bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypothalamic–pituitary–adrenal axis perturbations in patients with fibromyalgia
Authors: Crofford Leslie J. , Pillemer Stanley R. , Kalogeras Konstantine T. , Cash Joseph M. , Michelson David , Kling Mitchel A. , Sternberg Esther M. , Gold Philip W. , Chrousos George P. , Wilder Ronald L.
Published: February 2007

Objective. To examine basal and stimulated hypothalamic–pituitary–adrenal (HPA) axis and related hormone levels, including adrenocorticotropin (ACTH), cortisol, arginine vasopressin (AVP), and neuropeptide Y (NPY), in patients with fibromyalgia (FM).

Methods. Basal and ovine corticotropin‐releasing hormone (oCRH)–stimulated HPA axis function were assessed in 12 patients with FM and in age‐ and sex‐matched normal subjects. Basal plasma AVP levels and AVP release after postural change were assessed, and plasma NPY levels were measured in the same samples.

Results. Patients with FM had low 24‐hour urinary free cortisol, but normal peak and elevated trough plasma cortisol levels, compared with normal subjects. The net integrated ACTH response to oCRH in FM was not significantly different from that in normal subjects, but tended toward an exaggerated response. There was a significant decrease in net integrated cortisol response to oCRH in FM patients, indicating adrenal hyporesponsiveness. AVP levels were not significantly different between FM patients and control subjects, but variability was greater among the FM patients. Plasma NPY levels were significantly lower in FM patients than in normal subjects.

Conclusion. These data support the view that HPA axis function is perturbed in patients with FM. Further study is required to ascertain the cause of HPA axis perturbations and their relationship to symptoms in patients with FM.
Use of magnetic resonance imaging in diagnosing eosinophilic fasciitis. report of two cases
Authors: Al‐Shaikh A. , Freeman C. , Avruch L. , Mckendry R. J. R.
Published: February 2007

Objective. To determine the role of magnetic resonance imaging (MRI) in the diagnosis of eosinophilic fasciitis (EF), selection of appropriate biopsy site, and followup of treatment.

Methods. MRI was used to examine 2 patients with EF at the time of their initial clinical presentation and after several months of treatment. T2‐weighted axial, T2‐weighted axial with fat saturation, and T1‐weighted axial post‐gadolinium with fat saturation scans at 1.5T were obtained.

Results. MRI demonstrated hyperintensity within the fascia. This defect resolved with treatment and clinical improvement.

Conclusion. MRI is a useful noninvasive tool for diagnosing EF and for monitoring the effectiveness of therapy.
Systemic lupus erythematosus induced by ovulation induction treatment
Authors: Ben‐Chetrit Avraham , Ben‐Chetrit Eldad
Published: February 2007

Infertile women are treated with various regimens for ovulation induction. The ultimate end‐result of these treatments is a significant rise in levels of serum gonadotropins and estradiol—the most potent natural estrogen. Estrogens may affect diverse biologic functions, including immune and inflammatory reactions. A role for estrogens in the development or exacerbation of systemic lupus erythematosus (SLE) has been suggested by many studies. In this report, we present 3 cases of otherwise healthy women who received ovulation induction agents and subsequently developed full‐blown SLE. The possible association between this treatment and SLE is discussed.
Occult subacute thyroiditis mimicking classic giant cell arteritis
Authors: Rosenstein Elliot D. , Kramer Neil
Published: February 2007

We report the case of a 60‐year‐old man who presented with fever, weight loss, generalized aching, left temporal and ear pain, and an erythrocyte sedimentation rate of 125 mm/hour. Due to the presumed diagnosis of giant cell arteritis (GCA), the patient was treated with prednisone (60 mg daily), with immediate improvement in his symptoms. Biopsy of the temporal arteries revealed no significant inflammatory infiltrate. Further evaluation included assessments of thyroid function, which revealed an elevated T4 level, low thyroid‐stimulating hormone level, and suppressed radioactive iodine uptake on thyroid scintigraphy. A diagnosis of subacute thyroiditis was made, prednisone therapy was tapered over 3 weeks, and treatment with beta blockers was instituted. The patient remained asymptomatic and returned to a euthyroid state. This case illustrates that subacute thyroiditis should be considered in the differential diagnosis of GCA.
Primary systemic amyloidosis presenting as giant cell arteritis and polymyalgia rheumatica
Authors: Salvarani Carlo , Gabriel Sherine E. , Gertz Morie A. , Bjornsson Johannes , Li Chin‐Yang , Hunder Gene G.
Published: February 2007

Primary systemic amyloidosis may present with features suggesting a vasculitis, including giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). In this report, we describe the clinical characteristics, temporal artery biopsy findings, and the response of vascular and musculoskeletal symptoms to corticosteroid therapy in 4 patients with primary systemic amyloidosis who presented with manifestations of GCA or PMR.
Deficiency of the β subunit of the eighth component of complement presenting as arthritis and exanthem
Authors: Wulffraat N. M. , Sanders E. A. M. , Fijen C. A. P. , Hannema A. , Kuis W. , Zegers B. J. M.
Published: February 2007

A 13‐year‐old boy presented with juvenile chronic arthritis of 6 months' duration. Antinuclear antibodies, anti–double‐stranded DNA antibodies, and rheumatoid factor were not detected. Western blotting showed a deficiency of the β subunit of the eighth component of complement. The same deficiency was present in the patient's sister. C8β deficiency is usually detected in individuals who survive meningococcal disease. There was no such history in this family. Juvenile chronic arthritis has not previously been described in patients with C8β deficiency.
ELEVATED SERUM LEVELS OF INTERLEUKIN‐1 RECEPTOR ANTAGONIST IN POLYMYOSITIS/DERMATOMYOSITIS. A Biologic Marker of Disease Activity with a Possible Role in the Lack of Acute‐Phase Protein Response
Authors: Gabay Cem , Gay‐Croisier Fabienne , Roux‐Lombard Pascale , Meyer Olivier , Maineti C. , Guerne Pierre‐André , Vischer Thomas , Dayer Jean‐Michel
Published: February 2007

Objective. To determine whether the lack of acute‐phase protein (APP) response in numerous patients with polymyositis/dermatomyositis (PM/DM) is related to an imbalance between cytokines and cytokine inhibitors.

Methods. Levels of C‐reactive protein (CRP), interleukin‐1β (IL‐1β), tumor necrosis factor α (TNFα), IL‐6, IL‐1 receptor antagonist (IL‐1ra), TNF soluble receptor 55 kd (sTNFR 55 kd), and sTNFR 75 kd were tested in the serum of 15 patients with PM/DM, 14 patients with spondylarthropathies (SPA), and 12 healthy blood donors. Serum IL‐1β, TNFα, IL‐6, IL‐1ra, sTNFR were measured by specific immunoassays.

Results. Serum levels of CRP were lower in PM/DM patients than in SPA patients. Normal or slightly elevated CRP values were found in 10 of the 15 PM/DM patients, 7 of whom had active myositis. Serum IL‐6 levels were significantly higher in SPA patients than in PM/DM patients, whereas serum IL‐1ra and sTNFR levels were significantly higher in PM/DM than in SPA patients. IL‐1ra levels were particularly elevated in patients with active myositis and decreased in response to treatment.

Conclusion. These differences in cytokine levels, particularly IL‐1ra, between PM/DM and SPA patients are indicative of distinct pathogenic mechanisms. High levels of IL‐1ra may account for the weak APP response in some PM/DM patients. Our results suggest that measurement of IL‐1ra, together with clinical examination, may provide useful information for the followup of PM/DM patients.
Methotrexate concentrations in synovial membrane and trabecular and cortical bone in rheumatoid arthritis patients
Authors: Bologna Christophe , Edno Leila , Anaya Juan‐Manuel , Canovas Francois , Berghe Marc Vanden , Jorgensen Christian , Galtier Marc , Combe Bernard , Bressolle Francoise , Sany Jacques
Published: February 2007

Objective. To determine methotrexate (MTX) concentrations in the synovial membrane (SM) and cortical and trabecular bone of rheumatoid arthritis (RA) patients.

Methods. Ten RA patients (9 women, 1 man; mean ± SD age 49.2 ± 10.6, mean disease duration 13.2 ± 9.9 years) undergoing surgical procedures for rheumatoid articular lesions participated in this study. Mean ± SD MTX treatment duration was 26.4 ± 21.3 months. The day preceding surgery, 10 mg of MTX was administered intramuscularly. During surgery, a mean ± SD of 19.7 ± 2.6 hours after MTX administration, SM, bone fragments, and blood were collected simultaneously. MTX was assayed by fluorescence polarization immunoassay in plasma and tissues.

Results. The mean ± SD plasma concentration was 0.0252 ± 0.01 nmoles/ml at the time of tissue sampling. The mean MTX concentration in SM was 0.285 ± 0.159 nmoles/gm. The mean MTX concentrations in trabecular and cortical bone were 0.292 ± 0.164 and 0.286 ± 0.126 nmoles/gm, respectively.

Conclusion. After intramuscular administration, high MTX concentrations are found in SM and cortical and trabecular bone of RA patients.
Antibodies to histone (h2a–h2b)–dna complexes in the absence of antibodies to double‐stranded dna or to (h2a–h2b) complexes are more sensitive and specific for scleroderma‐related disorders than for lupus
Authors: Wallace Daniel J. , Lin Hun‐Chi , Shen Guo Qiu , Peter James B.
Published: February 2007

Objective. To assess the role of antibodies to histones H2A, H2B, and anti–double‐stranded DNA which form (H2A–H2B)–DNA complexes in patients with scleroderma‐related disorders.

Methods. Antihistone antibodies were measured, by enzyme immunoassay, in 26 patients with scleroderma‐related disorders, 100 patients with systemic lupus erythematosus (SLE), and 24 patients with rheumatoid arthritis.

Results. Antibodies to histone (H2A–H2B)–DNA complex were more commonly seen in patients with scleroderma‐related disorders than in those with SLE (P < 0.0001).

Conclusion. Scleroderma‐related disorders should be included among conditions in which various types of antihistone antibodies are produced. A hypothesis to account for this finding is discussed.
Changes in cartilage composition and physical properties due to stromelysin degradation
Authors: Bonassar Lawrence J. , Frank Eliot H. , Murray Jane C. , Paguio Claribel G. , Moore Vernon L. , Lark Michael W. , Sandy John D. , Wu Jiann‐Jiu , Eyre David R. , Grodzinsky Alan J.
Published: February 2007

Objective. To determine the effects of stromelysin treatment on biochemical, histologic, and swelling characteristics of intact cartilage explants and to correlate these effects with changes in the functional physical properties of the tissue.

Methods. Bovine articular cartilage explants were cultured for up to 3 days in the presence or absence of recombinant human stromelysin (SLN). Damage to matrix proteoglycans and collagens was assessed and characterized by N‐terminal sequencing and Western blot analysis, respectively. Explants were mechanically tested to assess the ability of the tissue to withstand cyclic and static compressive loads.

Results. Treatment with SLN resulted in a time‐and dose‐dependent loss of proteoglycans from cartilage explants, with significant loss seen after 3 days of exposure to 20 nM SLN. Histology indicated that initial loss of proteoglycans occurred in regions near the tissue surface and proceeded inward with increasing time of SLN exposure. SLN treatment resulted in degradation of matrix collagen types IX and II, and a concomitant increase in tissue swelling. This matrix degradation resulted in severe alterations in functional physical properties of the tissue, including compressive stiffness. The initial, focal loss of proteoglycans that resulted from SLN treatment was most accurately detected with highfrequency streaming potential measurements.

Conclusion. Exposure of intact cartilage to SLN caused specific, molecular‐level degradation of matrix molecules, which resulted in changes in the swelling behavior and marked deterioration of functional physical properties of the tissue.
Acceleration of experimental lapine osteoarthritis by calcium pyrophosphate microcrystalline synovitis
Authors: Fam Adel G. , Morava‐Protzner Isabella , Purcell Carrie , Young Beverly D. , Bunting Peter S. , Lewis Anthony J.
Published: February 2007

Objective. To investigate the effects of chronic calcium pyrophosphate dihydrate (CPPD) synovitis on the development of osteoarthritic (OA) lesions in an animal model.

Methods. OA was induced in the right knees of 30 male New Zealand white rabbits by partial lateral meniscectomy and section of the fibular collateral and sesamoid ligaments (PLM/LS), followed by 8 weekly intraarticular (IA) injections of 1 mg (low‐dose) or 10 mg (high‐dose) of CPPD crystals in 3 sets of experiments (10 rabbits each). The contralateral left knees served as controls: experiment 1 PLM/LS alone, experiment 2 8 weekly IA injections of CPPD crystals alone, and experiment 3 sham surgery plus 8 weekly IA injections of CPPD crystals.

Results. At 8 weeks, repeated IA injections of low‐dose and high‐dose CPPD crystals into meniscectomized right knees resulted in more severe OA than in meniscectomized but noninjected left knees (experiment 1) (P = 0.003 and P = 0.001, respectively). One‐fourth of the meniscectomized knees (11 of 40), both CPPD‐injected and noninjected, showed embedded synovial cartilage shards.

Conclusion. The data demonstrate a worsening effect of chronic CPPD crystal‐induced synovitis on experimental OA produced in the rabbit knees by PLM/LS, and support a possible role for CPPD microcrystalline inflammation in the progression of OA lesions in clinical CPPD crystal deposition disease.
The independence and stability of socioeconomic predictors of morbidity in systemic lupus erythematosus
Authors: Karlson Elizabeth W. , Daltroy Lawren H. , Lew Robert A. , Wright Elizabeth A. , Partridge Alison J. , Roberts W. Neal , Stern Steven H. , Straaton Karin V. , Wacholtz Mary C. , Grosflam Jodi M. , Liang Matthew H.
Published: February 2007

Objective. We studied the relationship between systemic lupus erythematosus (SLE) morbidity and socioeconomic status (SES) at 5 centers.

Methods. Ninety‐nine patients who met American College of Rheumatology criteria for SLE were randomly sampled at each center, balancing by race and insurance status. Subjects were interviewed for current and past SES factors, such as insurance, occupation, employment, education, and income. SLE disease activity was measured by the SLE Activity Measure (SLAM).

Result. Higher education, private insurance/Medicare, and higher income were associated with less disease activity at diagnosis. Controlling for SES, race, and center, the best predictors of less active disease at diagnosis were private insurance/Medicare (P = 0.002) and higher education (P = 0.007). From the time of diagnosis to the study visit (mean 3.5 years), insurance, income, and employment status changed for a significant number of subjects (37%, 16%, and 21%, respectively).

Conclusion. Private insurance or Medicare and higher education are associated with less active disease at diagnosis of SLE. Health insurance, income, and employment status are unstable measures of socio‐economic status and may explain the variability in conclusions of previous studies on the role of SES in SLE.
The cost‐effectiveness of liver biopsy in rheumatoid arthritis patients treated with methotrexate
Authors: Bergquist Steven R. , Felson David T. , Prashker Mark J. , Freedberg Kenneth A.
Published: February 2007

Objective. To assess the cost‐effectiveness of liver biopsy in monitoring rheumatoid arthritis (RA) patients for methotrexate (MTX)–induced cirrhosis.

Methods. A decision analytic model was used to compare a strategy of no biopsy versus strategies of biopsy after 5 years or 10 years of MTX treatment.

Results. Biopsy after 5 years of MTX treatment had a cost‐effectiveness ratio of $1,891,830 per year of life saved, while biopsy after 10 years of treatment had a cost‐effectiveness ratio of $52,374 per year of life saved. Sensitivity analyses revealed that the cost‐effectiveness of biopsy was most dependent on the probability of cirrhosis.

Conclusion. Liver biopsy to monitor for MTX‐induced cirrhosis in RA patients is not cost effective after 5 years of treatment, and even biopsy after 10 years has a high cost.
Guidelines for clinical trials in systemic sclerosis (scleroderma)
Authors: White Barbara , Bauer Eugene A. , Goldsmith Lowell A. , Hochberg Marc C. , Katz Linda M. , Korn Joseph H. , Lachenbruch Peter A. , Carwile Leroy E. , Mitrane Margaret P. , Paulus Harold E. , Postlethwaite Arnold E. , Steen Virginia D.
Published: February 2007

Objective.To develop guidelines for therapeutic trials designed to improve the overall course of systemic sclerosis (SSc), that is, to reduce the development of significant organ damage or death.

Methods.A committee developed general guidelines for patient inclusion and exclusion criteria, randomization, blinding of patients and physicians, controls, duration of the trial, investigator training, responses, samples size, study dropouts, statistical analyses, data management, and safety monitoring. Delphi and nominal group techniques were used.

Results.Briefly, patients with diffuse cutaneous SSc of less than 24 months' duration should be included because they are at greatest risk for the development of severe organ damage and death. Patients should be excluded if they have other connective tissue diseases, SSc‐like illnesses related to exposures or ingestions, severe existing internal organ damage, an unacceptable risk of side effects, or concurrent therapies that might independently influence the outcome. Randomized, double‐blind, placebo‐controlled trials are preferred. The treatment and followup period must be long enough to permit observation of any disease modification, which is likely to require 18–36 months, unless an extraordinarily effective therapy is identified. Responses selected should be quantitative, consistently and accurately reflect activity of SSc in major target organs (not solely the skin), be sensitive to change, and be standardized, with limited variability. An example of a set of responses is given. Surrogate responses are desirable, but none have been validated as correlating with organ damage.

Conclusion.Guidelines have been established for trials of disease‐modifying interventions in SSc. These guidelines will need to be altered as additional information becomes available. Any given protocol will be individualized based on the nature of the intervention and objectives of the study. Nonetheless, each study team should develop a protocol that meets the spirit of these guidelines.
Correlation between infection and the onset of the giant cell (temporal) arteritis syndrome
Authors: Russo Michael G. , Waxman Jack , Abdoh Ahmed A. , Serebro Leonard H.
Published: February 2007

Objective. To assess for a correlation between infection and the onset of the giant cell (temporal) arteritis (GCA) syndrome.

Methods. A matched case‐control study design was used. Records of 100 patients with biopsy‐proven GCA and 100 patients undergoing corrective surgery for hip fracture who did not have GCA were retrospectively reviewed. Non‐GCA patients were sex‐matched with GCA patients and were as old or older in age. The review period for GCA patients was up to 4 months before and during the occurrence of symptoms (median 2 months), and for non‐GCA patients, it was up to 7 months before hip fracture. The prevalence of infection was compared using matched‐pairs odds ratios and their 95% confidence intervals.

Results. Infections were 3 times more likely to occur in GCA patients than in non‐GCA patients (P < 0.05).

Conclusion. A correlation between the occurrence of infection and the onset of GCA is strongly suggested. We speculate that infection may act as a trigger mechanism in the pathogenesis of this syndrome.
Increased insulin‐like growth factor 1 production by human osteoarthritic chondrocytes is not dependent on growth hormone action
Authors: Doré Sylvain , Abribat Thierry , Rousseau Nicole , Brazeau Paul , Tardif Ginette , Dibattista John Anthony , Cloutier Jean‐Marie , Pelletier Jean‐Pierre , Martel‐Pelletier Johanne
Published: February 2007

Objective. To investigate insulin‐like growth factor 1 (IGF‐1) production in normal and osteoarthritis (OA) chondrocytes and to further examine the role of growth hormone (GH) in adult human cartilage and, in particular, in diseased tissue.

Methods. IGF‐1 production was measured with a radioimmunoassay. Binding assay, Northern blot, and reverse transcriptase polymerase chain reaction (RT‐PCR) techniques were used for GH receptor (GHR) detection. The biological response to GH was estimated via IGF‐1 production.

Results. We observed that basal levels of IGF‐1 production were significantly higher in OA chondrocytes than in normal cells (P < 0.005). Adult human chondrocytes, however, were unresponsive to GH stimulation with regard to IGF‐1 production, as shown in dose‐response (0–1,000 ng/ml) and time‐course (days 1–8) studies. In addition, no specific 125I‐GH binding was detected in either cell type. Northern blot analysis revealed a 5.5‐kb GHR messenger RNA (mRNA) species, but semiquantitative RT‐PCR revealed no difference in GHR mRNA expression by normal and OA chondrocytes.

Conclusion. This study indicates that the elevated synthesis of IGF‐1 by adult human OA chondrocytes occurs through a GH/GHR‐independent mechanism, suggesting that other factors are capable of controlling local IGF‐1 production in these cells.
Excessive function of peripheral blood neutrophils from patients with behcet's disease and from hla‐b51 transgenic mice
Authors: Takeno Mitsuhiro , Kariyone Ai , Yamashita Naomi , Takiguchi Masafumi , Mizushima Yutaka , Kaneoka Hidetoshi , Sakane Tsuyoshi
Published: February 2007

Objective. To elucidate the role played by HLA‐B51 in the neutrophil hyperfunction of Behcet's disease, we determined the superoxide production by purified peripheral blood neutrophils from Behcet's disease patients, from HLA‐B51 positive healthy individuals, and from HLA‐B51 transgenic mice.

Methods. Neutrophil function was evaluated by flow cytometric analysis, detecting the conversion of 2′,7′‐dichlorofluorescin diacetate into dichlorofluorescein, induced by superoxide in the neutrophils.

Results. A significant correlation between the neutrophil hyperfunction and the possession of HLA‐B51 phenotype, regardless of the presence of the disease, was observed in humans. FMLP‐stimulated neutrophils (without in vitro priming) from HLA‐B51 transgenic mice, but not those from HLA‐B35 transgenic mice or from nontransgenic mice, produced substantial amounts of superoxide.

Conclusion. The HLA‐B51 molecule itself may be responsible, at least in part, for neutrophil hyper‐function in Behcst's disease.
Demonstration of granzyme A and perforin messenger RNA in the synovium of patients with rheumatoid arthritis
Authors: MÜLler‐Ladner Ulf , Kriegsmann JÖRg , Tschopp JÜRg , Gay Renate E. , Gay Steffen
Published: February 2007

Objective. To examine the gene expression of 2 highly specific markers of cytotoxic T lymphocyte (CTL) activation, the serine protease granzyme A and the poreforming protein perforin, in synovial tissue of patients with rheumatoid arthritis (RA), and to compare the findings with those in osteoarthritis (OA) synovial tissue.

Methods. Snap‐frozen synovial tissue specimens from 9 patients with RA and 5 patients with OA were examined. The number of CTL that expressed granzyme A or perforin messenger RNA was determined by in situ hybridization using nonradioactive riboprobes for granzyme A and perforin, and by a novel in situ reverse transcriptase technique. The signals were visualized by an immunogold–silver immunohistochemistry technique and compared with immunohistochemical labeling of T and B cells. Additional double‐labeling was achieved using anti–type IV collagen, anti‐macrophage (anti‐CD68), anti–T lymphocyte (anti‐CD45RO), anti–B lymphocyte (anti‐CD20), and anti–natural killer cell (anti‐CD56) antibodies in an alkaline phosphatase–anti–alkaline phosphatase assay.

Results. Granzyme A and perforin messenger RNA (mRNA) was observed in CTL in synovial specimens from all of the RA patients, whereas in specimens from OA patients only a few, single cells with a positive mRNA signal for these molecules could be detected. In the RA specimens, the number of lymphocytes showing a positive mRNA signal for granzyme A or perforin varied from 10% to 50%, reflecting the recent findings of other investigators studying synovial fluid.

Conclusion. Our results demonstrate that gene expression of at least 2 CTL products, granzyme A and perforin, is up‐regulated in the synovium of patients with RA compared with that in the synovium of patients with OA. These molecules presumably play an important role not only in lymphocyte‐mediated cytotoxicity, but also in facilitating the migration of blood‐born mononuclear cells through the vascular basement membrane into the rheumatoid synovium.
Impaired polyclonal t cell cytolytic activity
Authors: Stohl William
Published: February 2007

Objective. To determine whether impaired generation of polyclonal T cell cytolytic activity is over‐represented in systemic lupus erythematosus (SLE) compared with other rheumatologic diseases and whether such impaired generation of cytolytic activity waxes and wanes with disease activity and/or changes in medications.

Methods. Peripheral blood mononuclear cells from 84 SLE patients, 55 rheumatologic disease (RD) controls, and 44 normal subjects were stimulated with anti‐CD3 monoclonal antibody, maintained in interleukin‐2, and assayed for cytolytic activity against 51Cr‐labeled Daudi target cells.

Results. Generation of cytolytic activity was significantly lower in SLE patients than in either RD or normal controls. Abnormal cytolytic responses in SLE could not be attributed to the patient's sex, race, age, disease activity, or antirheumatic medications (including corticosteroids and cytotoxics), although both SLE and RD patients taking azathioprine (AZA) manifested lower responses than did corresponding patients not taking AZA. Abnormal cytolytic activity reflected, in large measure, impaired cytolytic activity of CD8+ T cells. No significant difference in the generation of cytolytic activity between RD and normal controls was detected.

Conclusion. Impaired generation of polyclonal T cell cytolytic activity may be a predisposing factor in the development of SLE.
Cross‐linked elastin and collagen degradation products in the urine of patients with scleroderma
Authors: Stone Phillip J. , Korn Joseph H. , North Heather , Lally Edward V. , Miller Laurie C. , Tucker Lori B. , Strongwater Steven , Snider Gordon L. , Franzblau Carl
Published: February 2007

Objective. To measure the urinary excretion of specific cross‐link amino acid markers for mature elastin (desmosine [DES] and isodesmosine [IDES]) and fibrillar collagen (hydroxylysylpyridinoline [HP] and lysylpyridinoline [LP]) in systemic sclerosis (SSc) patients and healthy controls.

Methods. Urine specimens from 20 patients with SSc and 22 controls were assessed for DES, IDES, HP, and LP using high performance liquid chromatography and ultraviolet absorption spectroscopy, in combination with an isotope dilution technique in which the urine specimen was spiked with isotopically labeled cross‐link amino acids.

Results. Mean ± SD levels of urinary DES and IDES were elevated in SSc patients by 2–3‐fold, and urinary HP and LP by 3–4‐fold, compared with controls (DES 21.0 ± 9.4 versus 7.5 ± 1.4 μg/gm creatinine; HP 109.0 ± 72.9 versus 24.9 ± 5.7 nmoles/mmole creatinine). Nineteen of the 20 SSc patients had urinary DES and HP values that were >3 SD above the control mean. A significant elevation in the HP:LP ratio in SSc patients as compared with controls (mean ± SD 6.9 ± 1.5 versus 5.5 ± 1.3) indicated a soft tissue origin for much of the increased HP.

Conclusion. Patients with SSc have higher levels of urinary cross‐link amino acids specific for the degradation of mature collagen and elastin. These markers distinguish most SSc patients from healthy controls.
Critical appraisal of continuing medical education in the rheumatic diseases for primary care physicians
Authors: Glazier Richard , Buchbinder Rachelle , Bell Mary
Published: February 2007

Objective. To critically appraise evidence of the effectiveness of continuing medical education (CME) in rheumatic diseases for primary care physicians.

Methods. Three physicians independently applied preset criteria to evaluated CME interventions published between January 1966 and August 1993.

Results. Eight of 166 articles identified were critically appraised, 7 of which had positive results. Marked heterogeneity in educational interventions, evaluative methods, and outcomes was noted.

Conclusion. Despite generally positive results, weak methodology precludes drawing firm conclusions about the effectiveness of CME in rheumatic diseases.
Gouty arthritis in the acquired immunodeficiency syndrome
Authors: Disla Eddys , Stein Scott , Acevedo Mabel , Cuppari Girolamo
Published: February 2007

Patients with the acquired immunodeficiency syndrome (AIDS) are characteristically hypouricemic. Therefore, the occurrence of gouty arthritis in association with AIDS would be expected to be a rare phenomenon. We describe a patient with AIDS in whom gouty arthritis developed. Features of both diseases in relation to their coexistence in this patient are discussed.
Every‐other‐week methotrexate in patients with rheumatoid arthritis
Authors: Kremer Joel M. , Davies Joanna M. S. , Rynes Richard I. , Fink Steven , Lawrence David A. , Petrillo Gayle F. , Mullaly Patrick M.
Published: February 2007

Objective. To determine if patients with rheumatoid arthritis (RA) that is stable with weekly methotrexate (MTX) therapy could be switched to an every‐other‐week regimen of MTX.

Methods. Forty‐seven patients with classic or definite RA who had received MTX for at least 8 months were studied. Clinical measurements consisted of the number of tender and swollen joints, physician and patient global evaluation of disease activity on a 5‐point scale, grip strength, patient evaluation of pain, morning stiffness, and the interval to onset of fatigue from time of awakening. Laboratory measures included the erythrocyte sedimentation rate (ESR), rheumatoid factor, C‐reactive protein (CRP), and baseline serum folate levels. Uptake of MTX was measured with tritiated thymidine from peripheral blood mononuclear cells (PBMC) from patients ex vivo. Serum measures of interleukin‐1β (IL‐1β), IL‐6, and tumor necrosis factor α (TNFα) were performed in sera, and TNFα was also measured on PBMC supernatants.

Results. Twelve of the 23 patients receiving every‐other‐week MTX (52%) were able to complete 6 months of this treatment without experiencing a disease flare. Eleven of the 23 patients receiving every‐other‐week MTX (48%) withdrew from the study before completing 6 months of treatment, because of a flare. No significant differences in clinical or laboratory parameters were seen when the 24 patients receiving weekly MTX were compared with the 12 patients in the every‐other‐week MTX group who successfully completed 6 months of the study. None of the changes in serum cytokine levels were significantly different between the patients receiving MTX weekly versus those receiving it every other week, and changes in ESR and CRP did not differ between groups. Age, sex, RA disease duration, MTX weekly dose or duration, baseline joint counts, or serum folate status did not predict a flare. Tritiated MTX uptake did not differ between groups.

Conclusion. Some patients with RA that is stable on weekly dosing are able to change to every‐other‐week dosing without experiencing a flare in their disease activity.
Sulfasalazine in the treatment of spondylarthropathy
Authors: Dougados Maxime , Linden Sjef VAN DER , Leirisalo‐Repo Marjatta , Huitfeldt Bernhard , Juhlin Roger , Veys Eric , Zeidler Henning , Kvien Tore K. , Olivieri Ignazio , Dijkmans Ben , Bertouch Jim , Brooks Peter , Edmonds John , Major Gabor , Amor Bernard , Calin Andrei
Published: February 2007

Objective. To assess the efficacy and tolerability of sulfasalazine (SSZ) in the treatment of spondyl‐arthropathy.

Methods. We conducted a 6‐month randomized, placebo‐controlled, double‐blind, multicenter study of patients with spondylarthropathy whose disease had remained active despite treatment with nonsteroidal antiinflammatory drugs. Patients were treated with SSZ (3 gm/day) or placebo. The primary efficacy variables were the physician's and patient's overall assessments, pain, and morning stiffness. End points were analyzed in the intent‐to‐treat and completer patient populations; the time course of effect was analyzed in the completer patient population.

Results. Of the 351 patients enrolled, 263 (75%) completed the 6‐month treatment period. The withdrawal rates were 35 (20%) and 53 (30%) in the placebo and SSZ groups, respectively. In the intent‐to‐treat analysis of end point efficacy, the between‐treatment difference reached statistical significance only for 1 of the 4 primary outcome variables, the patient's overall assessment of disease activity, for which 60% of the patients taking SSZ improved by at least 1 point on a 5‐point scale, in contrast to 44% of the patients taking placebo. Laboratory markers of inflammation also showed statistically significant change in favor of SSZ. In subgroup analysis, the most impressive effects were seen in patients with psoriatic arthritis, both for the 4 primary efficacy variables and for secondary efficacy variables such as the number of inflamed joints. Adverse events were more frequent in the SSZ group than the placebo group, but all were transient or reversible after cessation of treatment.

Conclusion. The results of this study show that SSZ had greater efficacy than placebo in the treatment of active spondylarthropathy, notably in patients with psoriatic arthritis.
Monoclonal antibodies that detect biochemical markers of arthritis in humans
Authors: Slater Robert R. , Bayliss Michael T. , Lachiewicz Paul F. , Visco Denise M. , Caterson Bruce
Published: February 2007

Objective. To evaluate the potential of using monoclonal antibodies (MAb) 3‐B‐3(–) and 7‐D‐4 to detect biochemical markers of altered cartilage metabolism in human arthritides.

Methods. Fifty‐five samples of normal articular cartilage (subjects' age range 18 weeks of gestation to 83 years of age) and 89 samples of arthritic cartilage (patients' age range 20–81 years) were collected, and their proteoglycans were extracted and analyzed for the presence of the epitopes recognized by MAb 3‐B‐3 and 7‐D‐4.

Results. Native 3‐B‐3(–) mimotope was expressed at a high incidence in proteoglycans extracted from the cartilage of patients with most of the arthritic diseases examined (osteoarthritis, juvenile rheumatoid arthritis, rheumatoid arthritis, avascular necrosis, and degenerative meniscal tears). Its expression in normal cartilage specimens was very low or absent, occurring mainly in the young, skeletally immature individuals. In contrast, expression of the 7‐D‐4 epitope was more variable in patients with different arthritides and was also frequently found in normal cartilage specimens. Immunohistochemical analyses with both 3‐B‐3(–) and 7‐D‐4 showed strong focal positive staining in superficial areas, where cartilage degeneration, remodeling, and repair were greatest.

Conclusion. The biochemical markers recognized by MAb 3‐B‐3(–) and 7‐D‐4 are indicative of altered proteoglycan synthesis and metabolism in human articular cartilage. The data suggest that in human cartilage, the 3‐B‐3(–) epitope might be a better marker of biochemical changes than the 7‐D‐4 epitope.
Large and small proteoglycans of osteoarthritic and rheumatoid articular cartilage
Authors: Cs‐Szabó Gabriella , Roughley Peter J. , Plaas Anna H. K. , Glant Tibor T.
Published: February 2007

Objective. To identify characteristic changes in large aggregating (aggrecan) and small proteoglycan (PG) populations in articular cartilages during osteoarthritis (OA) and rheumatoid arthritis (RA).

Methods. Aggrecan populations in guanidine extracts of femoral condylar cartilages of 46 OA and 8 RA patients who underwent total knee arthroplasty, as well as of 2 fetuses and 6 normal adults, were separated in agarose‐polyacrylamide composite gels. Small PGs (biglycan, decorin, and fibromodulin) in the same extracts were analyzed in 12% polyacrylamide gels. Gels were stained or electrophoretically transferred and probed with antibodies to aggrecan epitopes and to small PGs. Epitope contents of the samples were also compared by inhibition radioimmunoassay.

Results. There were significant differences found among normal and diseased samples in their electrophoretic mobilities, band distributions, and antibody staining. OA and especially RA samples were heavily degraded, lacked certain aggrecan populations, and contained fewer keratan sulfate and chondroitin‐6‐sulfate epitopes compared with normal samples. Levels of chondroitin‐4‐sulfate and “fetal‐type” epitopes were elevated in the OA samples compared with the normal ones. More core proteins of small PGs were found in diseased than in normal cartilages, but they were more heterogeneous in size and glycosaminoglycan substitution.

Conclusion. There is extensive degradation of both large and small PGs in diseased cartilages, but a repair process does exist, especially in OA cartilages. Chondrocytes of diseased cartilages are able to synthesize fetal‐type aggrecans. Small PGs are glycosylated differently in diseased cartilages than in normal ones.
Susceptibility to reiter's syndrome is associated with alleles of tap genes
Authors: Barron Karyl S. , Reveille John D. , Carrington Mary , Mann Dean L. , Robinson Mary Ann
Published: February 2007

Objective. Although HLA–B27 is strongly associated with susceptibility to Reiter's syndrome (RS), recent data suggest that an additional modifying or susceptibility gene(s) acts in concert with HLA–B27 to contribute to disease pathogenesis. The recently described TAP genes (transporters associated with antigen processing) are potential candidates because they are polymorphic and their function is to transport antigenic peptides to be loaded in HLA class I molecules.

Methods. TAP1 and TAP2 alleles were determined for 34 patients with RS (28 HLA–B27 positive, 6 HLA–B27 negative), and their frequencies were compared with those observed for 52 HLA–B27 positive and 80 random disease‐free control subjects.

Results. The allele frequency of TAP1C was greater in patients with RS (8 of 62, 13%) than in random controls (5 of 160, 3%) (P = 0.009). The frequency of TAP2A was greater in RS patients (51 of 66,77%) than in random controls (88 of 160, 55%) (P = 0.002); likewise, the frequency was greater in HLA–B27 positive RS patients (41 of 54, 76%) than in HLA–B27 positive disease‐free controls (49 of 94, 52%) (P = 0.004). Furthermore, the TAP2A allele was present in all RS patients (100%), whereas TAP2A was present in 79% (63 of 80) of the random controls (P = 0.003).

Conclusion. The association observed between TAP alleles and RS is independent of the presence of HLA–B27, and despite the physical proximity of TAP and HLA class II genes, linkage disequilibrium does not account for the observed associations between TAP and RS. Thus, TAP genes are genetically separated but functionally linked to class I genes, and both contribute to susceptibility to RS.
Distinct oligosaccharide content of rheumatoid arthritis‐derived immune complexes
Authors: Bond Angela , Kerr Michael A. , Hay Frank C.
Published: February 2007

Obective. To investigate the association between glycosylation and immune complex formation in various disease groups.

Methods. Immune complexes and IgG were isolated from serum and their carbohydrate content evaluated in a dot‐blot assay using specifically binding lectins.

Results. Significantly more N‐acetylglucosamine was detected in complexes from patients with rheumatoid arthritis (RA) than in those from patients with systemic lupus erythematosus, Crohn's disease, or infectious endocarditis, or from normal controls (P < 0.001). The immune complex concentration in the circulation was strongly associated with N‐acetylglucosamine levels (P < 0.001 by chi‐square analysis).

Conclusion. The composition of immune complexes from RA patients is distinct in carbohydrate content from those found in other disease groups.
The role of nitric oxide in lipoxin A4‐induced polymorphonuclear neutrophil‐dependent cytotoxicity to human vascular endothelium in vitro
Authors: Bratt Johan , Gyllenhammar Hans
Published: February 2007

Objective. To assess the mechanism for the cytotoxicity of human polymorphonuclear neutrophils (PMN) to human umbilical vein endothelial cells (HUVEC) induced by the 5‐ and 15‐lipoxygenase product of arachidonate, lipoxin A4 (LXA4), and the phorbol ester, phorbol myristate acetate (PMA).

Methods. HUVEC were grown to confluence and labeled with 51Cr. PMN and stimuli were added, and the release of 51Cr into supernatants was assessed after 4 hours.

Results. Both LXA4 and PMA conferred highly significant PMN‐dependent cytolysis. The cytotoxicity activated by LXA4 was inhibited by NG‐monomethyl‐L‐arginine (L‐NMA) and by nitro‐L‐arginine methyl ester, specific inhibitors of the nitric oxide (NO)‐producing enzyme NO synthase. Also, the scavenger of extracellular NO, oxyhemoglobin (HbO2), prevented LXA4‐induced cytolysis in a dose‐dependent manner. In sharp contrast, L‐NMA did not significantly affect the cytolysis induced by PMA. whereas HbO2 showed a modest inhibitory action. In experiments without PMN, addition of the NO donor S‐nitroso‐N‐acetyl‐penicillamine to HUVEC induced marked cytolysis, which was inhibited by HbO2, but not by L‐NMA. Addition of L‐arginine or arginine analogs did not affect superoxide anion production in a cell‐free hypoxanthine/xanthine oxidase system. Both LXA4 and PMA induced the production of superoxide anion from PMN and of NO from HUVEC.

Conclusion. NO produced by HUVEC, interacting with PMN which produce superoxide anions, is of marked significance for the endothelial cell damage in this in vitro model of vasculitis. This is probably due to the subsequent formation, via a radical‐radical interaction between NO and ·O2‐, of cytotoxic products, such as peroxynitrite and its metabolites. Furthermore, although LXA4 and PMA induced comparable cytolysis at optimal concentrations, the relative importance of NO compared with other mechanisms mediating cytotoxicity was stimulus dependent, and NO was relatively more important for LXA4‐induced PMN‐dependent endothelial injury.
Autoimmune response to the spliceosome
Authors: Hassfeld Wolfgang , Steiner GÜNter , Studnicka‐Benke Andrea , Skriner Karl , Graninger Winfried , Fischer Inge , Smolen Josef S.
Published: February 2007

Objective. To assess the significance of autoantibodies to RA33, the A2 protein of the heterogeneous nuclear ribonucleoproteins (hnRNP), and to the related hnRNP proteins A1, B1, and B2 in rheumatic diseases.

Methods. Using a partially purified preparation of hnRNP‐A and hnRNP‐B proteins, sera from 303 patients with various rheumatic diseases were investigated by immunoblotting. For the analysis of crossreactivities, autoantibodies were affinity purified by blot elution.

Results. Anti‐A2/RA33 was found in 35% of rheumatoid arthritis (RA) patients, 38% of mixed connective tissue disease (MCTD) patients, 23% of systemic lupus erythematosus (SLE) patients, and, apart from single exceptions, not in patients with other rheumatic diseases. All anti‐A2/RA33‐positive sera were also reactive with B1 and B2, and anti‐A2/RA33 antibodies cross‐reacted with both proteins. Antibodies to hnRNP‐A1 were found less frequently; moreover, the majority of anti‐A1‐positive sera also contained anti‐A2/RA33 antibodies. In anti‐A1, anti‐A2/RA33 doublepositive sera, cross‐reactivity between the 2 antibodies was generally observed. In SLE patients, the presence of anti‐A2/RA33 was correlated with the presence of anti‐(U1) small nuclear RNP (snRNP) and anti‐Sm (P < 0.0001 and P < 0.005, respectively), but there was no evidence for cross‐reactivity between antibodies to hnRNP and antibodies to snRNP antigens.

Conclusion. Since both hnRNPs and snRNPs are essential components of the spliceosome, the data show that the immune systems of patients with RA, SLE, and MCTD react to this functional complex. However, compared with MCTD and SLE patients, RA patients have a more restricted immune response to the spliceosome: they react to hnRNP proteins, particularly to hnRNP‐A2/RA33, but not to snRNPs.
The role of hla antigens as indicators of disease progression in psoriatic arthritis
Authors: Gladman Dafna D. , Farewell Vernon T.
Published: February 2007

Objective. To identify HLA markers for the development of severe disease in psoriatic arthritis (PsA).

Methods. Patients with PsA who were followed up prospectively over a 14‐year period were included. Clinical and laboratory assessments of both active inflammation and clinical damage were performed at 6‐month intervals according to a standard protocol, which also included serologic HLA typing for class I and II antigens. Progression of damage was defined as transition into higher damage states, defined by the number of damaged joints. Both univariate and multivariate models were developed to identify predictors for progression of damage.

Results. Univariate analysis revealed that the HLA antigens B27, B39, and DQw3 were associated with disease progression, while HLA‐DR7 was “protective.” The best multivariate model identified the HLA antigens B27, when DR7 was present, and DQw3, when DR7 was not present, as predicting disease progression across all transitions, while HLA‐B39 was associated with progression in early disease. The addition of these HLA indicators to a model containing clinical variables resulted in a significant improvement in fit.

Conclusion. The HLA antigens associated with PsA, B27 and B39, are risk factors for disease progression, as is the HLA class II antigen DQw3. In combination with clinical measures of disease, these HLA variables are the dominant predictors of progression.
Joint space measurement in hand radiographs using computerized image analysis
Authors: James Michael F. , Heald Geoff , Shorter John H. , Turner Robert A.
Published: February 2007

Objective. To compare computerized joint space (JS) measurements with conventional joint space narrowing (JSN) scores in patients with mild rheumatoid arthritis.

Methods. Serial paired hand and wrist radiographs from 34 patients with classic rheumatoid arthritis were evaluated. Purpose‐written software automatically measured the JS on test images and standard clinical hand radiographs; JSN was scored “blind” by 6 observers.

Results. The software proved reliable. JS values differed significantly (men > women; metacarpophalangeal > proximal interphalangeal joints), declining with disease duration more than with age; JSN scores correlated poorly and varied more.

Conclusion. Computerization permits sensitive JS measurement and should be of benefit in studies of early joint disease.
Autoantibodies to pyruvate dehydrogenase complex in patients with systemic sclerosis
Authors: Fujimoto Manabu , Sato Shinichi , Ihn Hironobu , Kikuchi Kanako , Tamaki Kunihiko , Takehara Kazuhiko
Published: February 2007

Objective. To determine the prevalence and clinical significance of anti‐pyruvate dehydrogenase complex (anti‐PDC) antibodies in systemic sclerosis (SSc).

Methods. Serum samples from patients with limited cutaneous SSc (n = 81) or diffuse cutaneous SSc (n = 63) were examined for anti‐PDC antibodies by enzyme‐linked immunosorbent assay (ELISA) and immunoblotting.

Results. IgG‐ and/or IgM‐isotype anti‐PDC antibodies were demonstrated by ELISA in 26 of 144 patients with SSc (18%). By immunoblotting, 19 patients had IgG anti‐PDC antibodies. Among these patients with IgG anti‐PDC antibodies, antibody to the E1α subunit was significantly associated with the presence of laboratory abnormalities typical of primary biliary cirrhosis (PBC).

Conclusion. Antibody to the E1α subunit of PDC may be a serologic indicator for the development of PBC in patients with SSc.