bluuebunny/crossref_metadata_2025 huggingface dataset:
The coexistence of systemic sclerosis and rheumatoid arthritis in five patients. Clinical and immunogenetic features suggest a distinct entity
Authors: Horiki Terumi , Moriuchi Junko , Takaya Masatoshi , Uchiyama Mitsuaki , Hoshina Yuichi , Inada Kenichi , Inoko Hidetoshi , Tsuji Kmiyoshi , Ichikawa Yukinobu
Published: February 2007

To elucidate the clinical characteristics and pathogenesis of scleroderma–rheumatoid arthritis (SSc‐RA) overlap syndrome, we analyzed the clinical features of 5 patients with SSc–RA overlap. Their HLA phenotypes and genotypes were also determined. Generalized skin sclerosis, severe seropositive polyarthritis, pulmonary fibrosis, anti–topoisomerase I antibodies, and HLA–DR4,53;DQA1*0301;DQB1*04 haplotype were observed in all of the patients. Similar clinical features were recognized in most of the 10 cases reported previously. Our case studies indicate that SSc–RA overlap may be a distinct entity.
Rocky mountain spotted fever presenting with acute monarticular arthritis
Authors: Sundy John S. , Allen Nancy B. , Sexton Daniel J.
Published: February 2007

This report describes a 30‐year‐old man who presented with an acute multisystem illness which was diagnosed as Rocky Mountain spotted fever (RMSF). Near the time of admission the patient was noted to have a newly developed aseptic monarticular arthritis of the right knee. The arthritis resolved in association with resolution of his systemic illness. To our knowledge, there have been no prior reports of acute arthritis in association with RMSF.
Recombinant human interleukin‐1 receptor type I in the treatment of patients with active rheumatoid arthritis
Authors: Drevlow Barbara E. , Lovis Rosa , Haag Mary Ann , Sinacore James M. , Jacobs Cindy , Blosche Consuelo , Landay Alan , Moreland Larry W. , Pope Richard M.
Published: February 2007

Objective. To determine the safety and efficacy of recombinant soluble human interleukin‐1 receptor type I (rHuIL‐1RI) administered subcutaneously in patients with active rheumatoid arthritis (RA).

Methods. Twenty‐three patients with active RA (>5 swollen joints) were enrolled into a randomized, double‐blind, 2‐center study. Patients received subcutaneous doses of rHuIL‐1RI or placebo for 28 consecutive days. Patients were treated with 125, 250, 500, or 1,000 μg/m2/day of rHuIL‐1RI. Physical examinations and laboratory assessments were performed at baseline (day 1), and 8, 15, 22, 29, 43, and 57 days after the start of the study. Analysis of peripheral blood by flow cytometry was performed on days 1 and 29 to determine the effects of rHuIL‐1RI on the distribution and phenotypic characteristics of circulating inflammatory cells.

Results. Four of 8 patients who received rHuIL‐1RI at 1,000 μg/m2/day demonstrated improvement in at least 1 of 8 individual measures of disease activity; however, only 1 of these 4 patients experienced clinically relevant improvement as defined by predetermined criteria. None of the patients treated with smaller doses of rHuIL‐1RI, and none of the placebo‐treated control patients, experienced any improvement as defined by the predetermined criteria. Monocyte cell surface IL‐1α was significantly reduced following treatemnt with rHuIL‐1RI at each dosage. Administration of rHuIL‐1RI was stopped prematurely because of dose‐limiting rashes in 2 pateints treated with 1,000 μg/m2/day. No other adverse events prevented completion of the study.

Conclusion. Only 1 patient, who was treated with the highest concentration of rHuIL‐1RI employed (1,000 μg/m2/day), demostrated clinically relevant improvement in this phase I study on this small group of patients with active RA. Dose‐limiting toxicity was also observed in 2 pateints treated with this highest concentration of rHuIL‐1RI. Treatment with rHuIL‐1RI did result in a reduction of monocyte cell surface IL‐1α, which indicates that the dosages of rHuIL‐1RI employed were functional.
Rheumatoid arthritis in a United States Public Health Service Hospital in Oklahoma. Serologic manifestations in rheumatoid arthritis vary among tribal groups
Authors: Scofield R. Hal , Fogle Mark , Rhoades Everett R. , Harley John B.
Published: February 2007

Objective. To study the serologic manifestations of rheumatoid arthritis (RA) at a United States Public Health Service Hospital that serves numerous tribes in Oklahoma.

Methods. Forty‐five patients with RA were identified, and serologic studies for antinuclear antibody (ANA), rheumatoid factor, and antibodies to extractable nuclear antigens were performed. Extraarticular manifestions of RA were also evaluated.

Results. Twelve of the 45 patients with RA were Kiowa. These patients were significantly more likely to have a positive ANA (75%) than the other patients with RA (28%). In addition, anti‐Ro was significantly more common among Kiowa (33%) than among members of other tribes (3%). There was no difference in the extraarticular manifestions of the Kiowa compared with the other Native American tribes.

Conclusion. RA can be distinctly characterized by serology among groups of American Indians living in the same geographic area.
Nonsteroidal antiinflammatory drug–induced enteropathy and severe chronic anemia in a patient with rheumatoid arthritis
Authors: Davies Neal M. , Jamali Fakhreddin , Skeith Kenneth J.
Published: February 2007

This report describes the case of a woman who was admitted to the hospital with severe anemia and refractory rheumatoid arthritis. She had been transfusion dependent for 8 years and was receiving a combination of indomethacin and naproxen. An indium‐111 white blood cell scan revealed small bowel inflammation. Salsalate was substituted for her previous nonsteroidal antiinflammatory drugs (NSAIDs), and metronidazole was initiated. This resulted in maintenance of a normal hemoglobin level for at least 1 year after discharge. Small intestine inflammation and bleeding (enteropathy) due to NSAIDs must be considered in the evaluation of anemia in patients with arthritis.
The effect of progressive resistance training in rheumatoid arthritis. Increased strength without changes in energy balance or body composition
Authors: Rall Laura C. , Meydani Simin Nikbin , Kehayias Joseph J. , Dawson‐Hughes Bess , Roubenoff Ronenn
Published: February 2007

Objective. To demonstrate the feasibility of high‐intensity progressive resistance training in rheumatoid arthritis (RA) patients compared with healthy control subjects.

Methods. Eight subjects with RA, 8 healthy young subjects, and 8 healthy elderly subjects underwent 12 weeks of high‐intensity progressive resistance training, while 6 elderly subjects performed warm‐up exercises only. Fitness, body composition, energy expenditure, function, disease activity, pain, and fatigue were measured at baseline and followup.

Results. All 3 training groups demonstrated similar improvements in strength compared with the change among control subjects (RA group 57% [P < 0.0005], young exercise group 44% [P < 0.01], elderly exercise group 36% [P < 0.05]). Subjects with RA had no change in the number of painful or swollen joints but had significant reductions in self‐reported pain score (21% [P < 0.05]) and fatigue score (38% [P = 0.06]), improved 50‐foot walking times (mean ± SD 10.4 ± 2.2 seconds versus 8.3 ± 1.5 seconds [P < 0.005]), and improved balance and gait scores (48.9 ± 3.8 versus 50.4 ± 2.0 [P = 0.07]).

Conclusion. High‐intensity strength training is feasible and safe in selected patients with well‐controlled RA and leads to significant improvements in strength, pain, and fatigue without exacerbating disease activity or joint pain.
Polymyositis, arthritis, and uveitis in a macaque experimentally infected with human T lymphotropic virus type I
Authors: Beilke Mark A. , Traina‐Dorge Vicki , England John D. , Blanchard James L.
Published: February 2007

Objective. To establish a simian model of human T lymphotropic virus type I (HTLV‐I) infection and disease.

Methods. Irradiated HTLV‐I–producing cells were used to infect two 2‐year‐old rhesus macaque monkeys (Macaca mulatta). One monkey was also simultaneously inoculated with a cell‐free suspension of simian immunodeficiency virus (SIV). Evidence of infection was monitored by serial clinical examinations and by serologic, molecular, and virologic assays.

Results. Both HTLV‐I‐inoculated monkeys became persistently infected following inoculation. Clinical disease was observed in the singly inoculated monkey, which developed arthritis (with synovial fluid positive for HTLV‐I by culture and polymerase chain reaction), anterior chamber uveitis, and steroid‐responsive polymyositis confirmed by electrophysiologic studies. The dually inoculated animal remained clinically healthy, despite high levels of SIV and HTLV‐I virus expression and loss of HTLV‐I‐specific antibodies.

Conclusion. These results indicate the utility of a nonhuman primate model for studying HTLV‐I disease pathogenesis and the dynamics of SIV‐1/HTLV‐I retroviral coinfection.
Elevated levels of the soluble form of bone marrow stromal cell antigen 1 in the sera of patients with severe rheumatoid arthritis
Authors: Lee Byung Ok , Ishihara Katsuhiko , Denno Kakuro , Kobune Yoshiko , Itoh Motoyuki , Muraoka Osamu , Kaisho Tsuneyasu , Sasaki Takeshi , Ochi Takahiro , Hirano Toshio
Published: February 2007

Objective. Bone marrow stromal cell antigen 1 (BST‐1) is a novel glycosyl phosphatidylinositol–anchored ectoenzyme, which is overexpressed on bone marrow stromal and synovial cell lines derived from patients with rheumatoid arthritis (RA). To investigate the pathophysiologic roles of BST‐1 in RA, we established an enzyme‐linked immunosorbent assay (ELISA) system to detect the soluble form of BST‐1 (sBST‐1) and examined levels of sBST‐1 in the sera of RA patients.

Methods. Concentrations of sBST‐1 in sera from healthy donors and from patients with RA, osteoarthritis, Sjögren's syndrome, and systemic lupus erythematosus were measured with the ELISA.

Results. In 7% of the RA patient samples (10 of 143), concentrations of serum sBST‐1 were higher (∼30–50‐fold) than in non‐RA samples. Serum sBST‐1 concentrations showed no correlation with age, C‐reactive protein level, or rheumatoid factor level. All RA patients with high concentrations of serum sBST‐1 had severe disease with involvement of several large joints.

Conclusion. We believe the measurement of serum sBST‐1 may have prognostic value, but further analysis is necessary to clarify the clinical significance of elevated sBST‐1 in RA.
Accelerated generation of CD14+ monocyte‐lineage cells from the bone marrow of rheumatoid arthritis patients
Authors: Hirohata Shunsei , Yanagida Tamiko , Itoh Kenji , Nakamura Hiroshi , Yoshino Shin'Ichi , Tomita Tetsuya , Ochi Takahiro
Published: February 2007

Objective. To examine the capacity of bone marrow progenitor cells to generate CD14+ cells, in order to assess the role of bone marrow in the pathogenesis of rheumatoid arthritis (RA).

Methods. CD14‐ cells purified from bone marrow specimens of 11 patients with active RA and 8 control patients (osteoarthritis or trauma) were cultured in the presence or absence of granulocyte–macrophage colony‐stimulating factor (GM‐CSF; 100 pg/ml). After incubation for various lengths of time, the cells were analyzed by flow cytometry for expression of CD14 and HLA‐DR.

Results. The spontaneous generation of CD14+ cells from bone marrow CD14‐ progenitor cells was accelerated in RA patients compared with control patients. Moreover, the expression of HLA–DR on the bone marrow–derived CD14+ cells was also accelerated in RA patients compared with controls. GM‐CSF significantly enhanced the generation of CD14+ cells, as well as the expression of HLA–DR, on CD14+ cells of control patients, but not those of RA patients. GM‐CSF levels in the culture supernatants of bone marrow CD14‐ cells were not significantly different between RA patients and control patients (undetectable in most cases).

Conclusion. These observations strongly support the hypothesis that the accelerated generation of CD14+ cells from bone marrow progenitor cells and the accelerated maturation of such CD14+ cells into HLA–DR+ cells play an important role in the pathogenesis of RA. Moreover, the data suggest a functional alteration of RA bone marrow CD14‐ cells in their responsiveness to GM‐CSF.
Outcome in patients with early rheumatoid arthritis treated according to the “sawtooth” strategy
Authors: Möttönen Timo , Paimela Leena , Ahonen Jari , Helve Tapani , Hannon Pekka , Leirisalo‐Repo Marjatta
Published: February 2007

Objective. To investigate the outcome of early rheumatoid arthritis (RA) when treated according to the “sawtooth” strategy, and to compare the results with the findings of other studies.

Methods. In this prospective study, 142 patients with early RA were treated actively with slow‐acting antirheumatic drugs (SAARDs) for an average of 6.2 years, and were closely monitored clinically. Several outcome measures were applied, and the results were compared with findings in previously described cohorts.

Results. The mean cumulative number of SAARDs used during the study was 3.3. Treatment changes were made because of inefficacy more often than because of adverse events. The percentage of patients whose disease entered remission increased with time to 32% (45 of 142). Only 24% of the patients (34 of 142) had deterioration to Steinbrocker functional class III or IV. The “sawtooth” treatment strategy seemed to improve the outcome of the patients with early RA.

Conclusion. In the majority of patients with early RA, “sawtooth” therapy remains beneficial for at least 6 years. However, in one‐fourth of the patients, the disease fails to respond to this drug treatment strategy.
Childhood‐onset scleroderma: Is it different from adult‐onset disease?
Authors: Vancheeswaran Rama , Black Carol M. , David Joel , Hasson Nathan , Harper John , Atherton David , Trivedi Premila , Woo Patricia
Published: February 2007

Objective. To distinguish childhood‐onset scleroderma from adult‐onset disease.

Methods. The clinical and serologic features of 58 patients with childhood‐onset scleroderma (11 patients with diffuse cutaneous systemic sclerosis [SSc], 16 with linear SSc, 14 with linear morphea, and 17 with morphea) were examined in the largest cohort of such patients studied to date. These parameters were compared with data obtained from patients with adult‐onset disease.

Results. Childhood‐onset scleroderma resembled adult‐onset disease with regard to the heterogeneity of clinical expression and subsets of disease, but it also differed from adult‐onset disease in a number of clinical and laboratory parameters. The predominant childhood‐onset disease presentation was the localized form of the disease, with limited and diffuse SSc being less notable. There was a significant association of trauma with childhood‐onset scleroderma (P < 0.0001), which was not noted in adult‐onset disease. Furthermore, in contrast to adult disease, patients with childhood‐onset disease had normal levels of parameters of vascular activation (von Willebrand factor, angiotensin‐converting enzyme, E‐selectin, and endothelin‐1), T cell activation (soluble interleukin‐2 receptors), and collagen synthesis (carboxy‐terminal type I and aminoterminal type III), a notable lack of anticentromere antibodies, and abnormal coagulation indices.

Conclusion. A number of features distinguish childhood‐onset scleroderma from adult‐onset disease.
Pyoderma gangrenosum in association with undifferentiated seronegative spondylarthropathy
Authors: Olivieri Ignazio , Costa Angela Maria , Cantini Fabrizio , Niccoli Laura , Marini Raffaela , Ferri Silvio
Published: February 2007

The cases of 2 women with pyoderma gangrenosum (PG) and undifferentiated seronegative spondylarthropathy (SpA) are described. These 2 cases, together with the recently reported case of PG and B27‐positive psoriatic spondylarthropathy, suggest that PG may also occur in association with forms of seronegative SpA that are different from primary ankylosing spondylitis (AS) and AS associated with inflammatory bowel disease.
Monoclonal cryo‐antifibrinogenemia
Authors: Euler Hans H. , Zeuner Rainald A. , Béress Rosemarie , Gutschmidt Hans J. , Christophers Enno , Schroeder Johann O.
Published: February 2007

We report on a 54‐year‐old female patient with arthritis and a severe cold‐induced leukocytoclastic vasculitis of the skin caused by a rare form of cryofibrinogenemia (“type II” cryofibrinogen). Affinity chromatography of cryoprecipitates from the patient's plasma revealed reversible cryoprecipitability of complexes composed of fibrinogen and a monoclonal antifibrinogen antibody (IgG3k). Conventional serum and plasma electrophoresis did not detect the paraprotein. Control of symptoms was achieved by long‐term plasmapheresis.
Inhibition of fas antigen‐mediated apoptosis of rheumatoid synovial cells in vitro by transforming growth factor β1
Authors: Kawakami Atsushi , Eguchi Katsumi , Matsuoka Naoki , Tsuboi Masahiko , Kawabe Yojiro , Aoyagi Takahiko , Nagataki Shigenobu
Published: February 2007

Objective. To investigate the mitogenic and anti‐apoptotic effects of transforming growth factor β1 (TGFβ) on rheumatoid synovial cells in vitro.

Methods. Synovial cells were cultured with or without TGFβ1. After incubation, the proliferative response of synovial cells and the expression of Fas antigen and bcl‐2 on synovial cells were examined. Finally, Fas antigen‐mediated apoptosis of synovial cells was investigated by the addition of anti‐Fas antibody.

Results. TGFβ1 enhanced the proliferation of synovial cells in a dose‐dependent manner. In addition, Fas antigen expression on synovial cells was inhibited by the addition of TGFβ1 with up‐regulation of bcl‐2 expression. The addition of anti‐Fas antibody induced synovial cell apoptosis. However, stimulation of synovial cells with TGFβ1 became markedly resistant to Fas antigen‐mediated apoptosis. The results were not affected by the addition of a neutralizing antibody to platelet‐derived growth factor type AA (PDGF‐AA), which suggests that the effect of TGFβ1 on synovial cells was promoted via PDGF‐AA‐independent mechanisms.

Conclusion. Our results suggest that TGFβ1 promotes synovial cell proliferation through its mitogenic effect on synovial cells and interference with the apoptotic process mediated by the Fas antigen, resulting in the perpetuation of the synovial hyperplasia in patients with rheumatoid arthritis.
Detection of autoantibodies to nucleolar transcription factor NOR 90/hubf in sera of patients with rheumatic diseases, by recombinant autoantigen–based assays
Authors: Fujii Takao , Mimori Tsuneyo , Akizuki Masashi
Published: February 2007

Objective. We attempted to clarify the clinical characteristics of Japanese patients with autoantibodies to nucleolar transcription factor NOR 90/hUBF (anti‐NOR 90) and to analyze the autoantigenic epitopes recognized by anti‐NOR 90.

Methods. Ninety‐one patient sera containing anti‐nucleolar antibodies (ANoA) by indirect immunofluorescence were collected. Immunoblottings were performed using recombinant fusion proteins expressed from several cloned complementary DNA (cDNA) encoding the NOR 90/hUBF autoantigen.

Results. Anti‐NOR 90 were detected in sera from 9 (9.9%) of 91 patients with ANoA. Seven of these patients were diagnosed as having Sjögren's syndrome, 4 had concomitant rheumatoid arthritis, I had concomitant systemic sclerosis (SSc), and 2 had SSc alone. All 9 sera were reactive with more than 2 recombinant fusion proteins from cDNA encoding separate regions on the hUBF polypeptide.

Conclusion. The results suggest that while anti–NOR 90 antibodies are rare, they are associated with Sjögren's syndrome in Japanese patients, and that autoimmunity is targeted toward at least 2 separate regions (amino acids 89–310 and 310–633) of the hUBF polypeptide.
All‐trans‐retinoic acid in poems syndrome. Therapeutic effect associated with decreased circulating levels of proinflammatory cytokines
Authors: Authier François‐Jerome , Belec Laurent , Levy Yves , Lefaucheur Jean‐Pascal , Defer Gilles‐Louis , Degos Jean‐Denis , Gherardi Romain K.
Published: February 2007

Chronically elevated serum levels of proinflammatory cytokines is a feature of the syndrome known as POEMS (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal [M] protein, skin changes). A patient had a POEMS syndrome with thrombocytosis and biclonal gammopathy and was treated as follows: all‐trans‐retinoic acid (tretinoin) at 90 mg/day for 50 days, no treatment for 70 days, readministration of tretinoin at 75 mg/day for 180 days. Focal bone lesion irradiation was performed from day 26 to day 50. Serum levels of interleukin‐6 (IL‐6), tumor necrosis factor a (TNFα), and IL‐1β normalized within 7 days after the first administration of tretinoin, transiently increased at the time of radiotherapy, increased again after withdrawal of the tretinoin, and decreased again after its reintroduction. The platelet count and gammopathy paralleled the changes in the cytokine levels. This study documents in vivo the ability of all‐trans‐retinoic acid to down‐regulate the release of IL‐6, IL‐1β, and TNFα, and illustrates its potential as a therapeutic agent in conditions associated with chronic overproduction of proinflammatory cytokines.
Epitope analysis of the major reactive region of the 100‐kd protein of PM‐Scl autoantigen
Authors: Ge Qun , Wu Yajuan , James Judith A. , Targoff Ira N.
Published: February 2007

Objective. To localize the epitope(s) bound by anti–PM‐Scl antibodies in the N‐terminal half of the 100‐kd protein, the major antigen of the PM‐Scl complex.

Methods. Investigations were performed by immunoblotting 20 anti–PM‐Scl positive sera against bacterially expressed, polymerase chain reaction–derived deletion mutants of the S1 fragment (amino acids 11–437), enzyme‐linked immunosorbent assay (ELISA) screening against synthesized serial octapeptides, and ELISA screening, with anti–PM‐Scl positive sera, against a synthesized 21–amino acid peptide covering the active region.

Results. Anti–PM‐Scl positive sera retained full immunoblot activity with fragment 207–436 and most activity with fragment 11–241, but had markedly decreased activity against fragments 236–436 and 11–212, indicating a major epitope in the aa 207–241 region. Fusion proteins with smaller fragments localized this activity between aa 226 and aa 246. Of 42 anti–S1‐positive, anti–PM‐Scl positive sera tested by ELISA against a synthetic peptide of this region, 36 were definitely positive, 4 borderline, and 2 negative. Similar activity was seen with a peptide from which proline 228 was deleted. Three additional epitope areas were found in S1, but each reacted with only a few sera. Anti–PM‐Scl positive sera did not react with any octapeptide spanning the major epitope area (aa 207–246).

Conclusion. The main immunoblot epitope of the PM‐Scl 100‐kd protein is within a central area of 21 aa (aa 226–246), but is longer than the usual linear epitope. This peptide may be useful in patient testing. Three minor epitopes in S1 may also be recognized by some sera.
Addition of corticosteroids to antibiotic treatment ameliorates the course of experimental Staphylococcus aureus arthritis
Authors: Sakiniene Egidija , Bremell Tomas , Tarkowski Andrzej
Published: February 2007

Objective. To evaluate the combined effect of systemic corticosteroid and antibiotic therapy on the course of septic arthritis.

Methods. The murine model of hematogenously acquired Staphylococcus aureus arthritis was used. Mice were treated with corticosteroids and antibiotics, and were followed up individually. Arthritis was evaluated clinically and histopathologically. Serum samples and bacterial isolates were also analyzed.

Results. The prevalence of arthritis 14 days after the onset of the disease was 22% in the corticosteroid and antibiotic–treated group, as compared with 81% in the control (nontreated) group and 48% in the antibiotic‐treated group. The severity of arthritis also decreased in the corticosteroid and antibiotic‐treated group, as did the mortality rate. Immunohistochemical analysis revealed a dramatic decrease in T cells and macrophages in the synovium of mice that took the combined therapy. The mechanisms leading to this outcome include the inhibitory effect of corticosteroids on T cell and B cell proliferation and differentiation, such as suppression of interferon‐γ (IFNγ) production. Serum levels of IFNγ were decreased 4‐fold in the antibiotic‐treated group compared with the controls; a 15‐fold decrease was observed in the corticosteroid and antibiotic–treated animals. In addition, serum NO3− was significantly decreased in mice treated with antibiotics (P ≤ 0.05), as well as in mice treated with corticosteroids and antibiotics (P ≤ 0.001).

Conclusion. Systemic corticosteroid administration along with antibiotic therapy had beneficial effects on the course and outcome of S aureus arthritis.
High prevalence of serum apolipoprotein E4 isoprotein in rheumatoid arthritis patients with amyloidosis
Authors: Hasegawa Hisashi , Nishi Shin‐Ichi , Ito Satoshi , Saeki Takako , Kuroda Takeshi , Kimura Hideki , Watababe Takeshi , Nakano Masaaki , Gejyo Fumitake , Arakawa Masaaki
Published: February 2007

Objective. To determine whether serum Apolipoprotein E (Apo E) type 4 isoprotein is a risk factor for the development of amyloidosis in patients with rheumatoid arthritis (RA).

Methods. Using isoelectric focusing, we studied Apo E phenotype expression and the corresponding allele frequencies (ϵ2, ϵ3, and ϵ4) in 35 patients with RA and amyloidosis, 65 patients with RA and without amyloidosis, and 63 healthy controls.

Results. The Apo E3/4 phenotype was significantly more common in the group with amyloidosis (31.4%) than in the patients without amyloidosis (12.3%; P < 0.05) or in healthy controls (12.7%; P < 0.05). The frequency of the ϵ4 allele was significantly greater in the group with amyloidosis (0.16) than in the patients without amyloidosis (0.07; P < 0.05) or in healthy controls (0.07; P < 0.05).

Conclusion. The presence of Apo E4 isoprotein may be a risk factor for the development of amyloidosis in patients with RA.
Autoreactivity to human heat‐shock protein 60 predicts disease remission in oligoarticular juvenile rheumatoid arthritis
Authors: Prakken A. B. J. , van Eden W. , Rijkers G. T. , Kuis W. , Toebes E. A. , de Graeff‐Meeder E. R. , van der Zee R. , Zegers B. J. M.
Published: February 2007

Objective. To determine whether T lymphocyte reactivity to endogenous human hsp60 plays a regulatory role in the course of oligoarticular juvenile rheumatoid arthritis (JRA).

Methods. A prospective, longitudinal study of T cell reactivity to HSP in 15 patients with newly diagnosed HLA‐B27 negative oligoarticular JRA was performed. Results were compared with those in a group of 20 patients with newly diagnosed polyarticular or systemic JRA or with acute arthritis caused by other systemic diseases or viral infections, as well as with those in a group of 9 healthy control subjects.

Results. In 86% of the patients with oligoarticular JRA (13 of 15), significant T lymphocyte proliferative responses to hsp60 were found in peripheral blood mononuclear cells and/or synovial fluid mononuclear cells within 3 months after the onset of arthritis. Only 5% of the patients in the rheumatologic disease control group (1 of 20) showed such positivity. All patients with oligoarticular JRA and positive responses to human hsp60 developed a remission of their disease within 12 weeks. During this period of remission, blood samples were taken from 8 patients and showed significantly lower and even negative responses to hsp60, compared with active disease, when all 8 patients had good responses.

Conclusion. The results show that significant proliferative responses to human hsp60 can be found early in the course of oligoarticular JRA. Furthermore, these responses correlate with disease activity in such a manner that T cell reactivity to human hsp60 seems to be associated with disease remission.
Abnormal carnitine distribution in the muscles of patients with idiopathic inflammatory myopathy
Authors: Arenas Joaquin , Gonzalez‐Crespo Maria R. , Campos Yolanda , Martin Miguel A. , Cabello Ana , Gomez‐Reino Juan J.
Published: February 2007

Objective. To analyze the levels of free carnitine and carnitine esters in the muscles of patients with inflammatory myopathies.

Methods. Six men and 7 women with inflammatory myopathy and 25 age‐matched healthy controls were studied. Free carnitine and carnitine esters in muscle homogenates were measured by a radiochemical procedure. Muscle histochemical staining and measurement of respiratory chain enzyme activity were also performed.

Results. Eleven patients had muscle carnitine insufficiency. Five of them had subsarcolemmal oxidative accumulations, 5 had lipid droplets, and 4 had defects of the respiratory chain enzyme complexes.

Conclusion. Abnormal distribution of muscle carnitine is present in patients with inflammatory myopathies and could impair muscle function. Coexistent mitochondrial dysfunction may contribute to carnitine insufficiency.
Lymphocyte apoptosis and apoptosis‐associated gene expression in Sjögren's syndrome
Authors: Ogawa Noriyoshi , Dang Howard , Kong Liping , Anaya Juan‐Manuel , Liu George Tye , Talal Norman
Published: February 2007

Objective. To study the mechanism and regulation of apoptosis in peripheral blood T and B lymphocytes from patients with Sjögren's syndrome (SS).

Methods. The mode of in vitro lymphocyte death in the peripheral blood of patients with SS was determined by fluorescence microscopic analysis, terminal deoxynucleotidyl transferase assay, and DNA fragmentation analysis. Apoptotic cell death of T and B cells was determined at 48 hours of culture by fluorescence‐activated cell sorter analysis of propidium iodidestained cells. Messenger RNA (mRNA) expression of bcl‐2, bcl‐x, bax, and c‐myc in T and B cells was determined by enzyme‐linked immunosorbent assaypolymerase chain reaction (ELISA‐PCR). Expression of bcl‐xL and bcl‐xS was determined by Southern blot analysis of PCR products. Gene expression was calculated as the ratio of each gene message to the message of the GAPDH gene. Bcl‐2 protein levels in SS T cells were determined by ELISA.

Results. SS T cells showed increased in vitro apoptosis compared with normal T cells (mean ± SD 12.3 ± 4.5% versus 7.3 ± 2.0%; P < 0.01). Freshly isolated SS T cells showed increased expression of bcl‐2 mRNA compared with normal controls (mean ± SD 1.50 ± 0.65 versus 0.88 ± 0.23; P < 0.05). There was no significant difference in levels of bax or c‐myc mRNA in T cells and B cells between SS patients and normal controls. When SS T lymphocytes were cultured in vitro for 72 hours, Bcl‐2 protein levels decreased with time.

Conclusion. SS T cells showed accelerated apoptosis in vitro. Freshly isolated SS T cells had increased expression of bcl‐2. An increase in death‐promoter signals and decrease in death‐suppressor signals in vitro may have been responsible, in part, for the apoptosis in SS T lymphocytes.
Specificities of human tap alleles for HLA—B27 binding peptides
Authors: Kuipers Jens G. , Raybourne Richard B. , Williams Kristina M. , Zeidler Henning , Yu David Tak Yan
Published: February 2007

Objective. Allelic TAP polymorphism has been linked to susceptibility to Reiter's syndrome and was suggested to influence disease phenotype in HLA‐B27 positive patients with ankylosing spondylitis. In the present study, we examined whether the human TAP alleles functionally differ in their translocation specificity for HLA‐B27‐binding nonamers.

Methods. TAP translocation of a panel of HLA‐B27‐binding peptides was measured with a labeled reporter peptide containing an N‐linked glycosylation acceptor site in streptolysin O‐permeabilized cells with different TAP alleles.

Results. The different human TAP alleles tested did not measurably differ in their peptide specificity.

Conclusion. The polymorphism of human TAP does not affect the translocated repertoire of HLA‐B27 ligands and is therefore unlikely to play a decisive role in the development of HLA‐B27‐associated disease.
Synovial distribution of αd/CD18, a novel leukointegrin. Comparison with other integrins and their ligands
Authors: El‐Gabalawy Hani , Canvin Janice , Ma Guoping M. , van der Vieren Monica , Hoffman Patricia , Gallatin Michael , Wilkins John
Published: February 2007

Objective. To define the synovial distribution of the novel leukointegrin αd/CD18, and compare this with other members of the β2‐integrin family of adhesion molecules, and their counter‐receptors.

Methods. Monoclonal antibodies to the CD3, CD14, CD29, CD68, β2‐integrin, and immunoglobulin supergene families were used to immunohistologically define the distribution of these molecules in synovial tissue samples from normal subjects and osteoarthritis (OA) and rheumatoid arthritis (RA) patients.

Results. The normal synovial lining cell layer (SLC) expresses CD68, vascular cell adhesion molecule 1, β1‐integrin (CD29), the β2‐integrins CD11b/CD18 (αm/β2, Mac‐1), and α/CD18, whereas CD11a/CD18 (αL/β2, lymphocyte function‐associated antigen 1) and CD11c/CD18 (αx/β2, gp150/95) expression is generally absent. In RA synovitis, expression of β2‐integrins in the SLC increases in proportion to the degree of hyperplasia. The ratio of cells in the SLC which express CD11c/CD18 increases substantially, approaching that of CD11b/CD18 and αd/CD18, while there is minimal increase in CD11a/CD18 expression. In the sublining areas of the tissues, aggregates and diffuse infiltrates of CD3/CD11a/ICAM‐3+ lymphocytes are interspersed among CD68/CD14/CD11b/αd+ macrophages. A number of aggregates demonstrate intense αd staining of the lymphocytes. The synovial endothelium variably expresses intercellular adhesion molecule‐1 (ICAM‐1), ICAM‐2, and vascular cell adhesion molecule 1 (VCAM‐1), with minimal evidence of ICAM‐3 expression.

Conclusion. The leukointegrin αd/CD18 is expressed constitutively by synovial macrophages and macrophage‐like lining cells. In rheumatoid synovitis, the intense coexpression of this integrin and its known counter‐receptor, ICAM‐3, in the inflammatory infiltrates, suggests a potential role for this adhesion pathway in cellular interactions occurring the synovium.
Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation
Authors: Mahmud Taher , Rafi Sue S. , Scott David L. , Wrigglesworth John M. , Bjarnason Ingvar
Published: February 2007

Objective. There is a lack of correlation between cyclooxygenase (COX) inhibition and nonsteroidal antiinflammatory drug (NSAID)—induced gastrointestinal (GI) damage; it has been suggested that mucosal damage may be initiated by a “topical” action of NSAIDs involving mitochondrial injury. We evaluated the effect of a range of NSAIDs and related compounds on mitochondrial function and assessed the differences between them in relation to their physicochemical properties.

Methods. Stimulation of respiration, as an indicator of mitochondrial uncoupling, was measured in isolated coupled rat liver mitochondrial preparations, using an oxygen electrode.

Results. Conventional NSAIDs and acidic prodrugs all had stimulatory effects on mitochondrial respiration at micromolar concentrations (0.02–2.7 μM); higher concentrations were inhibitory. The uncoupling potency was inversely correlated with drug pKa (r = −0.87, P < 0.001; n = 12). Drugs known to have good GI tolerability, including modified flurbiprofen (dimeroflurbiprofen and nitrobutyl‐flurbiprofen), nabumetone (a non‐acidic prodrug), and non‐acidic highly selective COX‐2 inhibitors, did not cause uncoupling.

Conclusion. The ability to uncouple mitochondrial oxidative phosphorylation is a common characteristic of antiinflammatory agents with an ionizable group. Modification or absence of an ionizable moiety reduces the effect on mitochondria and could lead to improved NSAID GI safety.
Analysis of cognitive and psychological deficits in systemic lupus erythematosus patients without overt central nervous system disease
Authors: Kozora Elizabeth , Thompson Laetitia L. , West Sterling G. , Kotzin Brian L.
Published: February 2007

Objective. To examine cognitive and psychological functioning in relation to antiribosomal P protein autoantibodies in patients with systemic lupus erythematosus (SLE) who had no previous history of central nervous system disease (non‐CNS SLE).

Methods. Comprehensive neuropsychological and psychological tests were administered to 51 non‐CNS SLE patients, 29 rheumatoid arthritis (RA) patients, and 27 healthy controls.

Results. Twenty‐nine percent of the non‐CNS SLE patients, 31% of the RA patients, and 11% of the control subjects were classified as cognitively impaired. Similar reductions in intelligence, attention, and fluency were detected in the non‐CNS SLE and RA patients compared with controls. The non‐CNS SLE patients showed a distinct deficit in learning compared with the RA and control groups. Forty‐two percent of the non‐CNS SLE patients demonstrated psychological distress, compared with 7% of the RA patients and 6% of the controls. In the patient groups, neither cognitive dysfunction nor psychological distress was associated with disease activity or prednisone dosage. Elevated serum levels of autoantibodies to ribosomal P protein were not associated with either psychological or cognitive abnormalities.

Conclusion. These results suggest that certain cognitive deficits in non‐CNS SLE patients may not be specific to the immunopathology of SLE. In contrast, it is possible that deficits in learning, as well as psychological distress without major psychiatric pathology, may be subtle manifestations of CNS lupus.
T cell cytokine pattern in the joints of patients with lyme arthritis and its regulation by cytokines and anticytokines
Authors: Yin Zhinan , Braun Jürgen , Neure Lucia , Wu Peihua , Eggens Ulrich , Krause Andreas , Kamradt Thomas , Sieper Joachim
Published: February 2007

Objective. To investigate whether type 1 helper (Th1) or Th2 cytokines are found in the joints of patients with Lyme arthritis, and whether the cytokine pattern can be modulated by cytokines or anticytokines.

Methods. The cytokine pattern in the joints of 10 patients with Lyme arthritis was investigated. Expression of interferon‐γ (IFNγ), tumor necrosis factor α (TNFα), interleukin‐4 (IL‐4), and IL‐10 was measured by enzyme‐linked immunosorbent assay (ELISA), after stimulation of synovial fluid mononuclear cells (SFMC) with Borrelia burgdorferi (Bb) in the supernatant. Expression of cytokine messenger RNA and protein in synovial membrane (SM) and nonstimulated SFMC was studied using semiquantitative reverse transcriptase‐polymerase chain reaction and immunohistologic techniques. The effects of recombinant cytokines or neutralizing anticytokine antibodies on cytokine production in Bb‐stimulated SFMC were investigated by ELISA.

Results. SFMC produced high amounts of IFNγ and TNFα, but little or no IL‐4, upon stimulation with Bb antigen, indicating a Th1‐type cytokine pattern. In SM, IFNγ was detectable in all patients, while the other cytokines were less frequently found. Serial sections of SM revealed that all cytokines were located in the same area. The Th1 response, especially the production of TNFα, could be down‐regulated in vitro by both endogenous and exogenous IL‐10, but not by IL‐4 or anti‐IL‐12.

Conclusion. A Th1‐type cytokine pattern was found in the joints of patients with Lyme arthritis. This Th1 response could be down‐regulated by IL‐10, suggesting insufficient IL‐10 production in vivo.
Prevention of cytokine‐induced changes in leukocyte adhesion receptors by nonsteroidal antiinflammatory drugs from the oxicam family
Authors: García‐Vicuña Rosario , Díaz‐González Federico , González‐Alvaro Isidoro , Del Pozo Miguel A. , Mollinedo Faustino , Cabañas Carlos , González‐Amaro Roberto , Sánchez‐Madrid Francisco
Published: February 2007

Objective. To explore the effect of the nonsteroidal antiinflammatory drugs (NSAIDs) piroxicam and meloxicam on quantitative and qualitative changes in leukocyte adhesion receptors induced by cytokines and other activation stimuli.

Methods. The expression of CD11b and L‐selectin during neutrophil activation with tumor necrosis factor α (TNFα), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), FMLP, phorbol myristate acetate (PMA), and calcium ionophore A23187 was assessed by flow cytometry. Enzyme‐linked immunosorbent assays were used to quantitate soluble L‐selectin shed after neutrophil stimulation. Enzyme release was measured to determine neutrophil degranulation by proinflammatory stimuli. Changes in affinity state of β1 and β2 integrins after neutrophil and T lymphocyte stimulation were assessed, by flow cytometry, using the monoclonal antibodies (MAb) HUTS‐21 (anti‐β1) and CBRM1/5 (anti‐CD11b), which recognize activation‐dependent epitopes on these two integrins.

Results. Pretreatment of neutrophils with either NSAID prevented the changes in L‐selectin and CD11b expression induced by TNFα, GM‐CSF, and FMLP, but not those induced by PMA or A23187. Furthermore, piroxicam significantly decreased the amount of L‐selectin shed by cytokine‐treated neutrophils, whereas it did not exert this effect on PMA‐ or A23187‐treated neutrophils. Piroxicam also decreased the release of gelatinase and lysozyme induced by TNFα, but not by PMA. Interestingly, piroxicam prevented the conformational changes that β2 integrins underwent upon activation of neutrophils: the appearance of the activation epitope of CD11b, detected by the CBRM1/5 MAb, was blocked by piroxicam in TNFα‐treated neutrophils. Moreover, in chemokine‐treated T lymphocytes, the expression of activation epitopes on β1 integrins was also diminished by piroxicam. In contrast, this NSAID did not affect the β1 integrin conformational changes induced by PMA or Mn++.

Conclusion. Our results indicate that members of the oxicam family are able to interfere with events of neutrophil function, such as their degranulation and cytokine‐mediated activation changes in adhesion molecules, both in neutrophils and in lymphocytes. Such effects may significantly contribute to the antiinflammatory activity of these drugs.
Quantitative studies of the risk of serious hepatic injury in persons using nonsteroidal antiinflammatory drugs
Authors: Walker Alexander M.
Published: February 2007

Objective. To quantify the risk of symptomatic hepatic injury associated with nonsteroidal antiinflam‐matory drugs (NSAIDs).

Methods. Five population‐based studies were summarized to evaluate information on more than 1,000,000 patients using NSAIDs.

Results. The risk of clinically apparent liver injury was ˜ 1 case per 10,000 patient‐years of NSAID use. Only sulindac, associated with a 5–10‐fold higher incidence of hepatic injury, differed significantly from other NSAIDs. Patients using diclofenac showed no higher incidence of serious liver disease than did patients using other NSAIDs.

Conclusion. Symptomatic hepatic effects attributable to most NSAIDs are extremely rare and usually mild.
Involvement of nuclear factor kB in the regulation of cyclooxygenase‐2 expression by interleukin‐1 in rheumatoid synoviocytes
Authors: Crofford Leslie J. , Tan Bing , McCarthy Conor J. , Hla Timothy
Published: February 2007

Objective. To evaluate involvement of the transcription factor nuclear factor kB (NF‐kB) in the increased expression of cyclooxygenase‐2 (COX‐2) stimulated by interleukin‐1β (IL‐1β) in primary rheumatoid synoviocytes.

Methods. We treated early‐passage rheumatoid synoviocytes with IL‐1β and examined the time course of NF‐kB translocation to the nucleus by Western blot analysis, as well as NF‐kB binding to the COX‐2 promoter/enhancer by electrophoretic mobility shift assay. We correlated the time course of NF‐kB binding with expression of COX‐2 messenger RNA (mRNA) and protein. Synoviocytes were then treated with either sense or antisense phosphorothioate‐modified oligonucleotides derived from the transcription start site of the human NF‐kB p65 RNA. We analyzed NF‐kB binding to the COX‐2 promoter and COX‐2 protein levels after these treatments.

Results. IL‐1β rapidly stimulated the translocation of the p65, p50, and c‐rel NF‐kB subunits from the cytoplasm to the nucleus. Electrophoretic mobility shift assay demonstrated binding to 2 NF‐kB sites within the COX‐2 promoter/enhancer, with a time course identical to that of nuclear localization of NF‐kB. Supershift analysis revealed that binding activity was due primarily to the p65–p50 heterodimer and the p50 homodimer. With appropriate lag time after NF‐kB binding, COX‐2 mRNA and protein were increased. Pretreatment of RA synoviocytes with NF‐kB p65 antisense oligonucleotides resulted in decreased binding to the COX‐2 promoter and decreased COX‐2 protein expression.

Conclusion. These data demonstrate that signaling via the NF‐kB pathway is involved in regulation of COX‐2 expression induced by IL‐1β in RA synoviocytes.
HLA markers and prediction of clinical course and outcome in rheumatoid arthritis
Authors: Wagner Ulf , Kaltenhäuser Sylke , Sauer Heidemarie , Arnold Sybille , Seidel Wolfram , Häntzschel Holm , Kalden Joachim R. , Wassmuth Ralf
Published: February 2007

Objective. To evaluate HLA markers as early prognostic factors for disease severity in rheumatoid arthritis (RA).

Methods. HLA genotyping was carried out in a retrospective analysis of 66 RA patients and in a prospective study of 55 RA patients and 87 healthy controls using polymerase chain reaction‐based methods for HLA‐DRB1 specificities, DR4 alleles, and their linked DQB1 alleles, as well as HLA‐B27. The clinical course of RA was assessed by clinical and radiologic scores. The impact of HLA markers was evaluated by epidemiologic means in addition to modeling using multiple logistic regression analysis.

Results. Shared epitope‐positive (HVR3+) DR4 alleles and the HVR3 amino acid cassette QKRAA were associated with RA in both longstanding (relative risk [RR] 3.34 and 3.19) and recent‐onset (RR 2.1 and 2.37) RA. In longstanding RA, radiologic evidence of severe joint destruction (Larsen score > 1.62) was seen more often in HVR3 shared epitope‐positive patients than in epitope‐negative patients (odds ratio [OR] = 25.67, X2 = 13.59, P = 0.0003). Moreover, rank sum analysis of Larsen indices indicated significantly higher ranking for the presence of the RA‐associated HVR3 cassettes (QKRAA, QRRAA) when expressed on a DR4 allele (P < 0.0001). In the prospective study, DR4‐positive patients had a significantly increased risk (OR = 13.75, P = 0.00083) of developing bony erosions. In addition, HVR3 epitope‐positive DR4‐positive individuals had significantly higher Larsen indices than did epitope‐negative patients (P = 0.0083). In particular, the presence of the HVR3 epitope on DR4 resulted in an increased a posteriori likelihood (0.91) of developing early erosive disease compared with an a priori risk of 0.62. Conversely, the likelihood decreased to a minimum of 0.35 when the HVR3 epitope was absent.

Conclusion. While the contribution of HLA typing to establishing the diagnosis of RA is limited, HLA‐DR genotyping and DR4 subtype determination provide valuable markers for the prognosis of joint destruction in RA.