bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluorescent light photosensitivity in patients with systemic lupus erythematosus
Authors: Rihner Michael , Mcgrath Hugh
Published: February 2007

Objective. To determine the prevalence of fluorescent light toxicity in patients with systemic lupus erythematosus (SLE).

Methods. SLE patients were polled about their symptomatic responses to sunlight and cool white fluorescent light. Photometry was used to determine the levels of ultraviolet (UV) emissions from fluorescent lamps.

Results. Thirteen of 30 photosensitive SLE patients described increases in disease activity following exposure to unshielded fluorescent lamps. Photometry indicated that these lamps emit substantial levels of UV‐B (280–320 nm) radiation, which is toxic to patients with SLE. Standard acrylic diffusers absorbed this radiation, and their use was associated with almost no patient‐reported problems.

Conclusion. Fluorescent lamps, emitting UV‐B radiation, induce disease activity in photosensitive SLE patients. Standard acrylic diffusers absorb UV‐B radiation and appear to be protective against induction of disease activity with the use of fluorescent lamps.
Autoantigenic epitopes of the b polypeptide of SM small nuclear RNP particles
Authors: Ohosone Yasuo , Mimori Tsuneyo , Fujii Takao , Akizuki Masashi , Matsuoka Yasuo , Irimajiri Shoichiro , Hardin John A. , Craft Joe , Homma Mitsuo
Published: February 2007

Objective. To analyze the autoantigenic epitopes of the Sm B polypeptide of the U1 small nuclear RNP (snRNP) using complementary DNA (cDNA) clones.

Methods. Expression of Sm B fusion proteins in λ phage vectors, immunoblots, immunoprecipitations, and affinity purification of antibodies.

Results. Immunoblots using antibodies affinitypurified from B fusion proteins demonstrated that there were cross‐reactive epitopes between the B'/B and A polypeptides of the U1 snRNP. Immunoprecipitation assays suggested that there were at least 3 different autoantigenic epitopes on the B polypeptide that could be classified into 2 general groups based upon autoantibody reactivity. The first group of autoantibodies, which bound 2 separate autoantigenic epitopes (BU1–1, BU1–2), participated in immunoprecipitation of the U1 snRNP alone. The second group, which bound the third type of autoantigenic epitope (BSm‐1), immunoprecipitated all the abundant Sm snRNPs.

Conclusion. There is at least 1 region on the B proteins that is accessible to antibodies only within the structure of the U1 snRNP, as well as a region that is accessible on all Sm snRNPs. These data support the notion that the native U1 RNP, perhaps containing B proteins in a different conformation than those found on other Sm snRNPs, may drive the humoral immune response in systemic lupus erythematosus.
IX 207‐887 in Rheumatoid Arthritis. A double‐blind placebo‐controlled study
Authors: Dougados Maxime , Combe Bernard , Beveridge Thomas , Bourdeix Isabelle , Lallemand Anne , Amor Bernard , Sany Jacques
Published: February 2007

Objective. To determine the efficacy and the safety of IX 207‐887 treatment in rheumatoid arthritis. The IX compound [10‐methoxy‐4H‐benzo(4,5)cyclohepta‐(1,2‐b)thiophene‐4‐yliden acetic acid] is effective in several animal models of rheumatoid arthritis and has a mechanism of action involving the inhibition of interleukin‐1 release.

Methods. A double‐blind, controlled trial of 16 weeks' duration comparing placebo with IX at a daily dosage of 800 mg or 1,200 mg (20 patients/group) was conducted.

Results. Thirteen patients withdrew from the study, 3 because of lack of efficacy (all in the placebo group) and 10 because of side effects (1 in the placebo group [skin rash] and 9 in the IX groups [skin rash in 5, intestinal disturbances in 2, hepatitis in 1, meningitis in 1]). Intent‐to‐treat analysis showed a statistically significant difference in the variations of clinical and laboratory parameters between the 3 groups. Between‐group comparisons showed an improvement in all these variables in the IX groups versus the placebo group. According to Paulus' criteria, 2 of the 20 placebo‐treated patients (10%), 9 of the 20 IX 800 mg–treated patients (45%), and 11 of the 20 IX 1,200 mg–treated patients (55%) were considered responders (P = 0.008).

Conclusion. The findings of this study suggest that the tolerability of IX is acceptable in rheumatoid arthritis patients, and that IX is an effective slow‐acting drug for use in rheumatoid arthritis.
Variation in the risk of peptic ulcer complications with nonsteroidal antiinflammatory drug therapy
Authors: Savage R. L. , Moller P. W. , Ballantyne C. L. , Wells J. E.
Published: February 2007

Objective. To assess the risk of perforation or hemorrhage of peptic ulcer on treatment with nonsteroidal antiinflammatory drugs (NSAIDs), both as a class and as individual agents.

Methods. A case–control study of medication histories in 494 patients and 972 matched control subjects.

Results. The increase in risk (odds ratio) with NSAID therapy was 5.1 times the risk in controls. The odds ratio for piroxicam was 6.3 (95% confidence interval [CI] 3.3–12.0), as compared with 2.9 for diclofenac, ketoprofen, and sulindac combined (95% CI 2.0–4.2). The effect of other risk factors was also considered, and the adjusted odds ratios were 4.1 for all NSAIDs, 6.4 (95% CI 2.8–15.0) for piroxicam, and 3.3 (95% CI 2.0–5.5) for diclofenac, ketoprofen, and sulindac combined.

Conclusion. The estimate of overall risk of peptic ulcer complications with NSAIDs is similar to that found in other studies. There appear to be differences in risk between agents.
Superoxide anion production and phagocytosis of crystals by cultured endothelial cells
Authors: Falasca Gerald F. , Ramachandrula Anand , Kelley Kathleen A. , O'Connor Carolyn R , Reginato Antonio J.
Published: February 2007

Objective. To show that cultured human umbilical vein endothelial cells (HUVEC) are capable of phagocytizing inflammation‐causing crystals and of generating superoxide anion (SOA) during phagocytosis.

Methods. The superoxide dismutase‐inhibitable reduction of nitroblue tetrazolium (NBT) dye was used as a measure of SOA production. Phagocytosis was quantified by light microscopy and confirmed by transmission electron microscopy. Cytochrome C was also studied but was found to undergo spontaneous reduction by monosodium urate (MSU) without cells.

Results. Crystals of MSU, calcium oxalate, hydroxyapatite, and calcium pyrophosphate dihydrate (CPPD) were phagocytized and, except for the CPPD crystals, induced NBT reduction. Cholesterol and cholesterol monohydrate were neither phagocytized nor did they induce NBT reduction.

Conclusions. Endothelial cells may be a significant source of oxygen radicals in crystal‐associated and other arthritides.
Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with wegener's granulomatosis
Authors: Kerr Gail S. , Fleisher Thomas A. , Hallahan Claire W. , Leavitt Randi Y. , Fauci Anthony S. , Hoffman Gary S.
Published: February 2007

Objective. To assess the correlation and prognostic value of antineutrophil cytoplasmic antibody (cANCA) titers with disease activity in patients with Wegener's granulomatosis (WG).

Methods. One hundred six patients with WG had serum ANCA determinations; 72 had serial titers obtained routinely at 1–3‐month intervals. One hundred twelve subjects (19 of whom were healthy donors) served as controls. All serum samples were tested for cANCA by an indirect immunofluorescence technique. A prospective analysis of disease activity and cANCA values was performed. Disease activity was assessed according to clinical, laboratory, radiographic, and histopathologic findings.

Results. Positivity for cANCA was a sensitive (88%) marker of active WG. However, changes in serial titers temporally correlated with a change in disease status in only 64% of patients. Furthermore, an increase in the cANCA titer preceded clinical exacerbation of disease in only 24% of patients who had been in remission or had low‐grade, smoldering disease.

Conclusion. A rise in cANCA titer alone should not be considered adequate evidence of an impending clinical exacerbation, and therefore does not justify initiating or increasing immunosuppressive therapy.
Allotypic dependency of the specificity and avidity of human monoclonal igm rheumatoid factors derived from rheumatoid synovial cells
Authors: Robbins Dick L. , Kenny Thomas P. , Snyder Lisa L. , Ermel Richard W. , Larrick James W.
Published: February 2007

Objective. To better understand the genetic derivation and pathogenicity of rheumatoid factor (RF) molecules in rheumatoid arthritis (RA), we have focused our studies on rheumatoid synovial cells (RSC).

Methods. Five monoclonal human IgM rheumatoid factor (mRF)—secreting hybridomas were produced from the RSC of an RA patient. Fine subclass specificities and avidities of these RSC mRFs were compared with several paraprotein monoclonal IgM RFs using direct binding (reactivity) and competitive inhibition (specificity and avidity) enzyme‐linked immunosorbent assays.

Results. The following observations were made: 1) RSC mRF had greater avidity for IgG than did paraprotein mRF; 2) 4 of the 5 RSC RF were highly avid for IgG3; and, 3) the avidity of RSC RF binding for IgG3 was highest for IgG molecules expressing the G3m(5) allotype.

Conclusion. We conclude that RSC RF have different specificities and avidities than do paraprotein RF. This may suggest an antigen‐driven process in RA synovium, with the production of higher‐avidity IgG3m(5)‐specific RSC RF, which could have special pathogenetic importance.
Assessment of clinical competence of medical students by using standardized patients with musculoskeletal problems
Authors: Connell Karen J. , Sinacore James M. , Schmid Frank R. , Chang Rowland W. , Perlman Susan G.
Published: February 2007

Objective. To assess medical students' clinical competence in addressing musculoskeletal problems.

Methods. Nineteen junior medical students completed 2 standardized patient‐based tests structured to capture their clinical decisions from undiagnosed chief complaint to management.

Results. No student approached the highest possible score on either test, and the students as a group received less than half the possible points on 5 important aspects of diagnostic reasoning.

Conclusion. Standardized patient‐based tests can be structured to provide enlightening information about medical students' clinical competence with regard to musculoskeletal problems.
Linkage studies of hla and primary sjögren's syndrome in multicase families
Authors: Mrcp Helen Foster, , Stephenson Anthea , Walker David , Cavanagh Gary , Kelly Clive , Griffiths Ian
Published: February 2007

Objective. To define the role of HLA–DR pheno‐type in the expression of primary Sjögren's syndrome (SS).

Methods. A family study of Caucasian probands with definite primary SS was conducted. Relatives with features of primary SS were classified according to the Fox criteria. Several types of linkage analysis between primary SS and HLA haplotype (HLA–A, B, and DR) were performed.

Results. A trend toward haplotype sharing between affected siblings was evident for definite/probable primary SS when analyzed by the Green and Woodrow method. This reached statistical significance when data from other published family studies were included. LOD scores and analyses using the Penrose method showed little evidence of linkage.

Conclusion. In view of the strong association with HLA‐DR3, these results suggest that the HLA‐DR3 allele is an important susceptibility factor for expression of primary SS in Caucasians. The apparent haplotype sharing may be a consequence of this association. The potential influence of other genetic factors (major histocompatibility complex [MHC] and non‐MHC) is discussed.
A comparison of the effect of transforming growth factor β1 on pyrophosphate elaboration from various articular tissues
Authors: Rosenthal Ann K. , Mccarty Brian A. , Cheung Herman S. , Ryan M.
Published: February 2007

Objective. The purpose of this study was to determine the effect of transforming growth factor β1 (TGFβ1) on inorganic pyrophosphate (PPi) elaboration from articular tissues to better understand the pathophysiology of calcium pyrophosphate dihydrate (CPPD) crystal deposition in the joint.

Methods. PPi was measured in the media of adult porcine articular tissue in organ culture and monolayer cultures.

Results. TGF/β1 strongly stimulated PPi elaboration by porcine fibrocartilage and hyaline cartilage. It modestly increased PPi elaboration by ligament, and had no effect on PPi elaborated by synovium. Of all cell types tested in cell culture, only chondrocytes responded to TGF/β1 by significantly increasing PPi elaboration.

Conclusion. TGF/β1 stimulates PPi elaboration from hyaline cartilage, fibrocartilage, and ligament, indicating that there is in situ CPPD crystal formation in these tissues. The ability of tissues to respond to TGFβ1 by increasing PPi elaboration correlates with the prevalence of CPPD crystal deposition found clinically. The unique response of chondrocyte monolayers to TGF/β1 reinforces the key role of the chondrocyte in PPi elaboration in the joint. These findings support an etiologic role for responsiveness to TGFβ1 in CPPD disease.
Vh family utilization by igg anti‐dna–secreting lymphocytes derived from autoimmune mrl‐lpr/lpr mice
Authors: Klinman Dennis M. , Dellacqua Dale K. , Conover Jacqueline , Huppi Konrad
Published: February 2007

Objective. To evaluate the heterogeneity of the IgG anti‐DNA autoantibody response of MRL/lpr mice.

Methods. B cell clones were grown on nitrocellulose membranes. Those producing IgG anti‐DNA antibodies were identified by a modified enzyme‐linked immunospot assay, and their utilization of IgVH genes was determined by hybridization.

Results. Four hundred sixty‐eight IgG anti‐DNA–secreting colonies were derived from 9 autoimmune MRL/lpr mice. Individual VH families contributed to anti‐DNA production at a frequency roughly proportional to their representation in the expressed repertoire (except for the more frequent use of VH 7183 and less frequent use of VH 36‐60). In individual mice, anti‐DNA antibodies were encoded by 2–5 different IgVH families, with no single family constituting more than 27–65% of any animal's anti‐DNA response.

Conclusion. The IgG anti‐DNA response of individual MRL/lpr mice is oligoclonal.
Ai/learn/rheumatology. a comparative study of computer‐assisted instruction for rheumatology
Authors: Bridges Alan J. , Reid John C. , Cutts James H. , Wood Susan Hazel , Sharp Gordon C. , Mitchell Joyce A.
Published: February 2007

Objective. To assess the effectiveness of AI/ LEARN/Rheumatology, a computer‐controlled interactive videodisc system for teaching.

Methods. We assessed improvement in knowledge about rheumatic diseases, using a pretest and posttest in a control year and a treatment year. The subjects were medical students and postgraduate trainees taking the rheumatology elective. The control year used traditional lectures and the standard rheumatology curriculum. The treatment year used AI/LEARN/ Rheumatology in place of lectures on rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.

Results. The trainees showed significant improvement in knowledge in both the control year and the treatment year (P < 0.0001 for both). The average time spent using AI/LEARN/Rheumatology was similar to the time spent in lectures (3 hours). The number of patient consultations in which trainees participated was lower in the treatment year than in the control year; however, the adjusted posttest scores using the pretest as a covariate tended to be higher in the treatment year (P = 0.10). Analysis of covariance of the adjusted posttest scores for the treatment year only showed that the trainees who spent more time using AI/LEARN/Rheumatology learned more (r = 0.57). Trainees felt that AI/LEARN/Rheumatology was the most helpful educational experience of the elective.

Conclusion. AI/LEARN/Rheumatology is an effective means of teaching about the rheumatic diseases. It has many advantages: availability for independent study, effective use of trainee's time, and liberation of faculty time from lectures. Trainees enjoyed using AI/LEARN/Rheumatology.
Subpopulations of primed t helper cells in rheumatoid arthritis
Authors: Matthews Nick , Emery Paul , Pilling Darrell , Akbar Arne , Salmon Mike
Published: February 2007

Objective. To analyze subsets of primed T helper cells, defined by expression of the CD45RB isoform of the leukocyte common antigen, in the blood and synovial fluid (SF) of patients with rheumatoid arthritis (RA).

Methods. Three‐color immunofluorescence was used to study CD45 isoform expression by peripheral blood and SF CD4+ T cells.

Results. CD45 isoform expression in the peripheral blood of patients with either RA or reactive arthritis did not differ from that in healthy controls. SF T cells from both RA patients and reactive arthritis patients were almost exclusively primed (CD45RO+) cells. RA SF T cells expressed very low levels of CD45RB; this is the most highly differentiated subset of primed cells. Patients with acute reactive arthritis showed higher levels of CD45RBbright cells in their synovial fluid.

Conclusion. The highly selected cell population in SF, representing one subset of primed cells, may relate to the apparent functional abnormalities of cells from this site in patients with RA.
Familial versus sporadic ankylosing spondylitis. two different diseases?
Authors: Calin Andrei , Gail Kennedy L. , Edmunds Laurel , Will Rob
Published: February 2007

Objective. To define potential differences and the possible contribution of susceptibility or severity genes in familial versus sporadic ankylosing spondylitis (AS).

Methods. Three hundred twenty patients with AS were studied: 160 who had first‐degree relatives with AS (familial) and 160 age‐ and sex‐matched controls who had no first‐degree relative with the disease (sporadic). Disease expression in the two groups was evaluated using an index of physical, psychological, and social functioning (the Arthritis Impact Measurement Scales [AIMS]) and an assessment of spinal mobility.

Results. Familial disease was significantly milder than sporadic disease as assessed by all measures, e.g., spinal mobility score (mean 4.08 versus 4.65, P < 0.038), AIMS overall impact score (mean 2.63 versus 3.59, P = 0.002), AIMS physical activity score (4.19 versus 5.10 [P = 0.004]), AIMS social function score (4.02 versus 4.60, P = 0.023), and AIMS pain score (4.15 versus 5.33, P = 0.002).

Conclusion. The greater prevalence of AS in at‐risk families may be explained by the occurrence of more AS “susceptibility” genes in those families, whereas the more severe disease, seen in patients with sporadic AS, is conferred by the presence of more “severity” genes than “susceptibility” genes.
Gastrointestinal regulatory peptides in systemic sclerosis
Authors: Åkesson Anita , Ekman Rolf
Published: February 2007

Objective. Gastrointestinal involvement commonly occurs in systemic sclerosis (SSc), but its pathogenesis is not well understood. Since there is evidence of a defect in neurotransmitter release, we were interested in examining the relationship between gastrointestinal dysfunction and plasma concentrations of gastrointestinal regulatory peptides in patients with SSc. We studied 43 consecutive patients, 18 with diffuse and 25 with limited cutaneous disease.

Methods. Levels of corticotropin‐releasing hormone (CRH), gastrin, motilin, neuropeptide Y (NPY), and peptide YY (PYY) were determined by radioimmunoassay and high‐performance liquid chromatography (HPLC).

Results. Plasma concentrations of CRH, motilin, NPY, and PYY were significantly increased among SSc patients compared with healthy control subjects, and HPLC‐characterization of motilin, NPY, and PYY showed a different pattern of fragments. No correlation was found between esophageal hypomotility and the concentration of peptide. Acid output did not correlate with gastrin levels, but was more often increased in patients with increased CRH and NPY values. Fat malabsorption, assessed by the triolein breath test, was more common among patients with increased motilin and PYY.

Conclusion. This study shows that elevated peptide concentrations commonly occur in patients with SSc. Since regulatory peptides are involved in gastrointestinal motility, secretion, and absorption, further characterization of this neuroendocrine system may help in understanding the complex regulation of gastrointestinal dysfunction in SSc.
Calcium pyrophosphate dihydrate crystal deposition in synovium. relationship to collagen fibers and chondrometaplasia
Authors: Beutler Anna , Rothfuss Susan , Clayburne Gilda , Sieck Marie , Ralph H. Schumacher
Published: February 2007

Objective. Reasons for apparent primary deposition of calcium pyrophosphate dihydrate (CPPD) crystals in some synovial membranes have not been systematically examined. We undertook the present study to investigate for and compare possible cellular and matrix factors related to the presence of these crystals in synovium and cartilage.

Methods. Ten synovial membrane specimens and 6 cartilage specimens were obtained at the time of joint surgery from 10 patients with CPPD crystal deposition disease, for light microscopic (LM) and electron microscopic (EM) studies.

Results. In all synovial and cartilage specimens, we found many of the small CPPD crystals aligned on or in parallel to collagen fibers, as seen by EM. In 9 of the 10 crystal‐containing synovia, we found foci of chondrometaplasia adjacent to CPPD, by LM. In 7 of the synovia, including the one without LM evidence of chondrometaplasia, we observed the presence of chondrocyte‐like cells by EM. We did not note any predictable relationship between the crystals and matrix vesicles, either in synovium or in cartilage.

Conclusion. Our EM findings provide evidence of the relationship of small CPPD‐like crystals, presumably early forms, to collagen fibers both in synovium and in cartilage. By LM and EM, we also demonstrate evidence of a close association between chondrometaplasia and CPPD deposits in synovium. We suggest that chondrometaplasia might be responsible for synovial CPPD formation in predisposed patients. Both the collagen fibers and chondrocyte‐like cells seem to be involved in the primary formation of CPPD deposits in the synovium as well as in the cartilage.
Levels of synovial fluid interleukin‐1 receptor antagonist in rheumatoid arthritis and other arthropathies. potential contribution from synovial fluid neutrophils
Authors: Malyak Mark , Swaney Robert E. , Arend William P.
Published: February 2007

Objective. To measure synovial fluid (SF) levels of interleukin‐1 receptor antagonist (IL‐1ra) and to determine the capacity of SF neutrophils (PMN) to synthesize and release IL‐1ra.

Methods. A sensitive and specific enzyme‐linked immunosorbent assay was used to measure SF IL‐1ra protein concentrations and IL‐1ra production by isolated SF PMN.

Results. SF IL‐1ra levels were elevated in 13 of 16 samples from patients with rheumatoid arthritis (RA) (mean 17.1 ng/ml), in 6 of 18 samples from patients with infectious or inflammatory, non‐RA arthropathies (mean 10.6 ng/ml), and in none of 11 noninflammatory SF samples. SF IL‐1ra levels correlated with SF PMN concentrations (r = 0.680, P < 0.00001). Isolated SF PMN contained preexisting IL‐1ra protein in the absence of messenger RNA (mRNA). In addition, both lipopolysaccharide and granulocyte‐macrophage colonystimulating factor induced modest increases in IL‐1ra mRNA by cultured SF PMN.

Conclusion. IL‐1ra levels are increased in >80% of RA SF samples. SF PMN produce IL‐1ra, possibly contributing to the levels of IL‐1ra present within the SF.
Elevated synovial fluid levels of interleukin‐6 and tumor necrosis factor associated with early experimental canine osteoarthritis
Authors: Venn G. , Nietfeld J. J. , Duits A. J. , Brennan F. M. , Arner E. , Covington M. , Billingham M. E. J. , Hardingham T. E.
Published: February 2007

Objective. To measure levels of cytokines, proteases, and glycosaminoglycans (GAG) in synovial fluid (SF) from the knees of animals with experimental osteoarthritis (OA) and from their contralateral (control) knees, and to compare and correlate these values with each other as well as with measures of proteoglycan synthesis in the corresponding articular cartilage. This study will help to identify cytokines of potential importance in the early stages of the development of OA.

Methods. OA was induced in 12 mature animals by sectioning the anterior cruciate ligament. After 3 months, SF from the operated and contralateral (control) knee joints was assayed for interleukin‐6 (IL‐6), tumor necrosis factor (TNF), IL‐1, latent metalloproteinase, and sulfated GAG. Proteoglycan synthesis in the corresponding articular cartilage was also measured.

Results. IL‐6 levels in SF from the operated joint compared with the control joint were significantly elevated in 11 of 12 animals. TNF levels were also elevated in 10 of 11 SF samples from operated joints, but to a lesser extent than those of IL‐6. IL‐1 and IL‐1 inhibitors were undetectable in either the operated or control joint SF. The GAG concentration was elevated in SF from experimental OA joints. This elevation correlated with that of TNF, but not IL‐6. There was no significant difference in the concentration of APMA‐activatable metalloproteinase. The rate of proteoglycan synthesis was higher in the cartilage from the operated joint in 8 of 12 animals, and the mean rate of synthesis was significantly higher than in the control joint. There was a positive correlation between this increase in cartilage proteoglycan synthesis (operated versus control) and the increase in SF IL‐6, but there was no correlation with the levels of TNF or GAG.

Conclusion. This is the first study of SF levels of cytokines in early experimental OA. Our results show surprisingly high levels of IL‐6 in operated joints, where the cytokine could act directly on the chondrocytes, and thus play a role in mediating their responses to cartilage injury.
Autoantibodies to chromatin components in juvenile rheumatoid arthritis
Authors: Burlingame Rufus W. , Rubin Robert L. , Rosenberg Alan M.
Published: February 2007

Objective. To characterize autoantibodies to chromatin components in patients with juvenile rheumatoid arthritis (JRA).

Methods. The sera of 50 children with JRA were analyzed for antinuclear antibodies (ANA) by immunofluorescence and enzyme‐linked immunosorbent assay (ELISA) techniques.

Results. By immunofluorescence, ANA and antibodies to high‐mobility group proteins or to DNA‐free histones were common in patients with pauciarticular JRA and rheumatoid factor–positive polyarticular JRA. However, reactivity with histone–DNA complexes was rare.

Conclusion. Because antihistone antibodies detected by ELISA failed to bind chromatin or other histone–DNA complexes, they are not likely to represent the immunofluorescent ANA activity in serum.
Bilateral tumoral infiltration of the achilles tendons revealing chronic myelomonocytic leukemia
Authors: Chevalier Xavier , Hermine Olivier , Rahmouni Alain , Voisin Marie‐Catherine , Laatiri Mohamed , Gaulard Phillipe , Larget‐Piet Bruno , Pignon Jean‐Michel
Published: February 2007

Extrahematologic manifestations, such as symptoms of rheumatic disease, have been recorded in association with myelodysplastic syndromes, including chronic myelomonocytic leukemia (CMML). We report the case of a 51‐year‐old woman with tumoral infiltration of the Achilles tendons bilaterally, indicating CMML. This diagnosis was confirmed at postmortem examination.
Restricted cytokine expression in rheumatoid arthritis
Authors: Chen E. , Keystone E. C. , Fish E. N.
Published: February 2007

Objective. To determine the cytokine profile of the phenotypically activated T cell in rheumatoid arthritis (RA) synovium.

Methods. Interleukin‐2 (IL‐2), IL‐2 receptor (IL‐2R), IL‐6, IL‐4, and interferon‐γ (IFNγ) gene expression was examined in T cells from freshly isolated synovial fluids (SF) and synovial tissues (ST) from patients with RA. Estimates of baseline expression were determined using unstimulated peripheral blood (PB) T cells from healthy individuals. The corresponding positive controls were phytohemagglutinin‐activated tonsil T cells.

Results. In studies of paired PB and SF T cell samples from 17 RA patients, IL‐2 messenger RNA (mRNA) levels in only 1 PB and 3 SF samples were more than 2 standard deviations above the mean of levels in unstimulated PB from healthy donors. Similarly, only 5 PB and 7 SF samples exhibited elevated IL‐2R mRNA levels. IFNγ gene expression was not detected in any of the paired RA PB or SF samples. Fractionated T cells from 12 RA ST were screened with similar results: Only 1 of 12 samples exhibited IL‐2 mRNA levels more than 2 standard deviations above levels in baseline controls. IL‐2R mRNA levels were low or not detected, and IFNγ mRNA was absent. Subsequent studies showed that IL‐4 and IL‐6 gene expression levels were also low in RA tissues compared with tonsil T cell–positive controls.

Conclusion. These data provide evidence for restricted cytokine expression in the T cell population in RA tissues.
Rheumatoid factors from patients with rheumatoid arthritis react with tryptophan 60 and 95, lysine 58, and arginine 97, on human β2‐microglobulin
Authors: Williams Ralph C. , Malone Christine C. , Harley John B.
Published: February 2007

Objective. To define precise epitopes on human β2‐microglobulin (β2m) reacting with polyclonal IgM rheumatoid factors (RF) from patients with rheumatoid arthritis (RA).

Methods. Ten polyclonal RF were tested for their human β2m epitope–binding specificities using the entire 99–amino acid sequence synthesized as overlapping 7‐mers in an enzyme‐linked immunosorbent assay. Glycine substitution for each residue within RF‐reacting linear regions was employed to define major reactive sites.

Results and Conclusion. Major β2m residues contributing to RF reactivity were tryptophans at positions 60 and 95, lysine at 58, and arginine at position 97.
Generation and molecular analyses of two rheumatoid synovial fluid–derived IgG rheumatoid factors
Authors: Lu Edward W. , Deftos Michael , Olee Tsaiwei , Huang De‐Feng , Soto‐Gil Rafael W. , Carson Dennis A. , Chen Pojen P.
Published: February 2007

Objective. To study the Ig genes that encode IgG rheumatoid factor (IgG‐RF) from rheumatoid synovial fluid.

Methods. We used rheumatoid synovial fluid B cells to generate IgG‐RF–secreting hybridomas. We then characterized their binding properties and determined their nucleotide sequences.

Results. Two monospecific IgG‐RFs were obtained. Sequence analysis of the RFs revealed a new Vλ gene family (designated Vλ9) and extensive somatic diversification, including a duplication‐insertion of 18 nucleotides (6 amino acid residues) into a hypervariable region.

Conclusion. The data provide further support for an antigen‐driven response in the sustained production of potentially pathogenic IgG‐RFs in rheumatoid synovium.
A molecular and serologic analysis of the major histocompatibility complex and complement component c4 in systemic sclerosis
Authors: Briggs David , Stephens Clare , Vaughan Robert , Welsh Ken , Black Carol
Published: February 2007

Objective. To investigate the contributions of the major histocompatibility complex (MHC) and C4 alleles to systemic sclerosis (SSc), and to pulmonary fibrosis and autoantibody expression in SSc, by analysis at the DNA level.

Methods. One hundred fifteen patients with SSc were tested serologically for alleles of the class I MHC loci, and were tested for class II alleles (DRB, DQA, and DPB) by a combination of restriction fragment length polymorphism (RFLP) analysis and oligonucleotide probes with polymerase chain reaction amplification. C4 was studied by protein phenotyping and RFLP analysis in 80 patients. Correlations were made between disease status, pulmonary fibrosis, and expression of anticentromere antibodies (ACA) and anti–Scl‐70.

Results. The C4A‐null phenotype was found to provide the strongest disease association factor of the MHC region (P = 0.000064, relative risk [RR] = 2.8, etiologic fraction [EF] = 32.1). The primary MHC susceptibility allele was found to be DQA2 (Pcorrr = 0.0009, RR = 2.5, EF = 35.6), which is in linkage disequilibrium with both DR3 and DR11. DR2 was protective, but only for female patients (P = 0.0021, RR = 0.42, protective fraction = 19.4). DR52a was the primary MHC allele associated with pulmonary fibrosis in SSc patients. Expression of ACA was associated with the presence of either DR1 or DR4 (P = 0.0015, RR = 6.7, EF = 78.0). Anti–Scl‐70 expression correlated with an acidic residue of DPβ (DPB1:69:E) (P = 0.0063, RR = 4.6, EF = 53.1).

Conclusion. Of all the potential markers of disease susceptibility analyzed, the C4A locus was the strongest. C4AQ0 and DQA2 are independent susceptibility factors for SSc. The development of pulmonary fibrosis in SSc patients can be predicted using combined MHC and autoantibody analysis. The MHC alleles associated with the expression of disease‐specific autoantibodies are not markers for disease susceptibility.
Fcγ receptor activation of neutrophils in cryoglobulin‐induced leukocytoclastic vasculitis
Authors: Hundt Matthias , Zielinska‐Skowronek Margot , Schmidt Reinhold E.
Published: February 2007

Objective. The role of Fcγ receptors (FcγR) in type I cryoglobulinemia was investigated to characterize novel mechanisms of neutrophil activation in the pathogenesis of leukocytoclastic vasculitis.

Methods. Neutrophils from healthy donors were incubated with purified monoclonal IgG1k cryoglobulin complexes in vitro. Changes in surface antigen expression and mechanisms of intracellular hydrogen peroxide production and calcium release were measured by flow cytometry.

Results. After incubation for 2 hours, surface expression of FcγRI (CD64), CD66, and CD67 was up‐regulated; FcγRII (CDw32), FcγRIII (CD16), and LAM‐1 were down‐regulated. Using solubilized and complexed cryoglobulins, it was demonstrated that complex formation is necessary to induce intracellular H2O2 production and calcium release from intracellular stores. Both H2O2 generation and calcium mobilization could be inhibited by pretreatment with F(ab')2 fragments of monoclonal antibodies (MAb) against FcγRIII. In contrast, Fab fragments of anti‐FcγRII MAb failed to block these activations. Neither the cryoglobulin complex–induced production of H2O2 nor the increase in cytoplasmic calcium was affected by treatment with pertussis toxin, which suggests that pertussis toxin–sensitive G proteins are not involved in signal transduction.

Conclusion. These results indicate that FcγRIII plays a major role in the pathogenesis of leukocytoclastic vasculitis.
Triggering and exacerbation of autoimmune arthritis by the mycoplasma arthritidis superantigen mam
Authors: Cole Barry C. , Griffiths Marie M.
Published: February 2007

Objective. It has been postulated that superantigens might play a role in the human rheumatic diseases, by activation of self‐reactive T cells or by induction of autoantibodies. The Mycoplasma arthritidis superantigen MAM, which is derived from a naturally occurring murine arthitogenic mycoplasma, uses certain Vβ chains of the murine T cell receptor (TCR) that have been proposed to be involved in murine collagen‐induced arthritis (CIA). The present study was designed to determine whether MAM influences the course of arthritis mediated by immunization with porcine type II collagen (PII).

Methods. MAM or phosphate buffered saline (PBS) was injected locally or systemically into mice convalescing from CIA or mice suboptimally immunized with collagen.

Results. In contrast to PBS, MAM caused an exacerbation of arthritis in mice that were recovering from CIA. MAM also triggered arthritis onset in mice that had been suboptimally immunized with PII up to 160 days previously. Injection of MAM during the onset phase of CIA also triggered and enhanced the severity of arthritis in mice given low doses of PII.

Conclusion. MAM can both trigger and exacerbate murine autoimmune arthritis induced by immunization with type II collagen. Since T cells bearing the same Vβ TCRs as are used by MAM have been found to comprise a major portion of the activated cells in the synovial tissue of patients with rheumatoid arthritis, it is possible that superantigens similar to MAM may play a role in this human disease.
The repertoire of rheumatoid factor–producing b cells in normal subjects and patients with rheumatoid arthritis
Authors: He Xiaowen , Goronzy Jörg J. , Weyand Cornelia M.
Published: February 2007

Objective. To compare the B cell repertoire of normal individuals and patients with rheumatoid arthritis (RA) and, specifically, to identify precursor B cells with the potential to secrete rheumatoid factor (RF) and to understand the T helper cell requirements for the production of this autoantibody.

Methods. Frequencies of precursors of IgM, IgG, and RF‐producing B cells were measured in a limiting‐dilution system. Two distinct sources of T cell help were compared. T cell help was provided by anti‐CD3–activated CD4+ human T cell clones, or T cell–B cell interaction was facilitated by the bacterial superantigen staphylococcal enterotoxin D (SED).

Results. A subset of 2–14% of peripheral blood B cells secreted IgM and IgG in SED‐driven cultures. The SED‐responsive B cell subpopulation was present at 10 times higher frequency in normal donors compared with RA patients. However, the repertoires were very similar, particularly for RF+ precursors, which represented approximately one‐third of all SED‐responsive B cells. In normal individuals, most of these RF+ precursor B cells did not respond to anti‐CD3–activated T helper cells, with only a very small fraction of B cells activated by anti‐CD3–driven helper cells maturing into RF‐secreting B cells (from 1 of 182 to 1 of 889 IgM‐producing B cells). This subset was expanded approximately 50‐fold in RA patients.

Conclusion. Normal subjects and RA patients share a pool of B cells which secrete RF when activated in the presence of SED and T helper cells. These B cells are frequent and obviously anergic in normal individuals. The B cell subset with the potential to produce RF when help is provided in noncognate T–B interaction (anti‐CD3–driven T cells) is considerably expanded in RA patients, probably reflecting an increased responsiveness of such B cells to helper signals.
Connective tissue activation. xxxvi. the origin, variety, distribution, and biologic fate of connective tissue activating peptide–iii isoforms: characteristics in patients with rheumatic, renal, and arterial disease
Authors: Castor C. W. , Andrews P. C. , Swartz R. D. , Ellis S. G. , Hossler P. A. , Clark M. R. , Matteson E. L. , Sachter E. F.
Published: February 2007

Objective. To determine the origin, distribution, and biologic fate of platelet‐derived connective tissue activating peptide–III (CTAP‐III), to define the relative amounts of the antigen forms (CTAP‐III, betathromboglobulin [β‐TG], neutrophil activating peptide–2 [NAP‐2]) in plasma of normal persons and those with rheumatic or end‐stage renal disease, and to define the isoforms of CTAP‐III in platelets, plasma, transudates, and tissue deposits.

Methods. CTAP‐III in plasma was measured by enzyme‐linked immunosorbent assay, and growth promoting activity of CTAP‐III isoforms was tested in synovial and peritoneal cell cultures by measuring increased synthesis of 14C‐glycosaminoglycan (14C‐GAG) and 3H‐DNA. Isolated CTAP‐III was characterized by Western blotting, microsequencing, and mass spectrometry.

Results. CTAP‐III was the primary isoform of this antigen family in normal platelets and platelet‐rich plasma; β‐TG and NAP‐2 accounted for <1% of CTAP‐III isoforms. Previously undescribed isoforms, i.e., CTAP‐III des 1, des 1–2, des 1–3, and a phosphate adduct of CTAP‐III, were observed in varying amounts. Elevated plasma levels of CTAP‐III antigen were found in a substantial fraction of rheumatic disease patients: 24% of those with rheumatoid arthritis, 36% of those with systemic sclerosis, and 15% of those with systemic lupus erythematosus. All 10 patients with end‐stage kidney disease had marked elevations of plasma CTAP‐III levels, which stimulated DNA and GAG synthesis by peritoneal cells in culture. Only large isoforms (such as CTAP‐III) were detected in venous plasma of normal subjects, rheumatic disease patients, and patients receiving long‐term dialysis. Normal human spleen and kidney contained substantial (μ/gm) amounts of CTAP‐III and traces of an isoform with the electrophoretic mobility of CTAP‐III des 1–15/NAP‐2. Liver, lung, and urine contained lesser (ng/gm) amounts of CTAP‐III.

Conclusion. These data show that, among the 10 known isoforms, intact CTAP‐III itself was the major circulating isoform (>90%), and β‐TG was the most rare (0–1%). Deposition of CTAP‐III in tissues, such as synovium, spleen, and kidney, is associated with partial processing to NAP‐2–like isoforms and the potential to induce neutrophil and fibroblast activation in patients with rheumatic or end‐stage renal disease.
Sensory nerves only temporarily protect the unstable canine knee joint from osteoarthritis. evidence that sensory nerves reprogram the central nervous system after cruciate ligament transection
Authors: O'connor B. L. , Visco D. M. , Brandt K. D. , Albrecht M. , O'connor A. B.
Published: February 2007

Objective. The slow rate at which articular cartilage degrades in dogs after transection of the anterior cruciate ligament (ACLT) has been attributed to capsular thickening and buttressing by osteophytes. We investigated the roles of the peripheral and central nervous systems in protecting knee joints with chronic ACL deficiency from breakdown.

Methods. Five groups of dogs were studied; all were killed 72 weeks after left knee surgery. Group A had ACLT, group B had ACLT followed 52 weeks later by ipsilateral L4–S1 dorsal root ganglionectomy (DRG), group C had DRG followed 2 weeks later by ACLT, group D had sham DRG followed 2 weeks later by ACLT, and group E had DRG followed 2 weeks later by sham ACLT.

Results. Group E dogs did not develop knee pathology. All cruciate‐deficient knees were lax at the end of the study. The osteoarthritis (OA) that developed in groups A, B, and D was comparable (P > 0.05), and was significantly greater than that in group E (P < 0.05). Group C developed much more severe OA than any of the other groups (P < 0.05).

Conclusion. Ipsilateral sensory input is temporarily important in protecting the unstable joint from rapid breakdown. Over time, the central nervous system apparently acquires the ability to protect the unstable joint without continued ipsilateral sensory input.
Takayasu arteritis with acute interstitial pneumonia and coronary vasculitis: expanding the spectrum. report of a case
Authors: Kreidstein Sharon H. , Lytwyn Alice , Keystone Edward C.
Published: February 2007

We describe the first reported case of Takayasu arteritis presenting as idiopathic adult respiratory distress syndrome, with a pathologic diagnosis of acute interstitial pneumonia. In the same patient, rarely occurring, diffuse coronary vasculitis developed. This case vividly illustrates the extensive, clinically significant vascular involvement that can occur in Takayasu arteritis, as well as the potential extravascular, multisystemic nature of the disease.
Effect of piroxicam on gait in patients with osteoarthritis of the knee
Authors: Schnitzer Thomas J. , Popovich Jovan M. , Andersson Gunnar B. J. , Andriacchi Thomas P.
Published: February 2007

Objective. To determine whether the use of a nonsteroidal antiinflammatory drug (NSAID) in patients with painful osteoarthritis (OA) of the knee would result in alterations in specific biomechanical parameters of gait.

Methods. Eighteen patients with symptomatic knee OA and varus knee deformity underwent initial clinical evaluation for pain and activities of daily living, and assessment of parameters of gait utilizing a well‐described computerized system. All patients were then treated with piroxicam at 20 mg once daily, and clinical and gait analyses were repeated after 4 weeks.

Results. Fifteen of the 18 patients studied had a significant increase in the knee adduction moment after treatment. In the group as a whole there was a significant increase in knee adduction moment (mean percent body weight times height [%BWTH] 4.11 pretreatment versus 4.57 after 4 weeks of treatment; P < 0.01) and maximum quadriceps moment (mean %BWTH 2.13 pretreatment, 2.62 posttreatment; P < 0.01), as well as changes in other gait parameters that might be expected to be altered as a result of relief of pain. Sixteen of 18 patients experienced symptomatic relief, with a significant reduction in pain in the group as a whole after 4 weeks (P < 0.001).

Conclusion. NSAID treatment in patients with knee OA results in a reduction in symptomatic pain and an increase in loading of the knee. Whether the increased loading is due to the analgesic effects of the treatment is unknown, but if so, the development of agents capable of relieving pain while reducing loads at the knee may be desirable.
DAB486IL‐2 fusion toxin in refractory rheumatoid arthritis
Authors: Sewell Kathryn Lea , Parker Karen C. , Woodworth Thasia G. , Reuben James , Swartz William , Trentham David E.
Published: February 2007

Objective. To evaluate the safety and antiarthritic effects of DAB486IL‐2. This agent is a fusion toxin and the product of a synthetic gene, engineered by replacing the codons for the receptor‐binding domain of diphtheria toxin (DT) with the codons for human interleukin‐2 (IL‐2). DAB486IL‐2 targets cells expressing the 2‐chain, high‐affinity form of the IL‐2 receptor (IL‐2R), and achieves selective diphtheria toxin–mediated cytotoxicity of activated T cells by inhibition of protein synthesis.

Methods. Nineteen patients with rheumatoid arthritis (RA) that had been refractory to methotrexate participated in an open‐label, phase I/II trial evaluating 3 dose levels of intravenous DAB486IL‐2 given for 5 or 7 consecutive days. Thirteen patients received additional courses, at higher doses if the original response had been inadequate or at an equivalent dose if the original course produced a response, for a total of 38 courses. Arthritis response was assessed at 28 days, with biweekly followup of patients with substantial response (⩾50% improved) or meaningful response (⩾25% improved). Laboratory monitoring included measurement of CD4+ cells and circulating shed IL‐2R.

Results. Nine of 19 patients treated with high‐ or medium‐dose DAB486IL‐2 had a substantial or meaningful response after 1 or 2 treatment courses. No significant responses occurred with the low‐dose regimen. Clinical benefit was rapid, with full effect noted by 14 days following completion of infusions. Antibodies to DT developed in all patients, or levels of preexisting antibodies were boosted. Adverse effects included transient elevation of transaminase levels (55% of the patients), fever (40%), nausea or anorexia (30%), hypersensitivity (6%), and thrombocytopenia (5%). Repeat courses were associated with less transaminase elevation and were clinically effective despite induction of anti‐DT antibodies.

Conclusion. The results of this open trial provide preliminary evidence for a potential therapeutic effect of DAB486IL‐2 in RA, with an acceptable safety profile. Reversible transaminase elevations limit escalation of the dosage beyond 0.1 mg/kg/day. A controlled study of DAB486IL‐2 is required to determine the efficacy of this high‐affinity IL‐2R–targeted fusion toxin in the treatment of RA.