (P < 0.0005) and with levels of elastase–α1‐antitrypsin complexes and of lactoferrin (P < 0.00001 for both). Moreover, part of iα2M consisted of α2M complexed to elastase‐like and chymotrypsin‐like proteinases, presumably, neutrophil elastase and cathepsin G, respectively. However, the amount of iα2M was approximately 10‐fold larger than the amount complexed to these proteinases. In vitro inactivation of α2M by activated neutrophils was only partly inhibitable by eglin C, a specific inhibitor of both elastase and cathepsin G. Release of reactive oxygen species was presumably responsible for the additional inactivation of α2M, because eglin C completely abolished the inactivation of α2M by cell‐free supernatant of activated neutrophils. Thus, our results suggest a predominant role of neutrophils in the inactivation of α2M in the SF of patients with inflammatory joint diseases. However, this inactivation could be explained only in part by the release of neutrophilic proteinases. We propose that the inactivation of α2M in SF was due to the concerted action of both reactive oxygen species and lysosomal proteinases.
Isolation of YERSINIA‐Specific T Cell Clones from the Synovial Membrane and Synovial Fluid of a Patient with Reactive Arthritis
Authors: Viner N. J. , Bailey L. C. , Life P. F. , Bacon P. A. , Gaston J. S. H.
Published: February 2007

Synovial fluid (SF) mononuclear cells from patients with reactive arthritis (ReA) proliferate in vitro when challenged with ReA‐associated bacteria, the maximal response being for the organism causing the triggering infection. We report the results of a study of the antigenic specificity of synovial T lymphocytes from an HLA–B27 positive ReA patient whose SF mononuclear cells responded preferentially to Yersinia antigens. This is the first report of the isolation of Yersinia‐specific T cell clones from synovial membrane (obtained by closed‐needle synovial biopsy). We present a detailed analysis of these clones, together with others obtained from the SF.
Retardation of Radiologic Progression in Rheumatoid Arthritis With Methotrexate Therapy. A Controlled Study
Authors: Rau R. , Herborn G. , Karger T. , Werdier D.
Published: February 2007

We evaluated the effects of methotrexate (MTX) on radiographic changes of rheumatoid arthritis (RA) in the hands, wrists, and feet of 31 patients who completed at least 24 months of treatment. Radiographs were obtained at baseline and every 1 or 2 years thereafter. MTX was administered for 2–6 years (mean 3.9 years); the total dose was 1,925 mg (range 970–3,810 mg). The mean duration of disease at baseline was 8.1 years (range 1–26 years). Radiographs taken over 1–5 years during previous, clinically ineffective, gold therapy (mean 2.2 years) were available for 24 patients, and the changes over time were compared. During MTX treatment, the mean number of swollen joints decreased from 22.5 to 8.3 (40 joints evaluated), and the mean erythrocyte sedimentation rate decreased from 61.6 mm/hour to 28.4 mm/hour. Thirty‐six (19%) of 190 joints with Larsen scores of 0 at baseline progressed to a score of 1 or 2 within 1 year of beginning MTX, whereas with gold, 37 (44%) of 89 joints progressed (P < 0.001). Of 419 joints with Larsen scores of 1, 12.5% deteriorated within 1 year with MTX treatment, compared with 14.7% of 183 joints during gold therapy (P not significant). There were no between‐treatment differences for joints with higher Larsen scores. During gold therapy, the mean Larsen index (score per joint) for the hand and wrist joints (18 joints counted) progressed from 1.45 to 1.82 over a mean of 22.1 months, and during MTX, from 1.82 to 1.97 over a mean of 48.0 months. The mean rate of progression during MTX therapy (0.005/month) was significantly lower (P = 0.01) than that during gold therapy (0.025/month). The mean rate of progression in the metatarsophalangeal joints (0.011/month versus 0.010/month, MTX versus gold) was not significantly different. There was a sharp decrease in the proportion of radiologically active joints during MTX treatment. Our findings thus indicate that MTX may retard the radiologic progression of RA in patients with disease that is unresponsive to gold.
T Lymphocyte Adhesion to Human Synovial Fibroblasts. Role of Cytokines and the Interaction Between Intercellular Adhesion Molecule 1 and CD11a/CD18
Authors: Krzesicki Raymond F. , Fleming William E. , Winterrowd Greg E. , Hatfield Cheryl A. , Sanders Martin E. , Chin Jia En
Published: February 2007

We studied the adhesion of human peripheral blood T lymphocytes to human synovial fibroblasts stimulated with interferon‐γ (IFNγ), tumor necrosis factor α (TNFα), interleukin‐1β (IL‐1β), or combinations of these cytokines. T lymphocytes bound poorly to untreated human synovial fibroblasts. IFNγ treatment resulted in the largest increase in adhesion, followed by TNFα and IL‐1β. Combinations of IFNγ + TNFα and IFNγ + IL‐1β had a synergistic effect on intercellular adhesion molecule 1 (ICAM‐1) expression and adhesion. The increase in cellular adhesion induced by cytokines correlated with the up‐regulation of the number of cells expressing ICAM‐1 and the density of antigen/cell. There was no synergistic effect on leukocyte function–associated antigen 3 (LFA‐3) or on HLA class I or class II antigen expression. Adhesion was only partially inhibited by anti‐ICAM‐1, anti‐LFA‐1, or anti‐CD18. These findings suggest the existence of ICAM‐1‐independent and CD11/CD18‐independent adhesion mechanisms. Anti‐LFA‐3 was completely ineffective as an inhibitor of adhesion. There was no additive or synergistic advantage of using combinations of antibodies to increase the level of inhibition, i.e., anti–ICAM‐1 + anti–LFA‐3, anti–ICAM‐1 + anti‐CD18, or anti–ICAM‐1 + anti–LFA‐1 (CD11a). Our data indicate that proinflammatory cytokines may play a prominent role in the formation and exacerbation of synovial hyperplasia, by regulating the recruitment and retention of T lymphocytes via the up‐regulation of adhesion molecules on synovial fibroblasts.
Levels of Keratan Sulfate in the Serum and Synovial Fluid of Patients With Osteoarthritis of the Knee
Authors: Campion Giles V. , McCrae Fiona , Schnitzer Thomas J. , Lenz Mary Ellen , Dieppe Paul A. , J.‐M. A. Thonar Eugene
Published: February 2007

We examined the relationship between serum and synovial fluid (SF) levels of antigenic keratan sulfate (KS) and the clinical, laboratory, and radiologic features of disease in 125 well‐characterized patients with knee osteoarthritis (OA). KS was quantified by enzyme‐linked immunosorbent assay, using an antibody specific for a highly sulfated epitope on KS chains; the results were calculated as equivalents of an international standard of KS from human costal cartilage. The mean level of serum KS (393 ng/ml) was significantly higher than those previously reported for populations of adults without OA. There was a wide scatter of serum KS values (range 156–912 ng/ml), with little correlation with clinical or radiologic features. Men had significantly higher levels than women (456 ± 135 ng/ml versus 368 ± 110 ng/ml, mean ± SD), and there was a statistically significant but weak association with indicators of polyarticular involvement (number of symptomatic joints, Heberden's nodes, hip symptoms) in women. Despite the wide scatter of results in the population as a whole, individual levels of KS were stable for up to 4 consecutive years in the 9 patients studied. Levels of KS were much higher in SF (n = 25) than in serum, but the two were not correlated. There was an inverse correlation between radiographic evidence of cartilage loss and the level of KS in SF. The large variations in serum KS values suggest that this measure may not be of diagnostic significance among populations of patients. However, the stability of serum levels with time and the relationship between cartilage mass and SF levels may be useful for monitoring the individual patient's response to therapy, both systemically (serum KS) and in single joints (SF KS).
Human Basophil Releasability. VIII. Increased Basophil Releasability in Patients with Scleroderma
Authors: de Paulis Amato , Valentini Gabriele , Spadaro Giuseppe , Lupoli Salvatore , Tirri Giuseppe , Marone Gianni
Published: February 2007

We evaluated basophil releasability in 16 female patients with scleroderma (systemic sclerosis) and in 16 normal age‐ and sex‐matched donors. Basophils from patients with scleroderma released significantly more histamine „spontaneously”︁ than did those from normal donors (12.9 ± 2.1% versus 4.5 ± 0.7%; P < 0.0005). Basophil reactivity (maximal percentage histamine release) to anti‐IgE was higher in patients with scleroderma than in controls (57.0 ± 7.5% versus 35.4 ± 7.8%; P < 0.05). Basophil sensitivity (the concentration of anti‐IgE that causes 40% of maximal percentage histamine release) to anti‐IgE in scleroderma patients was similar to that found in controls (4.6 ± 2.8 × 10−2 μg/ml versus 2.3 ± 1.0 × 10−1 μg/ml; P not significant). Scleroderma patients also showed enhanced releasability compared with that of the controls when challenged in vitro with interleukin‐3 (8.3 ± 1.7% versus 3.2 ± 0.6% P < 0.01). Releasability induced by the formylcontaining tripeptide, f‐met peptide, was significantly higher in the scleroderma patients than in the controls at the 2 lower concentrations used. No differences in basophil reactivity and sensitivity to f‐met peptide and calcium ionophore A23187 were found between patients and normal donors. These results show that spontaneous basophil releasability and releasability in response to IgE cross‐linking and activation of interleukin‐3 receptors are increased in patients with scleroderma.
Secular Changes in Published Clinical Trials of Second‐Line Agents in Rheumatoid Arthritis
Authors: Anderson Jennifer J. , Felson David T. , Meenan Robert F.
Published: February 2007

The present investigation was undertaken to explore changes over time in the design and reporting of trials of second‐line drugs in rheumatoid arthritis, in the characteristics of patients included in the trials, and in the sources of funding. We studied 105 trials of second‐line agents for the treatment of rheumatoid arthritis, including placebo‐controlled and comparative trials involving 8 different agents. Three time periods, 1945–1969, 1970–1979, and 1980–1989, were compared. We found little change in the standards for reporting on the design of trials or for reporting information on patient dropout and drug side effects, some increase in the complexity of the statistical methods used, but no increase in the use of power analysis (reported in only 13% of trials). The average age of patients in clinical trials has increased. In recent years, there has been a substantial shift from placebo‐controlled to comparative trials, and it is increasingly common for trials to be financially supported by pharmaceutical companies. The possible effects of secular trends should be considered when combining or comparing results of trials conducted in different years.
HLA–DPB1*0301 is a Major Risk Factor for Rheumatoid Factor–Negative Adult Rheumatoid Arthritis
Authors: Gao Xiaojiang , Fernandez‐Vina Marcelo , Olsen Nancy J. , Pincus Theodore , Stastny Peter
Published: February 2007

HLA–DPB1 alleles were determined using the polymerase chain reaction and allele‐specific oligonucleotide probes in Caucasoid patients with rheumatoid arthritis (RA) and in healthy controls. DPB1*0301 was found to be increased in seronegative patients (50.0% versus 10.8% in controls; relative risk = 8.3, P < 0.0001). With our previous finding that DPB1*0301 is increased in seronegative children with polyarticularonset arthritis, the results suggest a relationship between this disease and seronegative RA in adults.
Antibodies to Retroviral Proteins and Reverse Transcriptase Activity in Patients With Essential Cryoglobulinemia
Authors: Perl Andras , Gorevic Peter D. , Condemi John J. , Papsidero Lawrence , Poiesz Bernard J. , Abraham George N.
Published: February 2007

Human T cell lymphotropic virus type I (HTLV‐I) gag and env protein–specific antibodies were identified in 6 of 13 patients with essential cryoglobulinemia (EC), by Western blot and radioimmunoprecipitation analysis. Supernatants of cells from 2 of the 5 EC patients tested showed reverse transcriptase activity. DNA sequences homologous to HTLV‐I could not be detected by polymerase chain reaction, thus excluding the presence of prototype HTLV‐I in each patient with EC. The data suggest that retroviral proteins distinct from but related to HTLV‐I may be involved in the pathogenesis of EC in some patients.