bluuebunny/crossref_metadata_2025 huggingface dataset:
The mitogenic response to stimulation with basic calcium phosphate crystals is accompanied by induction and secretion of collagenase in human fibroblasts
Authors: McCarthy Geraldine M. , Mitchell Peter G. , Cheung Herman S.
Published: February 2007

Synovial fluid basic calcium phosphate (BCP) crystals are associated with severe destructive arthro‐pathies that are characterized by synovial proliferation and digestion of articular collagenous structures. BCP crystals are potent mitogens, which may account for this proliferation. The role of collagenase in articular degradation is controversial because, despite the massive loss of collagen, no studies have confirmed collagenolytic activity in synovial fluid, as originally reported. We investigated collagenase messenger RNA induction and enzyme activity in human foreskin flbroblasts proliferating in response to stimulation with BCP crystals, and analyzed the associated secreted proteins. Northern blots revealed a dose‐dependent accumulation of collagenase message, evident by 4 hours and continuing to at least 36 hours, in BCP‐stimulated cultures. One‐ and 2‐dimensional polyacrylamide gel electrophoresis of conditioned media from BCP crystal–stimulated cultures revealed the selective induction of 2 proteins with molecular weight and pI values consistent with those of collagenase. Increased enzyme activity was also found. Thus, the mitogenic response of fibroblasts to BCP crystals is accompanied by collagenase induction and secretion, supporting the hypothesis that they act as a mediator of joint destruction in BCP crystal–associated arthropathies.
Enkephalinase: A physiologic neuroimmunomodulator detected in the synovial fluid
Authors: Appelboom Thierry , De Maertelaer Viviane , De Prez Eric , Hauzeur Jean‐Philippe , Deschodt‐Lanckman Monique
Published: February 2007

Enkephalinase (endopeptidase 24.11) is a metallopeptidase that is able to cleave not only neuropeptides and hormones but also immune mediators. The enzyme was quantified in synovial fluid obtained from 36 swollen joints. Its concentration correlated with the synovial fluid cell count, mainly the polymorphonuclear cells and lymphocytes, and with the erythrocyte sedimentation rate. No statistically significant difference in enkephalinase levels was demonstrated between the groups of patients with rheumatoid arthritis, seronegative spondylarthropathy, microcrystalline arthritis, or osteoarthritis. The presence of enkephalinase in the synovial fluid could reflect the intensity of the inflammatory process, or it could represent a physiologic regulator of inflammation and pain within the joint.
Effect of Medication on Synovial Fluid Leukocyte Differentials in Patients With Rheumatoid Arthritis
Authors: Bahremand Manijeh , Ralph Schumacher H.
Published: February 2007

We compared leukocyte populations in synovial fluid samples from 45 rheumatoid arthritis patients, grouped according to medications taken. Seventeen of the 22 patients receiving only nonsteroidal antiinflammatory drugs had lymphocytes as the single predominant cell. None of the 23 patients receiving second‐line agents had lymphocyte predominance. These findings may have important implications for drug mechanisms and must be considered in future studies of synovial fluid.
Autoantibodies to Nuclear Lamin C in the Eosinophilia—Myalgia Syndrome Associated with L‐Tryptophan Ingestion
Authors: Varga John , Maul Gerd G. , Jimenez Sergio A.
Published: February 2007

Objective. To examine the autoantibodies (antinuclear antibodies [ANA]) present in serum from a patient with eosinophilia—myalgia syndrome (EMS).

Methods. Sera obtained during the early phase of EMS and following therapy with prednisone were screened by indirect immunofluorescence on HEp‐2 cells, and ANA were characterized by immunoblotting on a purified nuclear lamin fraction.

Results. ANA with a ring‐like pattern of nuclear staining were identified at high titer by immunofluorescence, and immunoblotting experiments showed them to be directed against lamin C. The antibody titer declined dramatically after discontinuation of L‐tryptophan and therapy with prednisone.

Conclusion. This is the first characterization of an antigen/autoantibody system associated with EMS. The findings indicate that this EMS‐associated autoantibody recognizes epitopes localized in the carboxyterminal region of lamin C. The occurrence of antilamin C autoantibodies in one EMS patient expands the spectrum of clinical conditions associated with these antibodies, and provides evidence for an autoimmune response in EMS.
P‐31 Magnetic Resonance Spectroscopy in Polymyositis and Dermatomyositis
Authors: Newman Eric D. , Kurland Robert J.
Published: February 2007

Objective. To explore alterations in energy utilization as a potential etiology for weakness in polymyositis and dermatomyositis (PM/DM).

Methods. P‐31 magnetic resonance spectroscopy studies were performed in patients with acute and treated PM/DM and in normal controls, at rest and with exercise.

Results. Patients with acute and treated PM/DM showed increased ratios of inorganic phosphate to phosphocreatine (PCr) during exercise, with loss of ATP disproportional to loss of PCr.

Conclusion. This study demonstrates changes in energy utilization in PM/DM, thus supporting the notion of a metabolic etiology for the weakness associated with these diseases.
Increase in CD5+ B Cells in Juvenile Rheumatoid Arthritis
Authors: Jarvis James N. , Kaplan Joseph , Fine Nancy
Published: February 2007

Objective. To investigate the association between CD5+ B cell expression and IgM rheumatoid factor (IgM‐RF) in juvenile rheumatoid arthritis (JRA).

Methods. CD5+ B cell levels analyzed by flow cytometry and IgM‐RF expression determined by enzymelinked immunosorbent assay were compared in children with JRA, children with other collagen vascular diseases, and healthy controls.

Results. Children with polyarticular JRA had expanded populations of CD5+ B cells, and expansion of CD5+ B cells and IgM‐RF both correlated with disease activity.

Conclusion. The results indicate that an expanded CD5+ B cell population leads to IgM‐RF production in patients with polyarticular JRA, as well as patients with RA.
The radiographic criterion in the 1987 revised criteria for rheumatoid arthritis. Reassessment in a prospective study of early disease
Authors: Paimela Leena
Published: February 2007

Objective. To assess the radiographic criterion in the 1987 revised criteria for the classification of rheumatoid arthritis (RA), in patients with early RA.

Methods. The diagnostic value of radiologic changes in the hands was compared with that of radiologic changes in the feet, in a prospective study of 78 patients with early definite or classic RA (symptoms for ≤12 months) according to the 1958 criteria.

Results. At entry, 23% of the patients had erosions only in metatarsophalangeal (MTP) joints, 6% only in hands, and 5% both in hands and in feet. After 2 years of followup, 29% of the patients had only MTP joint erosions and 3% had only hand erosions. At study entry, the level of clinical activity in patients with erosions in the feet only was lower than that in other patients, and 44% of these patients would not have been diagnosed as having RA by the 1987 criteria.

Conclusion. In early RA, radiographic changes in the feet seem to be a more sensitive criterion than radiographic changes in the hands. Therefore, addition of radiographic evaluation of the feet to the revised criteria may improve the classification of recent‐onset RA.
Mycobacteria and human heat shock protein—specific cytotoxic t lymphocytes in rheumatoid synovial inflammation
Authors: Li Shu Guang , Quayle Alison J. , Shen Yamin , Kjeldsen‐Kragh Jens , Oftung Fredrik , Gupta Radhey S. , Natvig Jacob B. , Førre Øystein T.
Published: February 2007

Objective. To study the cytotoxic capacity of mycobacteria‐specific T lymphocyte lines and clones from sites of inflammation in patients with rheumatoid arthritis (RA). We also studied antigen specificity, surface phenotype, expression of T cell receptors (TCR), and HLA restriction.

Methods. Autologous macrophages (Mπ) from the synovial membrane (SM), synovial fluid (SF), or peripheral blood (PB) were used as target cells in cytotoxicity assays.

Results. All SM and SF cell lines tested thus far have shown specific lysis of the autologous Mπ from SM or PB that had been pulsed with BCG (bacillus Calmette‐Guerin), but no cytotoxicity when the targets were pulsed with irrelevant antigens such as tetanus toxoid and Chlamydia. Both CD4+ and CD8+ cells were shown to be involved in the specific cytolysis. The majority of the cytotoxic T lymphocyte (CTL) lines were TCRα/β+ cells. However, both TCRα/β+ and TCRγ/δ+ clones (TCR δ1+) from one RA patient showed antigen‐specific lysis. Antigen‐specific recognition by a number of CTL lines and clones generated from SF and SM was restricted by HLA—DR molecules. Two Mycobacterium bovis 65‐kd heat shock protein (HSP)–specific TCRα/β+ SF T cell clones also lysed Mπ that had been pulsed with a recombinant human 65‐kd HSP.

Conclusion. Joint inflammation and destruction might be partly attributable to a cross‐reaction of mycobacteria‐induced cytotoxic T cells with self HSP.
Elevated expression of β1 and β2 integrins, intercellular adhesion molecule 1, and endothelial leukocyte adhesion molecule 1 in the skin of patients with systemic sclerosis of recent onset
Authors: Sollberg Stephan , Peltonen Juha , Uitto Jouni , Jimenez Sergio A.
Published: February 2007

Objective. To investigate the possible role of integrins and cell adhesion molecules in the pathogenesis of the mononuclear cell infiltration and fibrosis of skin that occurs in systemic sclerosis (SSc).

Methods. The presence and topographic distribution of β1, β2, and β4 integrins, as well as of endothelial leukocyte adhesion molecule 1 (ELAM‐1) and intercellular adhesion molecule 1 (ICAM‐1), was examined immunohistochemically in affected skin from 8 patients with rapidly progressive SSc of recent onset. The expression of the β1 integrin gene was also investigated by in situ hybridization with a human sequence‐specific complementary DNA.

Results. The presence of β1 integrin epitopes and the corresponding messenger RNA within inflammatory cells surrounding small vessels was demonstrated in SSc skin but not in normal skin. Lymphocytes positive for β2 integrin were also found only in SSc skin, and they appeared in close proximity to small blood vessels and collagen bundles. Immunostaining for β4 integrin epitopes revealed no differences between normal and SSc skin. ELAM‐1 and ICAM‐1 monoclonal antibodies, which identify epitopes indicative of endothelial cell activation, stained endothelial cells in SSc skin but not normal skin.

Conclusion. These observations suggest that the complex interactions of β1 and β2 integrins, as well as ELAM‐1 and ICAM‐1, may be intimately involved in the pathogenesis of SSc, perhaps by mediating the homing and targeting of pathogenetic lymphocytes to the affected tissues.
Serosal mast cells maintain their viability and promote the metabolism of cartilage proteoglycans when cocultured with chondrocytes
Authors: Stevens Richard L. , Somerville Laura L. , Sewell Duane , Swafford James R. , Caulfield John P. , Levi‐Schaffer Francesca , Hubbard John R. , Dayton Elahe T.
Published: February 2007

Objective. To determine the consequences of mast cell (MC)–chondrocyte interactions.

Methods. Cocultured cells were analyzed histochemically, morphologically, biochemically, and functionally.

Results. Cocultured MC adhered to the chondrocytes and remained viable. Chondrocytes cocultured with nonactivated MC produced more proteoglycans than did chondrocytes cultured alone, and these proteoglycans possessed an intact hyaluronic acid—binding region. In contrast, most of the proteoglycans produced by chondrocytes cocultured with activated MC were degraded.

Conclusion. These studies indicate that a complex interaction occurs in which the nonactivated MC stimulates biosynthesis and the activated MC degrades cartilage proteoglycans.
Lymphocyte responses to DR4/1‐restricted peptides in rheumatoid arthritis. The immunodominant T cell epitope on the 19‐kd mycobacterium tuberculosis protein
Authors: Tan Paul L. J. , Farmiloe Sarah , Young Judy , Watson James D. , Skinner Margot A.
Published: February 2007

Objective. Peptides presented by DR4/1 may be involved in the pathogenesis of rheumatoid arthritis (RA). T cell responses to DR4/1‐restricted peptides unrelated to the causative antigen may be altered in RA. Thus, DR4/1‐restricted lymphocyte responses in healthy volunteers and patients with RA were determined.

Methods. Peripheral blood lymphocytes (PBL) and synovial lymphocytes were cultured with synthetic peptides spanning the 19‐kd Mycobacterium tuberculosis (MT) protein.

Results. 3H‐thymidine uptake by PBL from 5 of 7 healthy individuals and 5 of 7 RA patients increased in response to the N‐terminal peptide (residues 1–20). Eleven fresh synovial fluid and 4 fresh synovial tissue (ST) lymphocyte samples did not proliferate in response to any of the peptides. However, the same T cell epitope was identified by ST lymphocytes when these were precultured. The N‐terminal peptide was not a common antibody‐binding site, unlike several of the other peptides.

Conclusion. Similar responses by RA and normal PBL to a DR4/1‐restricted immunodominant T cell epitope on the 19‐kd MT protein were observed. The responses were more readily detected in PBL than in synovial lymphocytes. These observations may be relevant for assessing unrelated synthetic peptides in the development of DR4/1‐restricted peptide immunotherapy.
Inhibition of synovial fluid T cell proliferation by anti‐CD5 monoclonal antibodies. A potential mechanism for their immunotherapeutic action in vivo
Authors: Verwilghen Jo , Kingsley Gabrielle H. , Ceuppens Jan L. , Panayi Gabriel S.
Published: February 2007

Objective. Monoclonal antibodies (MAb) directed against the T cell surface molecule CD5 are able to provide accessory stimulatory signals to resting T cells. The potential role of CD5 as an immunoregulatory molecule in inflammatory synovitis was examined.

Methods. Synovial fluid and peripheral blood T cells of patients with active rheumatoid arthritis (RA) were purified and stimulated with interleukin‐2 (IL‐2), and the effect of MAb directed against CD5 on IL‐2 responsiveness was examined.

Results. IL‐2—induced proliferation of synovial fluid T cells was strongly inhibited by anti‐CD5 MAb, but not by anti‐CD28 or anti‐CD3 MAb. In RA peripheral blood T cells, MAb directed against CD5, CD3, and CD28 induced IL‐2—dependent T cell growth, similar to findings in healthy controls. The difference in activity of anti‐CD5 MAb on synovial fluid T cells compared with peripheral blood T cells was not due to different surface expression of CD5.

Conclusion. Anti‐CD5 has an inhibitory effect on in vivo—activated synovial fluid T cells. The disease‐ameliorative effects of anti‐CD5 immunotoxin treatment of RA may be partly due to “switching‐off” of T cell activation in the joints.
Antilactoferrin antibodies in patients with rheumatoid arthritis are associated with vasculitis
Authors: Coremans I. E. M. , Hagen E. C. , Daha M. R. , Van Der Woude F. J. , Van Der Voort E. A. M. , Kleijburg‐Van Der Keur C. , Breedveld F. C.
Published: February 2007

Objective. To determine the occurrence of antineutrophil cytoplasmic antibodies (ANCA) and the specificity of these antibodies (Ab) in serum from patients with rheumatoid arthritis (RA) and patients with rheumatoid arthritis complicated by vasculitis (rheumatoid vasculitis [RV]).

Methods. ANCA was detected with an indirect immunofluorescence test on ethanol‐fixed granulocytes. Ab against the cytoplasmic antigens proteinase‐3, elastase, lactoferrin (LF), and myeloperoxidase were measured by enzyme‐linked immunosorbent assay.

Results. ANCA were found in the serum of 43% of 49 patients with RV and in 36% of 50 patients with RA. Anti‐LF Ab occurred more frequently in RV patients (45%) than in RA patients (4%), whereas reactivity against the other cytoplasmic antigens did not differ significantly between these groups.

Conclusion. Anti‐LF Ab in serum of patients with RA may be useful in the diagnosis of vasculitis in RA.
Use of an antibody against the matrix metalloproteinase–generated aggrecan neoepitope fvdipen‐cooh to assess the effects of stromelysin in a rabbit model of cartilage degradation
Authors: Bayne Ellen Kahn , MacNaul KAREN L. , Donatelli Susan A. , Christen Amy , Griffin Patrick R. , Hoerrner Lori A. , Calaycay Jimmy R. , Ayala Julia M. , Chapman Kevin , Hagmann William , Weidner Jeffrey R. , Mcdonnell Joseph , Moore Vernon L. , Mumford Richard A. , Lark Michael W. , Hutchinson Nancy I.
Published: February 2007

Objective. To define the stromelysin cleavage site in the interglobular domain of rabbit aggrecan, and to determine whether the stromelysin‐generated neoepitope can be used as a marker of matrix metalloproteinase (MMP) activity in vivo.

Methods. The carboxy‐terminus sequence of the stromelysin‐generated hyaluronic acid–binding region (HABR) of rabbit aggrecan was determined by reverse transcription–polymerase chain reaction complementary DNA cloning and DNA sequence analysis, followed by purification and mass spectral protein sequence analysis of the HABR fragment. Active stromelysin was injected into the stifle joints of rabbits, and a stromelysin‐generated aggrecan neoepitope was analyzed by Western blotting and localized in situ by indirect immunofluorescence. Proteoglycan fragments in joint fluids were quantified by a dimethylmethylene blue dye‐binding assay.

Results. Stromelysin cleavage of rabbit aggrecan generated a 55‐kd HABR fragment that terminated in the sequence FMDIPEN. An anti‐FVDIPEN antibody recognized the FMDIPEN neoepitope in situ in cartilage from stromelysin‐injected joints. The appearance of the FMDIPEN neoepitope corresponded to the release of cartilage proteoglycan fragments into the joint fluid, and could be inhibited by pretreatment of the rabbits with a synthetic stromelysin inhibitor.

Conclusion. These results indicate that the anti‐FVDIPEN antibody can be used to assess the role of MMPs in cartilage degradation in vivo.
Effects of stress management on clinical outcomes in rheumatoid arthritis
Authors: Parker Jerry C. , Smarr Karen L. , Buckelew Susan P. , Stucky‐ropp RenéE C. , Hewett John E. , Johnson Jane C. , Wright Gail E. , Irvin William S. , Walker Sara E.
Published: February 2007

Objective. To examine the effects of stress‐management training on clinical outcomes in persons with rheumatoid arthritis (RA).

Methods. Patients with RA (n = 141) were randomly assigned to 1 of 3 groups: a stress management group, an attention control group, or a standard care control group. The stress management and the attention control groups received a 10‐w eek intervention followed by an additional 15‐m onth maintenance phase.

Results. The stress management group showed statistically significant improvements on measures of helplessness, self‐efficacy, coping, pain, and health status. Selected beneficial effects were still detectable at the 15‐m onth followup evaluation.

Conclusion. The data indicated that stress management interventions are capable of producing important clinical benefits for persons with RA.
Oral type II collagen treatment in early rheumatoid arthritis. A double‐blind, placebo‐controlled, randomized trial
Authors: Sieper Joachim , Kary Sonja , Sörensen Helmut , Alten Rieke , Eggens Ulrich , Hüge Werner , Hiepe Falk , Kühne ANDREA , Listing Joachim , Ulbrich Norbert , Braun Jürgen , Zink Angela , Mitchison Nicholas Avrion
Published: February 2007

Objective. To investigate the efficacy of oral type II collagen in the treatment of early rheumatoid arthritis (RA).

Methods. Ninety patients with RA (disease duration ⩽3 years) were treated for 12 weeks with oral bovine type II collagen at 1 mg/day (n = 30) or 10 mg/day (n = 30) or with placebo (n = 30), in a double‐blind randomized study.

Results. There was no significant difference between the 3 groups in terms of response to treatment. However, we observed a higher prevalence of responders in the type II collagen‐treated groups: 7 responders in the 10‐mg type II collagen group and 6 in the 1‐mg group, versus 4 in the placebo group. Furthermore, 3 patients in the 10‐mg type II collagen group and 1 patient in the 1‐mg type II collagen group, but no patients in the placebo group, had very good response. A total of 14 patients had to be withdrawn from the study: 2 because of side effects (nausea) and 12 because of lack of efficacy.

Conclusion. Only a minority of patients responded to treatment with oral type II collagen. These results justify further efforts to identify which patients will have a good response to such therapy.
Treatment of xerostomia with polymer‐based saliva substitutes in patients with Sjögren's syndrome
Authors: van der Reijden Willy A. , van der Kwaak Hanneke , Vissink Arjan , Veerman Enno C. I. , Amerongen Arie V. Nieuw
Published: February 2007

Objective. To determine the efficacy of 3 types of polymer‐based saliva substitutes in reducing oral dryness in patients with Sjögren's syndrome (SS).

Methods. Subjective efficacy of 3 different saliva substitutes (determined by self‐administered questionnaire) was evaluated in a double‐blind, placebo‐controlled trial in 43 patients with primary and secondary SS. High‐viscosity versus low‐viscosity xanthan gum‐based saliva substitutes were also compared in 33 SS patients. Salivary flow rates (SFR) were determined to examine correlations between the SFR and the subjective efficacy of the saliva substitute.

Results. Neither the saliva substitutes nor the placebo was truly effective. Preference for a particular saliva substitute over placebo was equally distributed among the 3 types of substitutes. The SFR of patients who preferred polyacrylic acid‐based saliva substitutes was lower than that in patients who preferred the porcine mucin‐based substitute (P < 0.05). Patients whose oral dryness was reduced by low‐viscoelastic substitutes had a low stimulated SFR (<0.20 ml/minute; P < 0.05).

Conclusion. The optimal properties of a saliva substitute are not the same for all patients with SS, but are dependent on such parameters as the individual SFR. Thus, to determine the best saliva substitute for a particular patient, it is necessary to have the patient try a number of substitutes of different viscoelastic properties.
Cutaneous lymphocyte antigen‐positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis
Authors: Pitzalis Costantino , Cauli Alberto , Pipitone Nicolo , Smith Catherine , Barker Jonathan , Marchesoni Antonio , Yanni Ghada , Panayi Gabriel S.
Published: February 2007

Objective. To investigate whether T cell migration into different sites of inflammation (skin and synovium) within the same individual is principally regulated by tissue‐specific homing or by more general mechanisms related to inflammation.

Methods. Expression of cutaneous lymphocyte antigen (CLA) and its ligand, E‐selectin, was analyzed by immunohistochemistry and immunofluorescence using paired skin and synovial membrane (SM) samples from patients with psoriatic arthritis (PsA). To investigate disease specificity, delayed‐type hypersensitivity (DTH) skin lesions, induced by tuberculin purified protein derivative, and SM from patients with rheumatoid arthritis (RA), were studied as controls. To directly examine cell migration in vivo, the proportion of CLA+ T lymphocytes migrating into suction‐induced skin blisters was assessed by flow cytometry. Using the same technique, levels of paired peripheral blood and synovial fluid (SF) T cells were also analyzed.

Results. CLA+ T cells preferentially accumulated in the skin, but not in the joint, of patients with PsA. Similarly, CLA+ T lymphocytes predominated in the DTH skin lesions of RA patients, but were very rare in the SM of RA patients, and were scarcely represented in the SF of patients with several chronic inflammatory arthropathies. In addition, CLA+ T lymphocytes preferentially migrated into epidermal skin blisters. This preferential pattern of CLA+ T cell accumulation was not related to the selective expression of E‐selectin, since this was similar in the skin and SM of both PsA and RA patients.

Conclusion. The distinct pattern of T cell infiltration into sites of inflammation within the skin and synovium is regulated by both organ‐specific homing and general inflammation‐related mechanisms.
Depletion of γ/δ T cells does not prevent or ameliorate, but rather aggravates, rat adjuvant arthritis
Authors: Pelegrí Carme , Kühnlein Petra , Buchner Eberhard , Schmidt Carsten B. , Franch Angels , Castell Margarida , Hünig Thomas , Emmrich Frank , Kinne Raimund W.
Published: February 2007

Objective. To investigate the role of γ/δ T cells in Mycobacterium tuberculosis–induced rat adjuvant arthritis.

Methods. Rats with adjuvant arthritis were injected with the anti–T cell receptor γ/δ (anti‐TCR γ/δ) monoclonal antibody V65 according to a preventive protocol, a pre–arthritis peak protocol, and a late therapeutic protocol. Arthritis severity and joint destruction were monitored, and depletion of target cells was analyzed by flow cytometry.

Results. Although all protocols led to successful depletion of TCRγ/δbright cells in peripheral blood and lymph nodes, none of the regimens influenced clinical parameters of adjuvant arthritis. If rats were treated before the clinical peak of adjuvant arthritis, however, joint destruction was significantly more severe than in vehicle‐treated rats.

Conclusion. Rat adjuvant arthritis is not promoted or perpetuated by γ/δ T cells. Aggravation of joint destruction with pre–arthritis peak anti‐γ/δ treatment suggests a stage‐dependent protective role of γ/δ T cells in adjuvant arthritis.
Calcific constrictive pericarditis. A rare complication of CREST syndrome
Authors: Panchal Prerana , Adams Elaine , Hsieh Annming
Published: February 2007

This report describes a patient with limited cutaneous scleroderma in whom calcific constrictive pericarditis developed. This complication of limited cutaneous scleroderma has not been reported previously.
Limited heterogeneity of rearranged T cell receptor Vα and Vβ transcripts in synovial fluid T cells in early stages of rheumatoid arthritis
Authors: Fischer Dagmar‐Christiane , Opalka Bertram , Hoffmann Axel , Mayr Wolfgang , Haubeck Hans‐Dieter
Published: February 2007

Objective. The identification of activated T cells in synovial fluid and synovium, and the association of rheumatoid arthritis (RA) with specific HLA–DR restriction elements, strongly suggest that these T cells play a critical role in the etiology and pathogenesis of RA. Analysis of the T cell receptor (TCR) repertoire in the early stages of RA might be an approach to identify those T cells involved in the initiation and/or perpetuation of the disease.

Methods. TCR Vα and Vβ transcripts of synovial T cells, sampled at the early stages of RA, were amplified by reverse transcriptase–polymerase chain reaction. HLA–DR subtyping was determined by serologic analysis and dot‐blot hybridization of polymerase chain reaction amplification products using digoxigenin‐labeled, sequence‐specific oligonucleotide probes.

Results. Our findings showed a limited heterogeneity of Vα and Vβ TCRs in synovial fluid T cells, and a preferential usage of TCR Vα17 in early RA. In contrast, in the later stages of RA, a more polyclonal TCR V α and V β gene usage was observed.

Conclusion. Our results support the view that induction of RA is driven by an oligoclonal immune response to an unknown antigen. These findings also suggest a pathogenetic role for Vα17 T cells in the early stages of RA.
src‐related tyrosine kinases regulate transcriptional activation of the interstitial collagenase gene, MMP‐1, in interleukin‐1‐stimulated synovial fibroblasts
Authors: Vincenti Matthew P. , Coon Charles I. , White Lori Anne , Barchowsky Aaron , Brinckerhoff Constance E.
Published: February 2007

Objective. To characterize tyrosine kinases that contribute to the transcription of interstitial collagenase.

Methods. Four thousand six hundred fourteen basepairs of the rabbit collagenase promoter region were cloned and sequenced. Plasmids containing collagenase promoter fragments linked to the luciferase reporter gene were transiently transfected into primary rabbit synovial fibroblasts. Regulation of gene activation by inflammatory mediators and tyrosine kinase inhibitors was assessed. To identify specific tyrosine kinases that contribute to collagenase gene expression, v‐src was transiently expressed in rabbit synovial fibroblasts along with collagenase promoter constructs, and basal and interleukin‐1 (IL‐1)‐induced collagenase transcription was assayed.

Results. An inhibitor of src‐related tyrosine kinases, herbimycin A, inhibited increases of collagenase messenger RNA in IL‐1– and phorbol myristate acetate‐treated fibroblasts. Transcriptional activation of collagenase by IL‐1 was also inhibited by herbimycin A. Expression of v‐src in synovial fibroblasts enhanced basal and IL‐1‐inducible transcription.

Conclusion. Activation of collagenase transcription by inflammatory mediators involves activation of an src‐related tyrosine kinase.
Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis?
Authors: McAlindon Timothy E. , Jacques Paul , Zhang Yuqing , Hannan Marian T. , Aliabadi Piran , Weissman Barbara , Rush David , Levy Daniel , Felson David T.
Published: February 2007

Objective. Cumulative damage to tissues, mediated by reactive oxygen species, has been implicated as a pathway that leads to many of the degenerative changes associated with aging. We hypothesized that increased intake of antioxidant micronutrients might be associated with decreased rates of osteoarthritis (OA) in the knees, a common age‐related disorder.

Methods. Participants in the Framingham Osteoarthritis Cohort Study underwent knee evaluations by radiography at examinations 18 (1983–1985) and 22 (1992–1993). Usual dietary intake was assessed using the Food Frequency Questionnaire, administered at examination 20 (1988–1989). Knees without OA at baseline (Kellgren and Lawrence [K&L] grade ⩾1) were classified as having incident OA if they had a K&L grade ⩽2 at followup. Knees with OA at baseline were classified as having progressive OA if their score increased by ⩽1 at followup. Knees were also classified as having cartilage loss or osteophyte growth if their maximal joint space narrowing or osteophyte growth score increased by ⩽1 (range 0–3). The association of vitamin C, beta carotene, and vitamin E intake, ranked in sex‐specific tertiles, with incidence and progression of OA was compared with that of a panel of nonantioxidant vitamins, B1, B6, niacin, and folate, using logistic regression and generalized estimation equations to adjust for correlation between fellow knees. The lowest tertile for each dietary exposure was used as the referent category. Odds ratios (OR) were adjusted for age, sex, body mass index, weight change, knee injury, physical activity, energy intake, and health status.

Results. Six hundred forty participants received complete assessments. Incident and progressive OA occurred in 81 and 68 knees, respectively. We found no significant association of incident OA with any nutrient. A 3‐fold reduction in risk of OA progression was found for both the middle tertile (adjusted OR = 0.3, 95% confidence interval [95% CI] 0.1–0.8) and highest tertile (adjusted OR = 0.3, 95% CI 0.1–0.6) of vitamin C intake. This related predominantly to a reduced risk of cartilage loss (adjusted OR = 0.3, 95% CI 0.1–0.8). Those with high vitamin C intake also had a reduced risk of developing knee pain (adjusted OR = 0.3, 95% CI 0.1–0.8). A reduction in risk of OA progression was seen for beta carotene (adjusted OR = 0.4, 95% CI 0.2–0.9) and vitamin E intake (adjusted OR = 0.7, 95% CI 0.3–1.6), but was less consistent. No significant associations were observed for the nonantioxidant nutrients.

Conclusion. High intake of antioxidant micronutrients, especially vitamin C, may reduce the risk of cartilage loss and disease progression in people with OA. We found no effect of antioxidant nutrients on incident OA. These preliminary findings warrant confirmation.
Detection of anticentromere antibodies using recombinant human CENP‐A protein
Authors: Sun Dongxu , Martinez Antigona , Sullivan Kevin F. , Sharp Gordon C. , Hoch Sallie O.
Published: February 2007

Objective. To evaluate CENP‐A reactivity with anticentromere antibodies (ACA) using recombinant protein (rCENP‐A).

Methods. Human CENP‐A antigen was overexpressed in insect cells using the baculovirus system. We tested for ACA activity against the full‐length recombinant polypeptide by immunoblot and by enzyme‐linked immunosorbent assay (ELISA).

Results. Of the ACA+ sera studied (n = 38), 95% were positive when tested against the rCENP‐A in the ELISA system. Of the ACA‐ sera (n = 100), only 2% gave false‐positive results in the assay. There was good correlation between the recombinant and bona fide antigens in assaying for ACA reactivity.

Conclusion. CENP‐A is a significant ACA target. The availability of the rCENP‐A assay is a valuable adjunct to the previously described rCENP‐B assay in analyses of the clinical significance of ACA.
In situ hybridization analysis of synovial and systemic cytokine messenger RNA expression in superantigen‐mediated Staphylococcus aureus arthritis
Authors: Zhao Yi‐Xue , Ljungdahl Åke , Olsson Tomas , Tarkowski Andrej
Published: February 2007

Objective. To investigate patterns of synovial and systemic cytokine messenger RNA (mRNA) expression in mice with superantigen‐mediated Staphylococcus aureus arthritis.

Methods. Mice were inoculated intravenously with 1 × 107 colony‐forming units of toxic shock syndrome toxin–1–producing S aureus LS‐1. Synovial tissues and spleens were obtained at varying time intervals after bacterial inoculation, and examined for mRNA expression of interleukin‐1β (IL‐1β), IL‐4, IL‐10, IL‐12, tumor necrosis factor α (TNFα), TNFβ, interferon‐γ (IFNγ), transforming growth factor β, and perforin, by an in situ hybridization technique.

Results. In situ hybridization revealed early synovial up‐regulation of TNFα and IL‐1β mRNA expression. Peak frequencies of these proinflammatory cytokines were observed at the second and third week of the infection. Expression of T cell‐derived cytokine mRNAs was detected later, and in a relatively low frequency. Notably, induction and peak numbers of Th2 cytokine (IL‐4 and IL‐10) mRNA expression preceded Th1 cytokine (IFNγ and TNFβ) mRNAs. In comparison with synovial tissues, peak spleen cytokine mRNA expression of IL‐1β, TNFα, TNFβ, IL‐12, and IFNγ occurred earlier, but displayed a clearly lower magnitude of expression.

Conclusion. These findings demonstrate synovial and systemic up‐regulation of cytokine mRNA expression during S aureus arthritis, indicating that both monocyte/macrophage and T cell–derived products are involved in the pathogenesis of this disease.
Protein metabolism in rheumatoid arthritis and aging. Effects of muscle strength training and tumor necrosis factor α
Authors: Rall Laura C. , Rosen Clifford J. , Dolnikowski Gregory , Hartman Wilburta J. , Lundgren Nancy , Abad Leslie W. , Dinarello Charles A. , Roubenoff Ronenn
Published: February 2007

Objective. To determine the effects of rheumatoid arthritis (RA) on whole‐body protein metabolism.

Methods. We examined protein metabolism and its hormonal and cytokine mediators before and 12 weeks after progressive resistance muscle strength training in 8 healthy young (mean ± SD age 25 ± 2 years) and 8 healthy elderly (70 ± 5 years) men and women, and in 8 adults with RA (42 ± 13 years). An additional 6 healthy elderly subjects (69 ± 3 years) served as a swimming‐only control group.

Results. Subjects with RA had higher rates of protein breakdown than did young or elderly healthy subjects (79.9 ± 17.2 versus 60.3 ± 5.8 and 63.7 ± 12.4 μmoles/gm total body potassium/hour, respectively, P < 0.05), while there was no effect of age per se. Patients treated with methotrexate had normal rates of protein breakdown (P < 0.01 versus RA without methotrexate; P not significant versus healthy young subjects). Increased protein catabolism in RA was no longer evident after strength training. In multiple regression analysis, levels of tumor necrosis factor α (TNFα) (r = 0.47, P = 0.01) and growth hormone (r = ‐0.51, P = 0.006) were associated with protein breakdown, and plasma glucagon levels were inversely correlated with protein synthesis (r = ‐0.45, P = 0.02). Growth hormone (r = ‐0.56, P = 0.002) and glucagon (r = 0.45, P = 0.04), levels were associated with protein oxidation.

Conclusion. Adults with RA have increased whole‐body protein breakdown, which correlates with growth hormone, glucagon, and TNFα production.
Significance of anti–nuclear matrix antibodies in patients with in vivo speckled antinuclear antibody staining
Authors: Deng Jau‐Shyong , Benedict Linda , Deng David H. , Oddis Chester V. , Fratto Jacqueline
Published: February 2007

Objective. Evidence suggests that patients with in vivo speckled antinuclear antibody (ANA) patterns have high titers of circulating ANA, specifically anti–U1 RNP antibody. A small percentage of patients with high titers of anti–U1 RNP antibody have anti–nuclear matrix antibodies, and some also demonstrate in vivo ANA. This study was designed to screen for the presence of antinuclear matrix antibodies in patients with in vivo ANA.

Methods. Anti–nuclear matrix antibodies were detected by indirect immunofluorescence on HCI‐extracted HEp‐2 cell substrate, by enzyme‐linked immunosorbent assay, and by immunoblot analysis.

Results. All 10 patients with in vivo ANA were found to have anti–nuclear matrix antibody demonstrated using HCI‐extracted HEp‐2 cell substrate, and all exhibited antibody activity to a 36‐kd protein from nuclear matrix antigen.

Conclusion. These results suggest that anti–nuclear matrix antibodies are a major factor in the development of in vivo ANA.
Novel autoantibodies directed against the common tertiary configuration of transfer RNA in a patient with interstitial lung disease
Authors: Matsumura Mami , Ohosone Yasuo , Miyachi Kiyomitsu , Akizuki Masashi , Matsuoka Yasuo , Irimajiri Shoichiro , Shimizu Mikio , Mimori Tsuneyo
Published: February 2007

Objective. To identify and characterize a novel autoantibody, anti‐WS, that binds total transfer RNA (tRNA).

Methods. Serum from patient WS, who had polyarthritis, Sjögren's syndrome, Raynaud's phenomenon, and interstitial pulmonary fibrosis, was used in this study. Characteristics of anti‐WS and antibody‐reactive determinants of tRNA were investigated by 32P immuno‐precipitation using HeLa cell RNA and deletion mutants of tRNA transcribed in vitro.

Results. WS serum produced nucleolar and cytoplasmic staining on indirect immunofluorescence. 32P immunoprecipitation assays demonstrated that this serum immunoprecipitated total tRNAs and 5.8S and 5S ribosomal RNAs from 32P‐labeled HeLa cell extract. When deproteinized RNA was used as antigen source, total tRNAs were still precipitated by WS serum. An immunoprecipitation study, using various deletion mutants of Escherichia coli tRNA, demonstrated that both D and T Ψ C loops were needed for antibody binding. Substitution of nucleotide 18G with 18A of E coli tRNA, which is essential in the formation of the tertiary “L” shape of tRNA, inhibited binding by anti‐WS antibodies.

Conclusion. Anti‐WS antibodies are novel auto‐antibodies directed against tRNAs. The antibody binding site is the common L‐shaped tertiary structure conformed by the D loop and T Ψ C loop of tRNA, suggesting that the antibodies are induced by a conserved sequence among all species. Furthermore, these antibodies could be a marker for a newly recognized subset of connective tissue disease.
Health outcomes of two telephone interventions for patients with rheumatoid arthritis or osteoarthritis
Authors: Maisiak Richard , Austin Janet , Heck Louis
Published: February 2007

Objective. The effects of treatment counseling or symptom monitoring telephone intervention strategies on the health outcomes of patients with rheumatoid arthritis (RA) or osteoarthritis (OA), compared with usual care, were assessed.

Methods. A 3‐group, randomized, controlled 9‐month trial was conducted incorporating 405 patients with RA or OA and using the Arthritis Impact Measurement Scales (AIMS2) as the outcome measure.

Results. Analyses of covariance showed that the AIMS2 total health status of the treatment counseling group (effect size = 33, P < 0.01), but not the symptom monitoring group (effect size = 0.21, P = 0.10), was significantly improved, compared with usual care, for both RA and OA patients. The specific types of benefits differed significantly between RA and OA patients. The mean number of medical visits by OA patients in the treatment counseling group was also significantly reduced (P < 0.01).

Conclusion. Telephone contact using the treatment counseling strategy produced significant, but different, health status benefits for RA and OA patients. The symptom monitoring strategy produced modest benefits.
Dactylitis in patients with seronegative spondylarthropathy. Assessment by ultrasonography and magnetic resonance imaging
Authors: Olivieri Ignazio , Barozzi Libero , Favaro Lucio , Pierro Antonella , de Matteis Massimo , Borghi Claudio , Padula Angela , Ferri Silvio , Pavlica Pietro
Published: February 2007

Objective. To establish by means of ultrasound and magnetic resonance imaging (MRI) the role of tenosynovitis and arthritis in determining the “sausage‐like” aspect of finger dactylitis and to compare the results of the 2 examinations.

Methods. Twelve dactylitic fingers and their corresponding normal contralateral fingers belonging to 10 patients who met the Amor criteria for the diagnosis of seronegative spondylarthropathy (SpA) were studied by ultrasonography and MRI.

Results. MRI revealed a significant increase in the volar bone‐to‐skin distance in dactylitic fingers with respect to that of the normal contralateral fingers (P < 0.001). This increase was due to distension of the flexor synovial sheaths (P < 0.00001) by fluid collection. Peritendinous soft tissues were not involved, since these were found to be significantly thicker in the normal fingers (P < 0.05). Of the 36 joints of the 12 dactylitic fingers, only 1 showed capsule distension. Using MRI as the “gold standard,” ultrasonography showed a 100% sensitivity and specificity for flexor tenosynovitis, but lacked sensitivity for joint involvement because it failed to reveal joint capsule distension in the only joint involved. Similarly, physical examination showed a 100% sensitivity and specificity for flexor sheath involvement.

Conclusion. Dactylitis is due to flexor tenosynovitis. Enlargement of the finger joint capsule is not an indispensable condition for the “sausage‐like” feature. Physical examination is a sufficient method for the diagnosis of dactylitis.
Novel autoantibodies against muscle‐cell membrane proteins in patients with myositis
Authors: Stuhlmüller Bruno , Jerez Ricardo , Hausdorf Gert , Barthel Hans‐R. , Meurer Michael , Genth Eckehard , Kalden Joachim R. , Burmester Gerd R.
Published: February 2007

Objective. To search for autoantibodies against muscle cell‐specific surface membrane antigens in patients with inflammatory myopathies.

Methods. A cell enzyme‐linked immunosorbent assay (cell ELISA) using a human rhabdomyosarcoma cell line (TE‐671) was developed and performed in serial dilutions with either nonfixed or fixed cells. A total of 141 different patient sera were tested: 90 from patients with various rheumatic diseases, 12 from patients with cardiomyopathies, 25 from patients with other muscular diseases, and 14 from patients who had undergone major surgery or who had other noninflammatory diseases. As controls, 20 sera were obtained from healthy donors. Results were correlated using immunofluorescence staining and flow cytometry.

Results. Using the nonfixed cell ELISA, the proportions of positive sera from the patient groups with rheumatic diseases were 71% with polymyositis (PM), 15% with dermatomyositis (DM), 18% with systemic sclerosis (SSc), 15% with systemic lupus erythematosus (SLE), and 7% with rheumatoid arthritis. Sera from healthy donors, as well as sera from patients with nonrheumatic diseases, did not show significant reactivities. When other cell lines, including a chondrosarcoma, a bladder carcinoma, a pancreas carcinoma, and human foreskin fibroblasts, were used as substrates, positive sera did not react in the cell ELISA. Results obtained with the cell ELISA system using nonfixed cells were confirmed by flow cytometry and immunofluorescence staining. A strong protein band of 50 kd was detected on plasma membrane preparations from TE‐671 muscle cells in 33% of PM sera (n = 12).

Conclusion. In most sera from patients with PM, DM, and some other rheumatic diseases (i.e., SSc and SLE), autoantibodies directed against muscle‐cell surface antigens can be detected. Since these molecules are localized in the muscle‐cell surface membrane, autoantibodies directed against these antigens could play a major role in the pathogenesis of PM.
Autoimmunity to RNA polymerase II is focused at the carboxyl terminal domain of the large subunit
Authors: Hirakata Michito , Kanungo Jyotshna , Suwa Akira , Takeda Yoshihiko , Craft Joe , Hardin John A.
Published: February 2007

Objective. Previous studies have demonstrated antibodies to the large (220 kd) polypeptide subunit of RNA polymerase II (Pol II) in sera from certain patients with scleroderma. In the present study, we sought to identify the autoantigenic region on this polypeptide.

Methods. A recombinant fusion protein, corresponding to the 52‐heptapeptide repeat found in the carboxyl terminal domain (CTD) of the large Pol II subunit, was used to identify 15 patient sera that contained autoantibodies. Synthetic peptides CTD7 (representing a single heptapeptide) and CTD18 (representing 2½ heptapeptide repeats) were used in a competitive inhibition assay to define the specificity of these sera and the importance of the CTD as an autoantigen.

Results. All 15 sera immunoprecipitated the Pol II subunit from radiolabeled cell extracts, and 11 of them bound the CTD fusion protein in immunoblots. Immunoprecipitation of Pol II was completely inhibited by CTD18 in 5 sera and partially inhibited in 4 additional sera.

Conclusion. These results indicate that the CTD heptapeptide repeat is a focal point for autoimmune responses in scleroderma. It is likely that the repetitive sequence and high content of charged residues of this structure contribute to its role as an autoantigen.