bluuebunny/crossref_metadata_2025 huggingface dataset:
AIMS2. The Content and Properties of a Revised and Expanded Arthritis Impact Measurement Scales Health Status Questionnaire
Authors: Meenan Robert F. , Mason John H. , Anderson Jennifer J. , Guccione Andrew A. , Kazis Lewis E.
Published: February 2007

Objective. The goal of this project was to develop a more comprehensive and sensitive version of the Arthritis Impact Measurement Scales (AIMS).

Methods. AIMS scale items were revised, and 3 new scales were added to evaluate arm function, work, and social support. Sections were also added to assess satisfaction with function, attribution of problems to arthritis, and self‐designation of priority areas for improvement. The new instrument was designated the AIMS2. A pilot test of format and content and a performance test of reliability and validity were carried out.

Results. Questionnaire completion times in a pilot study of 24 subjects averaged 23 minutes, and evaluations were positive regarding the instrument's length and ease of completion, and the subjects' willingness to complete serial forms and return them by mail. Measurement performance was tested in 408 subjects: 299 with rheumatoid arthritis (RA) and 109 with osteoarthritis (OA); 45 of these subjects completed a second AIMS2 within 3 weeks. Internal consistency coefficients for the 12 scales were 0.72—0.91 in the RA group and 0.74—0.96 in the OA group. Test‐retest reliability was 0.78—0.94. All within‐scale factor analyses produced single factors, except for mobility level in OA. Validity analyses in both the RA and the OA groups showed that patient designation of an area as a problem or as a priority for improvement was significantly associated with a poorer AIMS2 scale score in that area. Reliability, factor analysis, and validity results were consistent in age, sex, and education subgroups. Satisfaction was moderately correlated with level of function in the same health status area, and the satisfaction items formed a reliable scale. Responses to the arthritis attribution items showed that most dysfunction in this sample was due to arthritis.

Conclusion. The AIMS2 is a revised and expanded health status questionnaire with excellent measurement properties that should be useful in arthritis clinical trials and in outcomes research.
Variable‐Constant Segment Genotype of Immunoglobulin Kappa is Associated with Increased Risk for Rheumatoid Arthritis
Authors: Moxley George
Published: February 2007

Objective. To further investigate the association of rheumatoid arthritis (RA) with a particular genotype identified by a restriction site polymorphism near the constant segment of immunoglobulin kappa (Ck).

Methods. The frequencies of genomic DNA polymorphisms detected within or near Ck (the most Ck‐proximal variable segment [Vk] B3 and a T lymphocyte marker [CD8A]) were determined by Southern blotting and hybridization. The frequencies of coding‐region polymorphisms of Ck (Km allotypes) were determined by amplification by polymerase chain reaction followed by restriction enzyme digestion.

Results. Although the frequencies of B3, Km, and CD8A genotypes were not different between RA and normal control populations, more individuals were homozygous for both Ck and B3 in the RA group (relative risk 2.2, P < 0.01), especially in the DR4‐negative RA subgroup (relative risk 3.9, P < 0.001).

Conclusion. The homozygous genotype of an approximately 30,000‐base region including the Ck segment confers an elevated risk for RA, particularly in the DR4‐negative subgroup.
Detection of Stromelysin and Collagenase in Synovial Fluid From Patients with Rheumatoid Arthritis and Posttraumatic Knee Injury
Authors: Walakovits Lori A. , Moore Vernon L. , Bhardwaj Nina , Gallick Gregory S. , Lark Michael W.
Published: February 2007

Objective. To quantify stromelysin and collagenase in synovial fluid (SF) from patients with rheumatoid arthritis (RA) or traumatic knee injury.

Methods. Stromelysin and collagenase were measured in the SF of 33 patients with RA or posttraumatic knee injury, using specific double‐antibody sandwich enzyme‐linked immunosorbent assays. Stromelysin was fractionated from representative SF, and the molecular form was identified by immunoblot analysis.

Results. The stromelysin concentration was ˜20‐fold higher than the collagenase concentration in the fluids from patients with RA and ˜8‐fold higher in the fluids from patients with traumatic injury. For both metalloproteinases, there was a higher enzyme concentration in RA SF than in the SF from patients with trauma (stromelysin 40.1 ± 26 μ/ml [mean ± SD] in RA SF, 8.5 ± 15 μ/ml in trauma SF; collagenase 2.2 ± 3.3 μ/ml in RA SF, 1.1 ± 2.3 μ/ml in trauma SF). The majority of the stromelysin within the SF bound to reactive red—agarose and was identified as prostromelysin based on electrophoretic mobility and immunoblotting with monospecific antibodies.

Conclusion. The finding of high levels of stromelysin in SF from patients with RA supports the proposal that this enzyme may play a role in the connective tissue degradation observed in this disease.
Long‐Term Prospective Study of Methotrexate in the Treatment of Rheumatoid Arthritis
Authors: Weinblatt Michael E. , Weissman Barbara N. , Holdsworth Donald E. , Fraser Patricia A. , Maier Agnes L. , Falchuk Kenneth R. , Cobly Jonathan S.
Published: February 2007

Objective. To determine the long‐term efficacy and safety of low‐dose methotrexate (MTX) in rheumatoid arthritis (RA).

Methods. Eighty‐four—month open prospective trial at a single academic rheumatology center.

Results. Twenty‐six patients were enrolled in a prospective study of the long‐term efficacy of MTX in RA; a significant improvement had been demonstrated after 36 months of therapy. Twelve patients remained in the study at the 84‐month visit; the mean weekly dosage of MTX was 10.2 mg. A significant improvement was still noted at 84 months in the number of painful joints, number of swollen joints, joint pain index, joint swelling index, and physician and patient global assessments. A 50% improvement in the joint pain index and joint swelling index was observed in more than 80% of the 12 patients still enrolled. A significant reduction in prednisone dosage was achieved; of 14 patients taking prednisone at entry, 7 had discontinued prednisone completely. Fourteen patients withdrew from the study: 10 between 0 and 36 months, and 4 between 36 and 84 months. Toxicity in 3 patients and visit noncompliance in 1 patient were the reasons for withdrawal between 36 and 84 months. At 84 months, 46% of the patients remained in the study; 11.5% had discontinued due to MTX toxicity.

Conclusion. The effectiveness of MTX in the treatment of RA continues to be demonstrated in this prospective study, after 84 months of treatment.
Long‐Term Prospective Study of the Use of Methotrexate in the Treatment of Rheumatoid Arthritis
Authors: Kremer Joel M. , Phelps Carlton T.
Published: February 2007

Objective. To determine and describe the clinical, radiographic, and toxicity profile in a cohort of rheumatoid arthritis patients receiving weekly oral methotrexate (MTX) over a mean period of 90 months, and to compare and contrast these data with our previous data on this cohort, reported after 53 months.

Methods. Prospective, open observational study over a mean treatment period of 90 months (range 79—107 months). Standard clinical and laboratory measures of disease activity were assessed by the same investigator at baseline, 1 month, 3 months, and every 3 months thereafter.

Results. A significant improvement from baseline was maintained in all clinical parameters but the number of tender joints. Toxic reactions were as common in months 54—90 as during the first 53 months. The mean dosage of MTX decreased from 14.6 mg/week at the time of the last report to 11.7 mg/week, while the mean prednisone dosage increased from 1.9 mg/day to 2.1 mg/day. Radiographic scores for erosive disease became statistically significantly different from baseline at year 8, and scores for joint space narrowing differed significantly from baseline at years 5 and 8. Since study entry, 2 patients (6.9%) have experienced MTX pneumonitis.

Conclusion. We conclude that a majority of rheumatoid arthritis patients are able to continue MTX treatment with generally sustained efficacy, for intervals that meaningfully exceed those reported previously.
Timing of Pregnancy in Relation to the Onset of Rheumatoid Arthritis
Authors: Silman Alan , Kay April , Brennan Paul
Published: February 2007

The interval between the onset of rheumatoid arthritis (RA) and the most recent pregnancy prior to RA onset in 88 women was determined. These data were compared with data obtained from a group of 144 age‐matched normal women (controls) who had been assigned a “dummy date for RA onset” for the purposes of analysis. The frequency of disease onset during 3 time intervals within the period from conception to 1 year postpartum was compared with the frequency of disease onset outside this period. There was a reduction in the incidence of disease onset during pregnancy (adjusted odds ratio [OR] 0.30, 95% confidence interval [CI] 0.04—2.6) and a numerically greater increased risk of RA onset during the first 3 months postpartum (OR 5.6, 95% CI 1.8—17.6), which persisted for the subsequent 9 months (OR 2.6, 95% CI 0.8—7.9). A reduction in the incidence of disease onset was seen during all pregnancies; in contrast, the postpartum increase was greater in those with RA onset after the first pregnancy. The reduced incidence of RA onset during pregnancy, with the increased risk postpartum, mirrors the previously described suppression of disease activity during pregnancy and the subsequent flare postpartum in women with established RA. In addition, the increased postpartum risk after the first pregnancy might suggest that in susceptible women, either the hormonal changes or the exposure to the fetus's paternal HLA might represent a risk factor for disease causation.
The Rapid Assessment of Disease Activity in Rheumatology (Radar) Questionnaire
Authors: Mason John Hayes , Anderson Jennifer J. , Meenan Robert F. , Haralson Kathleen M. , Lewis‐Stevens Donna , Kaine Jeffrey L.
Published: February 2007

Objective. This study documents the measurement properties of a brief, self‐administered questionnaire of disease signs and symptoms in patients with rheumatoid arthritis.

Methods. The Rapid Assessment of Disease Activity in Rheumatology (RADAR) questionnaire assesses joint pain/tenderness and clinical status. One hundred ninety‐three pairs of RADAR forms were completed by 45 subjects and their assigned clinician evaluators.

Results. Subject—clinician agreement (intraclass correlation coefficients [ICC]) for joint pain/tenderness and clinical status ranged from 0.52 to 0.87 (P = 0.0001), with 83% ≥0.65. The ICC for change in joint scores over 6 months was 0.83 (P = 0.0001).

Conclusion. The 2‐page RADAR questionnaire produces valid estimates of joint count and clinical status that are sensitive to change.
Linkage Between Rheumatoid Arthritis Susceptibility and the Presence of HLA—DR4 and DRβ Allelic ThIrd Hypervariable Region Sequences in Southern Chinese Persons
Authors: Seglias Jakob , Li Edmund K. , Cohen Michael G. , Wong Raymond W. S. , Potter Paul K. , So Alex K.
Published: February 2007

Objective. To analyze HLA—DR and DQ associations with rheumatoid arthritis (RA) in patients from southern China.

Methods. In 66 patients and 45 controls, restriction fragment length polymorphism studies were performed using DRB, DQA, and DQB probes, and DRB allele—specific typing of polymerase chain reaction—amplified DRB DNA.

Results. The frequency of HLA—DR4 was significantly increased among RA patients (42.4% versus 17.8%). Increased frequencies of the DQA3 allele (77.8% versus 48.9%) and the DQB1*0302 allele (71.0% versus 46.3%), which are in linkage disequilibrium with DR4, were also found. Oligonucleotide typing showed that the amino acid sequence LLEQRRAA, spanning amino acid positions 67—74 of the DRβ molecule, was found in 19 of 49 patients and 5 of 32 controls. The main DR4 allelic subtypes found in the population were DRB1*0404 and DRB1*0405, both of which carried the sequence. There was no difference in subtype distribution between patients and controls.

Conclusion. Chinese RA patients have an increased frequency of HLA—DR4 alleles which possess the same DRB third allelic hypervariable sequence shown to be associated with susceptibility in Caucasian RA patients.
Lack of Superiority of Steroids Plus Plasma Exchange to Steroids Alone in the Treatment of Polyarteritis Nodosa and Churg‐Strauss Syndrome
Authors: Guillevin LOïc , Fain Olivier , Lhote François , Jarrousse Bernard , Huong Du Le Thi , Bussel Annette , Leon Anne
Published: February 2007

Objective.To define the most effective treatment for polyarteritis nodosa (PAN) and Churg‐Strauss syndrome (CSS).

Methods.We conducted a prospective, randomized, multicenter trial in which 78 patients were randomly assigned to receive either prednisone and plasma exchange (group A; n = 36) or prednisone alone (group B; n = 42) as first‐line treatment of PAN and CSS. Patients with hepatitis B virus—related PAN were not included in this study. The end point of the study was control of the disease (recovery and remission) or death.

Results.Clinical symptoms and laboratory findings did not differ statistically in the 2 groups at study entry. Initial control of the disease was similar in both groups. The assigned treatment was stopped in 16 patients because of lack of efficacy. Oral cyclophosphamide or dapsone therapy reversed the disease evolution in 7 of these 10 group A patients and in 4 of these 6 group B patients. At 7 years of followup, 56 patients had completely recovered (27 in group A, 29 in group B), 7 patients were in clinical remission, and 15 patients had died (19.2%; 6 group A patients and 9 group B patients). The prednisone—plasma exchange combination was no more beneficial than corticosteroids alone in preventing relapses over the long term. There was no significant difference in the 7‐year cumulative survival rates of the two groups (83% and 79%, respectively).

Conclusion.Based on our data, we conclude that combined treatment with prednisone and plasma exchange is not superior to treatment with prednisone alone and must not be systematically employed for initial treatment of PAN and CSS. In most cases, cyclophosphamide as second‐line treatment is effective and well tolerated.
Serologic Evaluation of Patients Receiving Procainamide
Authors: Mongey Anne‐Barbara , Donovan‐Brand Rebecca , Thomas T. J. , Adams Louis E. , Hess Evelyn V.
Published: February 2007

This controlled study examined the characteristics of serologic abnormalities in 52 patients receiving procainamide for cardiac arrhythmias, who had no symptoms of a connective tissue disease. Antinuclear antibodies occurred in 43 patients (83%). Significant elevation of antibody binding to single‐stranded DNA (mean ± SEM 30 ± 2.6%), double‐stranded DNA (13 ± 1.1%), Z‐DNA (optical density 0.54 ± 0.06), and poly A (7.2 ± 0.6%) was seen (P < 0.001). Thirty‐four patients (65.4%) had antibodies to total histones, most frequently, the H2A/2B dimer. IgG antibodies to H2A/2B correlated with the cumulative procainamide dose. One patient subsequently developed drug‐related lupus.
Comparison of auranofin, methotreaxate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial
Authors: Williams H. James , Ward John R. , Reading James C. , Brooks Raye H. , Clegg Daniel O. , Skosey John L. , Weisman Michael H. , Willkens Robert F. , Singer Joyce Z. , Alarcón Graciela S. , Field Elizabeth H. , Clements Philip J. , Russell I. Jon , Hochman Rodney F. , Boumpas Dimitrios T. , Marble Dwight A.
Published: February 2007

Objective. To compare the relative safety and efficacy of auranofin (AUR), metbotrexate (MTX), and the combination of both in the treatment of active rheumatoid arthritis (RA).

Methods. Three hundred thirty‐five patients with active RA were entered into a 48‐week, prospective, controlled, double‐blind, multicenter trial and were randomly assigned to 1 of 3 treatment groups.

Results. Two hundred eleven patients completed the trial. No remissions were seen, and there were no statistically significant differences among the treatment groups in the clinical or laboratory variables measured. Patients taking AUR alone had a slower onset of response than did patients taking MTX alone or in combination. Withdrawals because of adverse drug reactions were slightly more common for those taking combination therapy, but the differences were not statistically significant. Withdrawals because of lack of response were more common for single‐drug therapy, with the difference between AUR and the combination reaching statistical significance. No unexpected adverse drug effects were identified, and all reactions resolved without sequelae.

Conclusion. Except for fewer withdrawals because of lack of response, combination therapy did not demonstrate any advantage in efficacy over single‐drug treatment within the time frame of the study.
L‐tryptophan—associated eosinophilic fasciitis prior to the 1989 eosinophilia—Myalgia syndrome outbreak
Authors: Hibbs Jonathan R. , Mittleman Barbara , Hill Paula , Medsger Thomas A.
Published: February 2007

Objective. To investigate the relationship between L‐tryptophan (LT) ingestion and eosinophilic fasciitis (EF) occurring prior to the outbreak of eosinophiliamyalgia syndrome in 1989.

Methods. Interviews and record reviews of 45 EF case‐patients and 126 polymyositis patients (controls) diagnosed prior to 1988.

Results. Nine case‐patients (20%) and no controls recalled taking LT before onset of the disease (odds ratio = ∞, 95% confidence interval = 8.3–∞). Among EF case‐patients, LT ingestion was associated with dyspnea.

Conclusion. LT ingestion was associated with EF prior to the 1989 outbreak of eosinophilia‐myalgia syndrome. Lung abnormalities may be a distinguishing feature of LT‐mediated illness.
Nerve growth factor in the synovial fluid of patients with chronic arthritis
Authors: Aloe Luigi , Tuveri Marco A. , Carcassi Ugo , Levi‐Montalcini Rita
Published: February 2007

Cytokines regulate nerve growth factor (NGF) synthesis during inflammatory processes. Since cytokines are also involved in the inflammatory processes of autoimmune rheumatic diseases, we examined levels of NGF in patients with rheumatoid or other types of chronic arthritis. NGF was present in the synovial fluid and synovium of patients with chronic arthritis, but was undetectable in control fluids. We conclude that NGF might be involved in the pathogenesis of arthritis.
A systematic approach to defining the germline gene counterparts of a mutated autoantibody from a patient with rheumatoid arthritis
Authors: Soto‐Gil Rafael W. , Olee Tsaiwei , Klink Brenda K. , Kenny Thomas P. , Robbins Dick L. , Carson Dennis A. , Chen Pojen P.
Published: February 2007

Objective. To define the germline counterparts of potentially highly mutated autoantibodies in disease states.

Methods. We developed a systematic approach by first characterizing a rearranged Ig gene and its upstream flank, and then designing suitable primers to amplify specifically the putative germline counterpart.

Results. We identified and characterized the germline counterpart of a rheumatoid factor heavy chain variable region.

Conclusion. We showed unequivocally that the heavy chain of a rheumatoid factor, derived from synovial tissue, has 4 replacement mutations from the corresponding germline gene. The technique allows quick assessment of the degree of somatic mutation in many autoantibodies, and thus can help to elucidate the underlying mechanisms for the induction and sustained production of such antibodies in patients.
High percentage of CD8+, Leu‐7+ cells in rheumatoid arthritis synovial fluid
Authors: Burns Christopher M. , Tsai Van , Zvaifler Nathan J.
Published: February 2007

Objective. While analyzing the phenotype of the synovial fluid mononuclear cells (SFMC) clustered about dendritic cells in rheumatoid arthritis (RA) joint effusions, it was noted that most of the clustering cells were CD8+ and coexpressed Leu‐7. Therefore, the present study was conducted to investigate the frequency of CD8+, Leu‐7+ cells in RA SF.

Methods. SFMC from 13 patients with RA and from 12 patients with non‐RA inflammatory arthritides were examined for CD8 and Leu‐7 expression using 2‐color immunofluorescence flow cytometry.

Results. RA SFMC had statistically significantly greater percentages of total CD8+ cells, total Leu‐7+ cells, and CD8+, Leu‐7+ cells, compared with SFMC from the non‐RA patients. These RA CD8+, Leu‐7+ SFMC had a distinctive electron microscopic appearance compared with CD8+, Leu‐7– SFMC. When peripheral blood mononuclear cells (PBMC) from 31 RA patients (including 7 from the SFMC group) were compared with PBMC from 15 normal controls, the percentage of CD8+, Leu‐7+ cells was not significantly greater in the RA patients. However, the combination of a modest increase in CD8+, Leu‐7+ cells and a decrease in total CD8 cells in RA PBMC altered the composition of the RA CD8 population compared with normal PBMC, such that over 40% of RA peripheral blood CD8 cells coexpressed Leu‐7.

Conclusion. The increased frequency of CD8+, Leu‐7+ cells in RA SFMC may arise from the fact that a high percentage of the CD8+ PBMC in RA patients are also Leu‐7+. This altered composition of CD8 cells in RA SF may have a role in the pathogenesis of the disease.
Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline
Authors: Yu Lucino P. , Smith Gerald N. , Brandt Kenneth D. , Myers Stephen L. , O'Connor Brian L. , Brandt David A.
Published: February 2007

Objective. In vitro studies have indicated that levels of neutral metalloproteinases in osteoarthritic (OA) cartilage are elevated and that doxycycline (doxy) inhibits collagenolytic and gelatinolytic activity in extracts of OA cartilage. The purpose of the present study was to test the effect of oral doxy administration on the severity of cartilage degeneration in OA.

Methods. OA was induced in 12 adult mongrel dogs by transection of the anterior cruciate ligament (ACL) 2 weeks after dorsal root ganglionectomy. Six dogs received doxy orally from the day after ACL transection until they were killed 8 weeks later; the other 6 served as untreated OA controls.

Results. The unstable knee of each untreated dog exhibited extensive full‐thickness cartilage ulceration of the medial femoral condyle. In sharp contrast, cartilage on the distal aspect of the femoral condyle of the unstable knee was grossly normal in 2 doxy‐treated dogs, and exhibited only thinning and/or surface irregularity in the others. Degenerative cartilage lesions on the medial trochlear ridge, superficial fibrillation of the medial tibial plateau, and osteophytosis were, however, unaffected by doxy treatment. Collagenolytic activity and gelatinolytic activity in cartilage extracts from OA knees of untreated dogs were 5‐fold and 4‐fold greater, respectively, than in extracts from dogs given doxy.

Conclusion. Prophylactic administration of doxy markedly reduced the severity of OA in weight‐bearing regions of the medial femoral condyle. It remains to be determined whether administration of doxy after OA changes have developed is also effective.
Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases
Authors: Cope Andrew P. , Gibbons Deena , Brennan Fionula M. , Feldmann Marc , Aderka Dan , Doherty Michael , Jones Adrian C. , Engelmann Hartmut , Wallach David , Maini Ravinder N.
Published: February 2007

Objective. Recently, 2 classes of cytokine inhibitors have been defined at the molecular level. The largest group comprises the extracellular domains of cell surface cytokine receptors, and includes both tumor necrosis factor receptors (TNF‐R). The present study was conducted to investigate the role of TNF inhibitors in arthritis.

Methods. We measured p55 and p75 soluble TNF‐R (sTNF‐R) in serum and synovial fluid (SF) samples from patients with rheumatic diseases and compared their levels with levels of soluble interleukin‐2 receptors (sIL‐2R). Sensitive enzyme‐linked immunosorbent assays (ELISA), specific for p55 and p75 sTNF‐R and for sIL‐2R, were used.

Results. Serum levels of p75 sTNF‐R were 3–4‐fold higher than levels of p55 sTNF‐R, and both were significantly elevated in patients with osteoarthritis (OA) and rheumatoid arthritis (RA) compared with healthy controls. RA SF levels of sTNF‐R were 4–5‐fold higher than levels in serum, suggesting local production in the joint, and were significantly higher than levels in the SF of patients with seronegative arthropathy or OA. Furthermore, levels of p55 and p75 sTNF‐R, but not sIL‐2R or TNFα measured by ELISA, were increased in the SF of patients with clinically active RA. The soluble TNF‐R in RA and OA SF were functional since they inhibited TNF activity in a cytotoxicity assay in proportion to the levels of inhibitor present. Evaluation of serially obtained serum samples suggested that sTNF‐R may be a useful parameter for monitoring RA disease activity.

Conclusion. Biologically active soluble TNF‐R are up‐regulated in patients with rheumatic disease and are produced locally in the joints. Measurement of serum levels of TNF‐R may be useful for monitoring of disease, and determination of SF levels could be of diagnostic value.
Changes in anti–U1 RNA antibody levels correlate with disease activity in patients with systemic lupus erythematosus overlap syndrome
Authors: Hoet R. M. , Koornneef I. , van Venrooij W. J. , de Rooij D. J. , van de Putte L. B.
Published: February 2007

Objective. To evaluate correlations between changes in anti–U1 RNA antibody levels and disease activity in 9 patients with systemic lupus erythematosus (SLE) overlap syndrome who were prospectively followed up for at least 3 years.

Methods. Anti–U1 RNA antibody levels were measured quantitatively, using a nitrocellulose filter binding assay. Disease activity was measured with a validated SLE activity index.

Results. All 9 major disease exacerbations were associated with peaks in anti–U1 RNA antibody level.

Conclusion. These results seem to indicate that measuring anti–U1 RNA antibody levels can be useful for monitoring disease activity.
Serum autoantibody to the nucleolar antigen PM‐Scl. Clinical and immunogenetic associations
Authors: Oddis Chester V. , Okano Yutaka , Rudert William A. , Trucco Massimo , Duquesnoy Rene J. , Medsger Thomas A.
Published: February 2007

Objective. The inflammatory myopathies are characterized by distinctive autoantibodies that are associated with certain clinical features and immunogenetic patterns. Anti–PM‐Scl is one such antibody and is found in pure myositis, myositis in overlap, and systemic sclerosis (SSc). Our purpose was to describe the clinical and immunogenetic associations of the anti–PM‐Scl antibody.

Methods. Serum samples from 617 patients with various connective tissue diseases were screened for anti–PM‐Scl antibody by indirect immunofluorescence and Ouchterlony double immunodiffusion. Patients with anti–PM‐Scl were serologically typed for HLA–DR and DQ, and the genes encoding DQα and DQβ were characterized by hybridization of sequence‐specific oligonucleotide to amplified genomic DNA.

Results. Twenty‐three patients (4%) had serum anti–PM‐Scl. Sixteen had either pure myositis or myositis in overlap, 6 had SSc alone, and 1 had SSc and rheumatoid arthritis. Twenty of the antibody‐positive patients had serologic HLA typing performed; 15 (75%) were HLA–DR3 positive, and 17 (85%) expressed the DQw2 allele. None of the 5 DR3 negative patients shared a unique DR or DQ antigen with the DR3 positive patients, and further DNA analysis of 10 patients (4 of whom were DR3 negative) did not reveal any unique DQ alleles.

Conclusion. Anti–PM‐Scl identifies a subset of patients with myositis, SSc, or an overlap of the two disorders, and this antibody has a strong but not exclusive immunogenetic association with the HLA–DR3 antigen.
Activation of gold‐reactive T lymphocytes in rheumatoid arthritis patients treated with gold
Authors: Verwilghen Jo , Kingsley Gabrielle H. , Gambling Lorraine , Panayi Gabriel S.
Published: February 2007

Objective. To assess the role of T lymphocyte sensitization in the etiology of side effects of gold therapy in patients with rheumatoid arthritis (RA).

Methods. Lymphocyte proliferation induced by gold(III) and gold(I) salts was measured in 53 subjects: 30 RA patients with gold‐induced side effects (17 with dermatitis, 9 with proteinuria, 3 with hematologic complications, and 1 with colitis), 9 RA patients without side effects despite prolonged chrysotherapy, 4 RA patients who had never received gold, and 10 healthy controls. Peripheral blood lymphocytes were cultured with the different gold salts and proliferation was measured by 3H‐thymidine incorporation.

Results. Thirteen of the 17 RA patients who developed gold‐induced dermatitis showed significant T lymphocyte proliferation in response to gold(III) salts, and this proliferation could be completely blocked by monoclonal antibodies directed at the HLA—DR molecule. Such proliferative responses were not seen in patients with other gold‐induced side effects, in patients who had never received gold, or in healthy controls. Only 1 of 9 patients who had not developed side effects despite long‐term maintenance chrysotherapy showed significant lymphocyte activation with gold(III) salts. Lymphocyte proliferation could not be induced with gold(I) salts or with other metal salts.

Conclusion. Patients with RA who develop dermatitis following treatment with sodium aurothiomalate [gold(I)] have T cells which proliferate in an HLA—DR—restricted manner in response to HAuCl4 [gold(III)]. We believe this observation can lead to more accurate diagnosis and treatment of side effects, which currently limit the use of one of the most effective antirheumatic drugs.
Ankylosing spondylitis in rochester, minnesota, 1935–1989. Is the epidemiology changing?
Authors: Carbone Laura D. , Cooper Cyrus , Michet Clement J. , Atkinson Elizabeth J. , Michael O'Fallon W. , Joseph Melton L.
Published: February 2007

Objective. To determine trends in the incidence and clinical presentation of ankylosing spondylitis first diagnosed between 1935 and 1989 among residents of Rochester, Minnesota, and in the survival of the patients.

Methods. Population‐based descriptive study.

Results. The overall age‐ and sex‐adjusted incidence rate was 7.3 per 100,000 person‐years (95% confidence interval 6.1–8.4). The rate tended to decline between 1935 and 1989, but there was little change in the age at symptom onset or diagnosis over the 55‐year study period. Overall survival was not decreased up to 28 years following diagnosis.

Conclusion. These data indicate that there is a constancy in the epidemiologic characteristics of ankylosing spondylitis and suggest that previously study results indicating changes may have been due to biases in patient selection and study design.
Antibodies to retroviral proteins in autoimmune connective tissue disease. Relation to clinical manifestations and ribonucleoprotein autoantibodies
Authors: Ranki Annamari , Kurki Pekka , Riepponen Senja , Stephansson Eija
Published: February 2007

Objective. To study the relationship between antibodies that recognize human retroviral proteins and the presence of clinical features and ribonucleoprotein antibodies in patients with autoimmune connective tissue diseases (CTDs).

Methods. Antibodies against native human immunodeficiency virus type 1 (HIV‐1) and human T cell leukemia/lymphoma virus type I, recombinant HIV‐1 Nef protein, and ribonucleoprotein antigens were determined by immunoblot of sera from 65 prospectively studied patients with definite or suspected CTDs of autoimmune type.

Results. Antibodies to retroviral proteins (ARP), most frequently to HIV Gag proteins p55 and p24, were found in 64% of 22 patients with systemic lupus erythematosus (SLE), in 63% of 8 patients with discoid LE (DLE), in 75% of 8 patients with mixed connective tissue disease (MCTD), and in 26% of 19 individuals with chronic biologically false‐positive (CBFP) seroreactions, but not in 8 patients with subacute cutaneous lupus erythematosus. No clear correlation of ARP with antibodies to any specific small nuclear RNP antigen was observed. The most striking finding was that recurrent infections, both in LE patients and in those with CBFP reactions and widespread, acral discoid skin lesions, occurred significantly more often in ARP‐positive patients.

Conclusion. The occurrence of antibodies reacting with human retroviral proteins is associated with severe skin lesions and recurrent infections in SLE, DLE, and MCTD patients, and with a disposition toward developing systemic disease in CBFP reactors.
Induction of synthesis and release of interleukin‐8 from human articular chondrocytes and cartilage explants
Authors: Recklies Anneliese D. , Golds Elaine E.
Published: February 2007

Objective. The activation of neutrophils in the joint space may contribute to the destruction of cartilage matrix observed in rheumatoid arthritis. The capacity of articular chondrocytes to synthesize and secrete interleukin‐8 (IL‐8) and GROα, two potent neutrophil chemoattractant peptides, was investigated to determine whether cartilage itself could serve as a source of these small cytokines.

Methods. Induction of IL‐8 and GRO protein was studied both at the messenger RNA (mRNA) and the protein level by reverse transcriptase/polymerase chain reaction and metabolic labeling, respectively.

Results. Strong induction of IL‐8 was observed in primary cultures of articular chondrocytes as well as in cartilage explants stimulated with IL‐1β. The increased secretion of the IL‐8 protein was accompanied by corresponding increases in mRNA levels. In contrast to other connective tissue cells, a peptide corresponding in molecular size to the GRO proteins was only weakly induced in cartilage explants or primary chondrocyte cultures. However, mRNA for all 3 members of the GRO family was easily detectable in cultured chondrocytes following stimulation with IL‐1β. In explanted cartilage, mRNA for only GROγ was found to be induced. Newly synthesized IL‐8 was slowly released from cartilage explants over a prolonged time in culture.

Conclusion. The results suggest that synthesis and secretion of the diverse members of the IL‐8/GRO family is regulated in a tissue‐specific or cell‐specific manner. The slow release of IL‐8 from articular cartilage following induction by IL‐1β could establish a chemotactic gradient toward the articular surface and mediate the migration and attachment of neutrophils and lymphocytes to this tissue.
Causal link between nucleotide pyrophosphohydrolase overactivity and increased intracellular inorganic pyrophosphate generation demonstrated by transfection of cultured fibroblasts and osteoblasts with plasma cell membrane glycoprotein–1
Authors: Terkeltaub Robert , Rosenbach Michael , Fong Felicia , Goding James
Published: February 2007

Objective. In subjects with idiopathic calcium pyrophosphate dihydrate (CPPD) deposition disease, cartilage chondrocytes elaborate increased amounts of PPi. The mechanism of the intracellular PPi elevation is not known. Plasma membrane 5'‐nucleotide phosphodiesterase I/nucleotide pyrophosphohydrolase (NTPPPH) activity also is elevated in chondrocytes and dermal fibroblasts of patients with idiopathic CPPD deposition disease. NTPPPH, as an ecto‐enzyme, could act within certain intracellular compartments. Thus, we hypothesized a potential causal link between increased NTPPPH activity and increased intracellular PPi.
Methods. Transformed simian fibroblasts (COS cells) and human osteoblasts (U2OS cells) were transfected with the 5'‐nucleotide phosphodiesterase I ectoenzyme plasma cell membrane glycoprotein–1 (PC‐1), recently shown to be expressed in cartilage, osteoblasts, and fibroblasts.
Results. Transfection with PC‐1 markedly upregulated 5'‐nucleotode phosphodiesterase I activity and increased intracellular PPi concentrations by increasing the capacity of cells to generate PPi. Importantly, this did not require supplementation with exogenous nucleotides.
Conclusion. Cellular overexpression of PC‐1 produces NTPPPH overactivity and increased intracellular PPi generation in vitro. These findings support the potential importance of NTPPPH overactivity in Pi generation, both inside and outside the cell, in some subjects with CPPD deposition disease.
Translation and validation of arthritis outcome measures into spanish
Authors: González Virginia M. , Stewart Anita , Ritter Philip L. , Lorig Kate
Published: February 2007

Objective. To produce Spanish versions of common arthritis outcome measures: the Health Assessment Questionnaire (HAQ) Disability Scale, the Center for Epidemiologic Studies Depression Scale (CES‐D), the Medical Outcomes Study (MOS) Pain Severity Scale, the Arthritis Self‐Efficacy Scale for Pain and Other Symptoms (with the addition of 2 new items), the Visual Analogue Pain Scale, the MOS Self‐Rated Health Item, and a Physical Activities Scale that would be usable by most Hispanics living in the US. We tested these translated measures for reliability and, where appropriate, validity.

Methods. Instruments were translated and back translated by bilingual persons from 5 different countries of origin. Translators met to resolve variations in translation. The instruments were then administered to Hispanic arthritis patients in 6 geographic locations (5 in the United States and 1 in Latin America). All instruments underwent standard psychometric testing. As appropriate, the sample was stratified by level of acculturation, nation of origin, and geographic location.

Results. The translated instruments, with slight modification, met acceptable levels of reliability and validity. They are understood and easily usable by diverse Spanish‐speaking populations.

Conclusion. The availability of these translated outcome measures should enable investigators to include monolingual Spanish‐speakers into their studies, and should facilitate study of cross‐cultural differences with respect to these specific outcomes.
Reduction of synovial inflammation after anti‐cd4 monoclonal antibody treatment in early rheumatoid arthritis
Authors: Tak Paul P. , Van Der Lubbe Peter A. , Cauli Alberto , Daha Mohamed R. , Smeets Tom J. M. , Kluin Philip M. , Meinders A. Edo , Yanni Ghada , Panayi Gabriel S. , Breedveld Ferdinand C.
Published: February 2007

Objective. To study the effect of chimeric anti‐CD4 monoclonal antibody (MAb) therapy on synovial inflammation, in order to interpret the clinical experience with anti‐CD4 treatment.

Methods. The immunohistologic features of synovial biopsy specimens before and 4 weeks after anti‐CD4 MAb (cM‐T412) therapy were studied in patients with rheumatoid arthritis. The patients received intravenous doses of either placebo (n = 1) or 10 mg (n = 4), 25 mg (n = 2), or 50 mg (n = 1) of cM‐T412 daily for 5 consecutive days.

Results. Although the patients did not experience clinical improvement, significant decreases in the number of circulating CD4+ cells, the degree of synovial inflammatory infiltration, and the mean scores for expression of adhesion molecules were found in the 7 patients 4 weeks after receiving cM‐T412. The scores for infiltration with CD4+ and other inflammatory cells were particularly reduced following treatment with either 25 mg or 50 mg cM‐T412. Cytokines, such as interleukin‐1β and tumor necrosis factor α, could still be detected in the synovial tissue after treatment.

Conclusion. The decline in the numbers of inflammatory cells and adhesion molecules in synovial tissue after CD4+ cell depletion supports the view that CD4+ T cells orchestrate local cellular infiltration. The lack of clinical effect of anti‐CD4 therapy might be explained by an insufficient decrease in the number of synovial CD4+ cells and by the persistence of cytokines. Determination of whether more adequate dosing would lead to a clinical improvement must await further study.
The incidence and natural history of knee osteoarthritis in the elderly, the framingham osteoarthritis study
Authors: Felson David T. , Zhang Yuqing , Hannan Marian T. , Naimark Allan , Weissman Barbara N. , Aliabadi Piran , Levy Daniel
Published: February 2007

Objective. To determine the incidence of radiographic knee osteoarthritis (OA) and symptomatic OA (symptoms plus radiographic OA), as well as the rate of progression of preexisting radiographic OA in a population‐based sample of elderly persons.

Methods. Framingham Osteoarthritis Study subjects who had knee radiographs and had answered questions about knee symptoms in 1983–1985 were reexamined in 1992–1993 (mean 8.1‐year interval) using the same protocol. Subjects were defined as having new (incident) radiographic OA if they developed grade ≤2 OA (at least definite osteophytes or definite joint space narrowing). New symptomatic OA was present if subjects developed a combination of knee symptoms and grade ≤2 OA. Progressive OA was diagnosed when radiographs showing grade 2 disease at baseline showed grade ≤3 disease on followup.

Results. Of 1,438 participants in the original study, 387 (26.9%) died prior to followup. Of the 1,051 surviving subjects, 869 (82.7%) participated in the followup study (mean ± SD age 70.8 ± 5.0 at baseline). Rates of incident disease were 1.7 times higher in women than in men (95% confidence interval [CI] 1.0–2.7), and progressive disease occurred slightly more often in women (relative risk = 1.4; 95% CI 0.8–2.5) but rates did not vary by age in this sample. Among women, approximately 2% per year developed incident radiographic disease, 1% per year developed symptomatic knee OA, and about 4% per year experienced progres‐ sive knee OA.

Conclusion. In elderly persons, the new onset of knee OA is frequent and is more common in women than men. However, among the elederly, age may not affect new disease occurrence or progression.
Which outcome measures should be used in rheumatoid arthritis clinical trials?.
Authors: Buchbinder Rachelle , Bombardier Claire , Yeung Maria , Tugwell Peter
Published: February 2007

Objective. To determine the discriminant validity of the core set of outcome measures proposed by the American College of Rheumatology (ACR) and the Outcome Measures in Clinical Trials (OMERACT) conference committee to be used in clinical trials of rheumatoid arthritis (RA).

Methods. Utilizing data from a multicenter randomized double‐blind clinical trial of low‐dose cyclosporine and placebo in RA, we estimated the relative efficiency (RE) of measures to detect a treatment effect (relative to tender joint count, which was assigned a value of 1). Four pain measures (10‐cm visual analog scale [VAS], 5‐point categorical scale, Health Assessment Questionnaire [HAQ] pain index, Arthritis Impact Measurement Scales [AIMS] pain score) and 3 quality‐of‐life measures (Problem Elicitation Technique [PET], HAQ, AIMS) were compared.

Results. Physician and patient global measures were the most responsive instruments, although neither was statistically superior to tender joint count. Swollen joint count, grip strength, pain measured on a 10‐cm VAS, and functional status as measured by the PET and HAQ were all of intermediate responsiveness. Morning stiffness, 5‐point pain scale, and erythrocyte sedimentation rate were the least responsive instruments.

Conclusion. This study provides further evidence to support the core set of outce measures proposed by the ACR and OMERACT.
Percentage of anti‐CD4 monoclonal antibody‐coated lymphocytes in the rheumatoid joint is associated with clinical improvement. Implications for the development of immunotherapeutic dosing regimens
Authors: Choy Ernest H. S. , Pitzalis Costantino , Cauli Alberto , Bijl J. A. , Schantz Allen , Woody J. , Kingsley Gabrielle H. , Panayi Gabriel S.
Published: February 2007

Objective. We assessed the effect of a daily dosing schedule of the chimeric anti‐CD4 monoclonal antibody (MAb), cM‐T412, in rheumatoid arthritis (RA) patients, and compared lymphocyte changes in the peripheral blood (PB) and synovial fluid (SF) of these patients.

Methods. Twelve patients received 50 mg/day of cM‐T412 for 5 days, followed by a maintenance treatment of 50 mg/week for 5 weeks (6 patients), or a retreatment course of 50 mg/day for 5 days after 5 weeks (6 patients). Paired PB and SF samples were obtained during treatment for analysis.

Results. Changes in lymphocyte count and coating with the MAb in PB did not reflect changes in the SF. After 5 daily treatments, the percentage of cM‐T412‐coated CD4+ lymphocytes in SF correlated with the degree of clinical improvement seen in patients at 2 weeks after the initiation of therapy (r = 0.75, P < 0.05).

Conclusion. These results demonstrate the importance of antibody dosage and treatment regimen in determining clinical benefit. Our findings suggest that the percentage of cM‐T412‐coated CD4+ lymphocytes in SF may be a predictor of clinical outcome.
Relationship of running to musculoskeletal pain with age. A six‐year longitudinal study
Authors: Fries James F. , Singh Gurkirpal , Morfeld Dianne , O'Driscoll Peter , Hubert Helen
Published: February 2007

Objective. To determine, by longitudinal study, whether long‐distance running, maintained for many years, is associated with increased musculoskeletal pain with age.

Methods. A 6‐year prospective longitudinal study of 410 runners' club members and 289 community controls, age 53‐75 years at study initiation, was conducted. Subjects were also categorized as ever‐runners (n = 488) and never‐runners (n = 211). The primary dependent variable was pain score as indicated on a horizontal double‐anchored analog scale; data for this variable were available beginning in 1987. Statistical adjustment for age, education level, smoking, alcohol consumption, history of arthritis, and presence of other major medical conditions was done by analysis of covariance. Further analyses of previously reported associations of regular vigorous physical activity with decreased disability and mortality after 9 years were performed.

Results. The degree of musculoskeletal pain was slightly lower in the exercise group compared with controls, and the difference was statistically significant for women but not for men. Average adjusted pain scores for men were 18.3 (SEM 0.8) in runners' club members, 20.2 (1.2) in controls, 18.6 (0.8) in ever‐runners, and 20.3 (1.6) in never‐runners. For women, these scores were 17.5 (1.8) in runners' club members versus 22.8 (1.4) in controls (P < 0.05), and 17.2 in ever runners versus 23.7 (1.5) in never‐runners (P < 0.002). Disability had continued to develop in runners' club members at a rate only one‐third that in the controls after 9 years of observation. Mortality over 9 years consisted of 51 deaths, of which 41 were in the control group and only 10 were among runners' club members.

Conclusion. Vigorous running activity over many years is not associated with an increase in musculoskeletal pain with age, and there may be a moderate decrease in pain, particularly in women. Vigorous physical activity is associated with greatly decreased levels of disability and with decreased mortality rates.