bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunohistochemical analysis of 3‐b‐3(–) and 7‐d‐4 epitope expression in canine osteoarthritis
Authors: Visco Denise M. , Johnstone Brian , Hill Michael A. , Jolly Grant A. , Caterson Bruce
Published: February 2007

Objective. To examine the distribution of the 3‐B‐3(–) and 7‐D‐4 epitopes in proteoglycans from morphologically normal and osteoarthritic (OA) canine articular cartilage.

Methods. Cartilage samples from the femurs of stable and destabilized stifle joints of 9 dogs that had undergone transection of the cranial cruciate ligament were examined by immunohistochemistry.

Results. The 3‐B‐3(–) and 7‐D‐4 epitopes were expressed in the superficial zone of cartilage from the destabilized femorotibial joints in the early stages of developing OA. The staining patterns with these two antibodies differed, with 3‐B‐3(–) reactivity confined to the superficial and upper middle zones of the articular cartilage, and 7‐D‐4 reactivity more prominent in the matrix, extending into the deeper zones and increasing with progression of the lesion. Both epitopes were also expressed in the superficial and upper middle zones of areas peripheral to the lesions and were detectable before the loss of matrix and proteoglycans could be identified by histochemical staining with toluidine blue.

Conclusion. In this study, the expression of atypical chondroitin sulfate proteoglycans was demonstrated in osteoarthritic canine cartilage, and the pattern of expression changed as the lesions progressed. The occurrence of 3‐B‐3(–) and 7‐D‐4 epitopes appears to be associated with changes in chondrocyte metabolism in the early stages of cartilage degeneration in experimental osteoarthritis.
High Frequency of Silent Inflammatory Bowel Disease in Spondylarthropathy
Authors: Leirisalo‐Repo Marjatta , Turunen Ulla , Stenman Svante , Helenius Petri , Seppälä Kari
Published: February 2007

Objective. To search for an association between gut infection, gut inflammation, and spondylarthropathies.

Methods. Ileocolonoscopy was performed in 118 patients with various inflammatory and noninflammatory joint diseases and in 24 patients with uncomplicated acute bacterial gastroenteritis.

Results. Endoscopic lesions were more frequent in patients with spondylarthropathy (44%) compared with those with other inflammatory arthritides (6%; P = 0.001). Ileal changes were observed only in patients with spondylarthropathy (20% versus 0%; P = 0.01). Inflammatory bowel disease was the endoscopic diagnosis in 19% of the arthritis patients. Possible or definite Crohn's disease was diagnosed in 26% of patients with chronic spondylarthropathy, and ulcerative colitis in 1 patient with rheumatoid arthritis and in 1 with chronic uroarthritis. Histologic evidence of inflammation differed less distinctly than endoscopy findings between patient groups. There was no association of gut lesions with the use of nonsteroidal antiinflammatory drugs or with the presence of HLA‐B27.

Conclusion. Gut inflammation is frequent in patients with spondylarthropathy, and one‐fourth of the patients who have chronic disease have early features of Crohn's disease.
HIP Osteonecrosis Secondary to the Administration of Corticosteroids for Feigned Bronchial Asthma
Authors: Alarcön Graciela S. , Mikhail Isis , Jaffe Kenneth A. , Bradley Laurence A. , Bailey William C.
Published: February 2007

We describe the case of a woman who developed hip osteonecrosis after prolonged use of corticosteroids for feigned bronchial asthma. This type of musculoskeletal manifestation of the factitious disorders has not been reported previously.
Expression of L‐Selectin, CD43, and CD44 in Synovial Fluid Neutrophils from Patients with Inflammatory Joint Diseases
Authors: Humbría Alicia , Díaz‐González Federico , Campanero Miguel R. , Arroyo Alicia G. , Laffón Armando , González‐Amaro Roberto , Sánchez‐Madrid Francisco
Published: February 2007

Objective. To study the expression of L‐selectin, CD43, and CD44 on peripheral blood (PB) and synovial fluid (SF) neutrophils from patients with inflammatory joint diseases, and to investigate the presence of soluble L‐selectin in both SF and plasma from patients with acute and chronic arthritis.

Methods. PB and SF neutrophils were isolated from 13 patients with rheumatoid arthritis (RA) and 17 patients with various inflammatory joint diseases other than RA. Expression of L‐selectin, CD43, CD44, CD11a, and CD11b was determined in both unstimulated and in vitro—activated cells by immunofluorescence flow cytometry. Soluble L‐selectin levels were estimated in SF and plasma by a semiquantitative radioimmunoassay.

Results. Neutrophils from SF showed diminished expression of L‐selectin compared with PB neutrophils; CD43 expression and CD44 expression were decreased in SF neutrophils from most patients. In contrast, SF neutrophils exhibited significantly increased expression of CD11b, to an extent similar to that seen with in vitro—activated PB neutrophils. Soluble L‐selectin was detected at similar levels in SF and PB.

Conclusion. The phenotypic profile of SF neutrophils (low levels of L‐selectin, CD43, and CD44, and high levels of CD11b) from most patients with RA or other inflammatory joint conditions resembles that observed in in vitro—activated neutrophils. Our results suggest that SF neutrophils are activated to a similar degree in inflammatory joint diseases with different pathogenic mechanisms.
Effects of Peripheral Cold Exposure on Microvascular Dynamics in Systemic Sclerosis
Authors: Grassi Walter , Core Paolo , Carlino Giorgio , Cervini Claudio
Published: February 2007

Objective. To determine the influence of cold exposure on microvascular permeability in systemic sclerosis (SSc).

Methods. Thirteen patients with SSc were studied by dynamic fluorescence videomicroscopy under basal conditions and after exposure to cold.

Results. Exposure to cold caused a significant reduction in the interstitial concentration of sodium fluorescein (P < 0.05 to 0.001).

Conclusion. Our findings show that cold exposure has a striking effect on microvascular dynamics in SSc.
Inhibition of Collagenase Activity by N‐Chlorotaurine, a Product of Activated Neutrophils
Authors: Davies Joanna M. S. , Horwitz David A. , Davies Kelvin J. A.
Published: February 2007

Objective. To study the effects of N‐chlorotaurine on collagenase activity, as a model of the effects of neutrophil activation in inflammatory arthritis.

Methods. Collagen degradation by collagenase was measured by the release of acid‐soluble counts from 3H‐collagen.

Results. N‐chlorotaurine inhibited the degradation of collagen by bacterial collagenase. This result is explained by a direct inhibition/inactivation of collagenase, since N‐chlorotaurine had no effect on the proteolytic susceptibility of collagen itself. The effect appears to be specific to N‐chlorotaurine since N‐chloroalanine, N‐chloroleucine, and HOCl/OCl‐ failed to inhibit collagenase; in fact, N‐chloroalanine and N‐chloroleucine actually increased the proteolytic susceptibility of collagen.

Conclusion. N‐chlorotaurine may minimize damage to cartilaginous joint structures in inflammatory arthritis by inhibiting/inactivating collagenase.
Safe and effective isokinetic knee extension training in rheumatoid arthritis
Authors: Lyngberg Kirsten K. , Ramsing Benedicte U. , Nawrocki Anette , Harreby Mette , Danneskiold‐Samsøe Bente
Published: February 2007

Objective. To evaluate the safety of isokinetic knee extensor strength training, and its effectiveness with regard to knee extension, in patients with rheumatoid arthritis (RA).

Methods. Nine women with RA, all in functional stage II or III, underwent a low‐intensity strengthening protocol with 48 repetitions at 50% of maximal voluntary contraction, 3 times per week for 3 weeks, using an isokinetic dynamometer.

Results. Five patients had knee synovitis at entry; but neither synovitis nor joint pain increased. The mean gain in strength was 21%.

Conclusion. This training method was effective and safe in patients with RA.
Interleukin‐1β induces cytosolic phospholipase a2 and prostaglandin h synthase in rheumatoid synovial fibroblasts
Authors: Hulkower Keren I. , Wertheimer Stanley J. , Levin Wayne , Coffey John W. , Anderson Celia M. , Chen Ting , Dewitt David L. , Crowl Robert M. , Hope William C. , Morgan Douglas W.
Published: February 2007

Objective. In order to investigate potential regulatory mechanisms for the increased production of prostaglandin E2 (PGE2) in interleukin‐1β (IL‐1β)–stimulated rheumatoid synovial fibroblasts (RSF), this study examined the induction of phospholipase A2 (PLA2) and prostaglandin H synthase (PGHS) enzymes and the correlation of these events with PGE2 production in IL‐1β–stimulated RSF.

Methods. Protein and messenger RNA (mRNA) levels of cytosolic PLA2 (cPLA2) and PGHS‐2 enzymes in IL‐1β–stimulated RSF were measured by Western and Northern blotting, respectively, using specific antisera and complementary DNA probes. Enzymatic activity of cPLA2 was determined in cell‐free reaction mixtures utilizing mixed micelles of 14C‐phosphatidylcholine and Triton X‐100 as the substrate. PGE2 levels were quantitated using a commercial enzyme immunoassay kit.

Results. Incubation of RSF with IL‐1β increased the mRNA and protein levels for the high molecular weight cPLA2 as well as for the mitogen/growth factor–responsive PGHS (PGHS‐2). The IL‐1 receptor antagonist completely abolished the induction of these two enzymes and the stimulation of PGE2 production by IL‐1β in RSF. In contrast, levels of the other known forms of these enzymes, i.e., the 14‐kd secretory group II PLA2 (sPLA2) and the constitutive form of PGHS (PGHS‐1), were unaffected by IL‐1β treatment.

Conclusion. These are the first data to demonstrate the coordinate induction by IL‐1 of cPLA2 and PGHS‐2 in RSF. The time‐course for the induction of these enzymes suggests that their increase contributes to the increased production of PGE2 in IL‐1–treated RSF, and may help explain the capacity of RSF to produce large amounts of PGE2.
Modulation of helper T cell function by prostaglandins
Authors: Gold Kenneth N. , Weyand Cornelia M. , Goronzy JöRg J.
Published: February 2007

Objective. To determine the influence of prostaglandins on the production of interleukins 2, 4, and 5 (IL‐2, IL‐4, and IL‐5), interferon‐γ (IFNγ), granulocytemacrophage colony‐stimulating factor, and transforming growth factor β1 by CD4+ T cells.
Methods. TH0, TH1, and TH2 T cell clones were stimulated in the presence and absence of the prostaglandin E1 (PGE1) analog misoprostol and PGE2. Lymphokine production was analyzed by using a semiquantitative polymerase chain reaction with lymphokine‐specific primer sets and/or by determining lymphokine activity in bioassays.
Results. PGE2 and misoprostol have distinct effects on different functional T helper cells. TH1 cells, which predominantly produce IL‐2 and IFNγ, are completely inhibited, while TH2 cells, which preferentially produce IL‐4 and IL‐5, are largely unaffected. Misoprostol and PGE2 are equivalent in their ability to modulate T cell function. In the presence of prostaglandins, THO‐like helper cells, which are characterized by the coproduction of multiple lymphokines, function as TH2 cells; however, they do not differentiate into TH2 T cells.
Conclusion. Prostaglandins that are produced in inflamed tissue can regulate the functional capabilities of infiltrating T cells. In the presence of PGE2, TH1‐like responses are suppressed and TH0‐like responses are shifted toward a TH2‐like pattern dominated by the production of IL‐4 and IL‐5. Inhibition of prostaglandin production by antiinflammatory agents might restore TH1 responses with local production of IL‐2 and IFNγ.
Use of dynamic magnetic resonance imaging with fast imaging in the detection of early and advanced sacroiliitis in spondylarthropathy patients
Authors: Braun Jürgen , Bollow Matthias , Eggens Ulrich , König Hermann , Distler Armin , Sieper Joachim
Published: February 2007

Objective. To evaluate the new magnetic resonance imaging (MRI) method of dynamic MRI with fast imaging in the diagnosis of sacroiliitis among patients with spondylarthropathy.

Methods. Fifteen patients with a history of inflammatory back pain without radiographic evidence of grade II or greater sacroiliitis (group 1), 25 patients with definite ankylosing spondylitis (group 2), and 12 patients with noninflammatory spinal pain (controls) (group 3) were examined. Dynamic MRI with fast imaging was performed after intravenous bolus injection of the contrast agent gadolinium—diethylenetriamine pentaacetic acid. The degree of enhancement was graded as representing acute sacroiliitis, latent sacroiliitis, or no sacroiliitis.

Results. Acute sacroiliitis was detected in 22 of 30 sacroiliac (SI) joints in group 1 patients and in 27 of 50 SI joints in group 2 patients; latent sacroiliitis was seen in 25 of 80 SI joints in patients from groups 1 and 2. No group 3 patient was found to have sacroiliitis.

Conclusion. Early sacroiliitis can be demonstrated by dynamic MRI in spondylarthropathy patients in whom abnormalities are not revealed by conventional radiography.
Immunohistochemical characterization of inflammatory cells and immunologic activation markers in muscle and nerve biopsy specimens from patients with systemic polyarteritis nodosa
Authors: Cid Maria‐Cinta , Grau Josep Maria , Casademont Jordi , Campo Elías , Coll‐Vinent Blanca , López‐Soto Alfons , Ingelmo Miguel , Urbano‐Márquez Alvaro
Published: February 2007

Objective. To investigate the phenotype of infiltrating cells in classic lesions of polyarteritis nodosa (PAN).

Methods. Twenty‐one muscle and 10 sural nerve biopsy samples from 24 patients with systemic PAN were studied using avidin—biotin—peroxidase and alkaline phosphatase—anti—alkaline phosphatase immunohistochemical techniques.

Results. The inflammatory infiltrates consisted mainly of macrophages (41%) and T lymphocytes (41%), particularly of the CD4+ subset. Granulocytes were present in varying quantities (0–45%) and were more abundant in heavily infiltrated vessels and in those with fibrinoid necrosis. Dendritic cells could be identified in 4 samples. Proliferating and interleukin‐2 receptor—expressing cells, present in 71% and 79% of the patients, respectively, were more frequent in untreated patients.

Conclusion. T cell—mediated immune mechanisms may play a role in the development and perpetuation of PAN lesions.
Evidence of a local intestinal immunomodulatory effect of sulfasalazine in rheumatoid arthritis
Authors: Kanerud Lars , Scheynius Annika , Hafström Ingiäld
Published: February 2007

Objective. To analyze whether the intestinal mucosa in rheumatoid arthritis (RA) is immnunologically abnormal and whether sulfasalazine (SSZ) possesses any local intestinal immunoregulatory effect.

Methods. Lymphocyte subpopulations and HLA—DR expression were evaluated in biopsy specimens from the duodenal—jejunal mucosa and in peripheral blood samples obtained from 17 patients with RA, both before and after 16 weeks of SSZ treatment. The same mucosal assays were also performed in 7 controls.

Results. The mucosa of the small intestine in RA patients showed no differences in morphology, HLA—DR expression, or the amounts and distribution of CD3+, CD4+, CD8+, and γ/δ+ lymphocytes compared with the control group. However, there was a reduction in mucosal CD3+ and γ/δ+ lymphocyte numbers after SSZ therapy, which did not correspond to a change in peripheral blood CD3+ lymphocyte number. SSZ treatment also tended to diminish the peripheral blood CD4+:CD8+ cell ratio (P = 0.05).

Conclusion. No signs of inflammation or immunologic abnormalities were seen in RA duodenal‐jejunal mucosa. In this part of the intestine, however, SSZ exerted immunoregulatory effects that were not encountered in the peripheral blood.
Western blot band intensity analysis. Application to the diagnosis of lyme arthritis
Authors: Kowal Krzysztof , Weinstein Arthur
Published: February 2007

Objective. To determine the usefulness of quantitative band‐intensity analysis of Western blots for the diagnosis of Lyme arthritis.

Methods. IgG Western blots for antibodies to Borrelia burgdorferi were performed on sera from 39 patients with Lyme arthritis, 30 patients with syphilis, 50 patients with connective tissue diseases, and 10 healthy individuals. Band positions and band intensities were calculated using a computerized image analysis system.

Results. Lyme arthritis patients had more bands and higher‐intensity bands than did non‐Lyme patients. The presence of at least 2 bands of moderate to high intensity (>40 optical units) or at least 5 bands of lower intensity (>20 optical units) was over 90% sensitive and 100% specific for the diagnosis of Lyme arthritis. A 60‐kd band was present in all Lyme arthritis patients. The presence of an 83‐, 39‐, 21‐, or 18‐kd band was highly specific for Lyme arthritis.

Conclusion. Band intensity analysis increases the objectivity and accuracy of Western blot interpretation for the diagnosis of Lyme arthritis.
Investigating the genetic basis for ankylosing spondylitis. Linkage studies with the major histocompatibility complex region
Authors: Rubin Laurence A. , Amos Chris I. , Wade Judith A. , Martin John R. , Bale Sherri J. , Little A. Hugh , Gladman Dafna D. , Bonney George E. , Rubenstein Joel D. , Siminovitch Katherine A.
Published: February 2007

Objective. To assess the hypothesis that B27 or a gene(s) in close proximity (e.g., within or near the major histocompatibility complex [MHC]) represents a disease‐causing ankylosing spondylitis (AS) gene, and therefore contributes directly to the pathogenesis of this disorder.

Methods. MHC haplotypes were determined by both serologic and molecular analyses in 15 multiple‐case AS families from Toronto and Newfoundland. Segregation of MHC haplotypes with AS within these families was examined by linkage and identity‐by‐descent analyses. Attributable risk estimates for various genetic markers and for sex were calculated.

Results. Linkage analyses established significant linkage between AS and the MHC, the maximal logarithm of odds (LOD) score being 3.48 at a recombination frequency (θ) of 0.05. In a second analysis in which the population association of the MHC gene HLA—B27 with AS was taken into account, the maximal LOD score was 7.5 at θ = 0.05. Identity‐by‐descent analyses showed a significant departure from random segregation among affected avuncular (P< 0.05) and cousin (P< 0.01) pairs. The presence of HLA—B40 in HLA—B27 positive individuals increased the risk for disease more than 3‐fold, confirming previous reports. Disease susceptibility modeling suggested an autosomal dominant pattern of inheritance, with penetrance of approximately 20%.

Conclusion. These data provide the first conclusive demonstration of linkage between the MHC region and AS, and confirm that genes within this region contribute directly to the genetic susceptibility for AS.
Lack of a renal–protective effect of misoprostol in rheumatoid arthritis patients receiving cyclosporin a. results of a randomized, placebo–controlled trial
Authors: Weinblatt Michael E. , Germain Bernard F. , Kremer Joel M. , Wall Bruce A. , Weisman Michael H. , Maier Agnes L. , Coblyn Jonathan S.
Published: February 2007

Objective. To assess whether the synthetic prostaglandin misoprostol is renal protective in rheumatoid arthritis (RA) patients who are beginning cyclosporin A (CSA) therapy.

Methods. In this randomized, placebo–controlled, multicenter trial, 50 patients with active RA were randomized to receive either misoprostol (800 μg/day) or placebo for 16 weeks. After 2 weeks of pretreatment with misoprostol or placebo, all patients concomitantly received CSA at an initial and maximum dosage of 5 mg/kg/day for 12 weeks.

Results. A significant increase in the serum creatinine level was observed in both treatment groups, with no difference noted between groups. There was a high withdrawal rate in both groups, primarily due to adverse events.

Conclusion. A renal–protective effect was not demonstrated for misoprostol compared with placebo in RA patients who are beginning CSA therapy.
Therapeutic effect of recombinant vaccinia virus expressing the 60‐kd heat‐shock protein on adjuvant arthritis
Authors: Antonio López‐Guerrero José , Ortiz Maria Antonia , Páez Eduardo , Bernabéu Carmelo , Pedro López‐Bote Juan
Published: February 2007

Objective. To analyze the effects of recombinant viruses for 2 heat‐shock proteins in the treatment of adjuvant arthritis.

Methods. Virus vaccinia recombinant for mycobacterial heat‐shock protein 65 (hsp65‐VV) and human hsp60 (hsp60‐VV) were administered to rats during different stages of adjuvant arthritis. Arthritis score and immunity to the recombinant virus were analyzed.

Results. When delivered at the pre‐arthritis stage, both constructs ameliorated arthritis; greater protection was observed with hsp60‐VV. A specific T cell response to the recombinant proteins was detected. Furthermore, hsp60‐VV displayed a clear therapeutic effect on established arthritis.

Conclusion. Our results suggest novel avenues of therapeutic intervention in autoimmune arthritis associated with immunity to hsp60.
Methotrexate in rheumatoid arthritis. a five‐year prospective multicenter study
Authors: Weinblatt Michael E. , Kaplan Herbert , Germain Bernard F. , Block Sidney , Solomon Sheldon D. , Merriman Richard C. , Wolfe Frederick , Wall Bruce , Anderson Larry , Gall Eric , Torretti Dennis , Weissman Barbara
Published: February 2007

Objective. To evaluate the efficacy and tolerability of oral methotrexate (MTX) in rheumatoid arthritis (RA) in a long‐term prospective trial.

Methods. One hundred twenty‐three patients with RA who completed a 9‐month multicenter randomized trial comparing MTX and auranofin enrolled in this 5‐year prospective study of MTX.

Results. Significant (P = 0.0001) improvement compared with baseline was noted in all clinical disease variables, functional status, and the Westergren erythrocyte sedimentation rate (ESR). “Marked improvement” occurred in 87 (71%) and 85 (69%) of the patients, respectively, in the joint pain/tenderness index and the joint swelling index at the last evaluable visit. Forty‐four patients (36%) withdrew during the study. Eight (7%) withdrew due to lack of efficacy, and 8 (7%) due to adverse experiences, including 1 patient with cirrhosis. At 5 years, 64% of patients were still taking MTX and completed the study.

Conclusion. This large prospective study of long‐term MTX treatment demonstrates sustained clinical response and improvement in the Westergren ESR and functional assessment scores, with an acceptable toxicity profile.
In vivo production of interleukin‐10 by non–t cells in rheumatoid arthritis, sjöugren's syndrome, and systemic lupus erythematosus.
Authors: Llorente Luis , Richaud‐Patin Yvonne , Fior Renato , Alcocer‐Varela Jorge , Wijdenes John , Fourrier Brigitte Morel , Galanaud Pierre , Emilie Dominique
Published: February 2007

Objective. Interleukin‐10 (IL‐10) is a potent stimulator of B lymphocytes in vitro. In vivo dysregulation of IL‐10 gene expression was therefore analyzed in patients with rheumatoid arthritis (RA), primary Sjögren's syndrome (SS), and systemic lupus erythematosus (SLE).

Methods. Spontaneous production of IL‐10 by peripheral blood mononuclear cells was measured using reverse transcription polymerase chain reaction and enzyme‐linked immunosorbent assay in untreated patients with either RA (n = 10), SS (n = 10), or SLE (n = 10), and in 15 normal control subjects.

Results. IL‐10 production was dramatically higher in RA, SS, and SLE patients than in controls. In each group, both B lymphocytes and monocytes, but not T lymphocytes, produced IL‐10.

Conclusion. IL‐10 production is increased in RA, SS, and SLE. It may play a role in B lymphocyte hyperactivity and in the development of autoimmunity.
Interferon‐γ–inducible protein p16. a new target of antinuclear antibodies in patients with systemic lupus erythematosus
Authors: Seelig Hans Peter , Ehrfeld Hans , Renz Manfred
Published: February 2007

Objective. To determine the cellular expression and localization of interferon‐γ (IFNγ)–inducible protein p16, a new antigen specificity of antinuclear antibodies (ANA), and to evaluate the prevalence of anti‐p16, particularly in SLE patients.

Methods. Serum levels of anti‐p16 were determined by immunoblotting with recombinant p16 and cellular p16 messenger RNA (mRNA) by Northern blotting. We also utilized immunoprecipitation of 35Smethionine–labeled proteins, immunostaining of blotted proteins of subcellular fractions, and immunofluorescence studies with affinity‐purified rabbit and human anti–recombinant p16.

Results. Protein p16 was localized within the nucleolus and nucleoplasm and constitutively expressed in Raji, HeLa, HEp‐2, K562, and HL‐60 cells. Synthesis of mRNA and protein was increased in the presence of IFNγ. The prevalence of anti‐p16 was 29% in 374 SLE patients (35% in those positive for anti–double‐stranded DNA) and 0% in 188 healthy individuals. Anti‐p16 was always accompanied by positive findings on indirect immunofluorescence for ANA.

Conclusion. Anti‐p16 represents a main ANA specificity. Anti‐p16 may help to elucidate IFNγ‐dependent nuclear processes and to link autoantibody production to states of IFNγ activation.
Expression and shedding of intercellular adhesion molecule 1 and lymphocyte function–associated antigen 3 by normal and scleroderma fibroblasts.
Authors: Shi‐Wen Xu , Panesar Manvinder , Vancheeswaran Rama , Mason Justin , Haskard Dorian , Black Carol , Olsen Irwin , Abraham David
Published: February 2007

Objective. To examine intercellular adhesion molecule 1 (ICAM‐1) and lymphocyte function‐associated antigen 3 (LFA‐3) in cultures of normal and systemic sclerosis (SSc) dermal fibroblasts.

Methods. The surface and soluble forms of ICAM‐1 and LFA‐3 were measured by flow cytometry and capture enzyme‐linked immunosorbent assay, respectively.

Results. Surface ICAM‐1 was significantly higher on SSc fibroblasts compared with normal controls. β‐estradiol did not directly enhance ICAM‐1 or LFA‐3 expression in either normal or SSc cells, but significantly augmented the cytokine‐induced increase in ICAM‐1. Soluble ICAM‐1 (sICAM‐1) and sLFA‐3 were detected in fibroblast cultures. While no difference was found in the level of sLFA‐3, the shedding of sICAM‐1 was significantly increased (P < 0.001) in cells from SSc patients.

Conclusion. SSc fibroblasts express intrinsically elevated levels of surface ICAM‐1 and release higher levels of sICAM‐1 in vitro. Increased expression of ICAM‐1 by interferon‐γ and tumor necrosis factor α alone, and the further induction in combination with β‐estradiol may underlie an aspect of fibroblast dysfunction in SSc and the female predisposition to the disease.
Measurement of health status in children with juvenile rheumatoid arthritis
Authors: Singh Gurkirpal , Athreya Balu H. , Fries James F. , Goldsmith Donald P.
Published: February 2007

Objective. To develop and validate a self‐ or parent‐administered instrument for measuring functional status in children with juvenile rheumatoid arthritis (JRA).

Methods. We adapted the Stanford Health Assessment Questionnaire (HAQ) for use in children ages 1–19 years, by adding several new questions, such that for each functional area, there was at least 1 question relevant to children of all ages. The face validity of the instrument was evaluated by a group of 20 health professionals and parents of 22 healthy children. The questionnaire was then administered to parents of 72 JRA patients (mean age 9.1 years, onset type systemic in 16, polyarticular in 21, pauciarticular in 35).

Results. The instrument showed excellent internal reliability (Cronbach's α = 0.94), with a mean inter‐item correlation of 0.6. The convergent validity was demonstrated by strong correlations of the Disability Index (average of scores on all functional areas) with Steinbrocker functional class (Kendall's tau b = 0.77, P < 0.0001), number of involved joints (Kendall's tau b = 0.67, P < 0.0001), and morning stiffness (Kendall's tau b = 0.54, P < 0.0001). Spearman's correlation coefficient between Disability Index scores from questionnaires administered to parents and those from questionnaires administered to older children (>8 years) was 0.84 (n = 29; P < 0.001), showing that parents can accurately report for their children. The test–retest reliability, studied at a 2‐week interval, revealed virtually identical Disability Index scores measured on the 2 occasions (0.96 versus 0.96; P > 0.9 by paired t‐test; Spearman's correlation coefficient = 0.8, P < 0.002).

Conclusion. The Childhood HAQ, which takes less than 10 minutes to complete, is a valid, reliable, and sensitive instrument for measuring functional status in children with JRA.
Hla type as a predictor of mixed connective tissue disease differentiation ten‐year clinical and immunogenetic followup of 46 patients
Authors: Gendi Nagui S. T. , Welsh Ken I. , Van Venrooij Walther J. , Vancheeswaran Rama , Gilroy Jill , Black Carol M.
Published: February 2007

Objective. To determine any clinical or genetic markers of differentiation and outcome in a previously described cohort of 46 patients with mixed connective tissue disease (MCTD).

Methods. Patients were clinically evaluated, chart notes reviewed, and HLA subtyping and immunology profiles performed where possible. Eleven had died and 7 were lost to followup.

Results. MCTD had differentiated into systemic lupus erythematosus in 12 patients and into systemic sclerosis in 13. The latter was associated with HLA‐DR5 (P = 0.038), and nondifferentiation was associated with HLA‐DR2 or DR4 (P = 0.007). Three HLA‐DR4 positive patients had MCTD that evolved into rheumatoid arthritis. Erosive and/or deforming arthritis was associated with HLA‐DR1 or DR4 (P = 0.015). HLA‐DR3 was associated with interstitial lung fibrosis (P = 0.044) and keratoconjunctivitis sicca (0.001 < P < 0.01). Severe Raynaud's phenomenon predicted higher mortality (0.01 < P < 0.05).

Conclusion. We suggest that MCTD is, for most patients, an intermediate stage in a genetically determined progression to a recognized connective tissue disease. Those whose disease remains undifferentiated might be considered a distinct subset.
Long‐term survival in systemic lupus erythematosus patient characteristics associated with poorer outcomes
Authors: Ward Michael M. , Pyun Elise , Studenski Stephanie
Published: February 2007

Objective. To investigate the associations of age, sex, race, and socioeconomic status with long‐term survival in patients with systemic lupus erythematosus (SLE).

Methods. We examined survival in an inception cohort of 408 patients with SLE. The cohort included 177 black females, 162 white females, 49 white males, and 20 black males. The median duration of followup was 11 years (range 0.1‐22 years).

Results. One hundred forty‐four patients died during the study. The 5‐, 10‐, and 15‐year survival estimates for the entire cohort were 82%, 71%, and 63%, respectively. In univariate analyses, mortality rates increased with age and were higher among males, blacks, those without private medical insurance, and those living in census tracts with lower household incomes. In multivariate analyses, age, sex, and both socioeconomic indicators were associated with total mortality (mortality from any cause), while race was not. Lower socioeconomic status and increased age were also associated with higher rates of death from SLE.

Conclusion. Socioeconomic status, but not race, is associated with mortality in SLE. SLE‐related mortality also tends to increase with age, which suggests that SLE may not be less severe when it occurs later in life.
Prednisone treatment of elderly‐onset rheumatoid arthritis
Authors: Schaardenburg Dirkjan Van , Valkema Roelf , Dijkmans Ben A. C. , Papapoulos Socrates , Zwinderman Aeilko H. , Hubert Han K. , Pauwels Ernest K. J. , Breedveld Ferdinand C.
Published: February 2007

Objective.Prednisone is frequently used in the treatment of elderly‐onset rheumatoid arthritis (RA), but the balance between efficacy and toxicity, including the effect on bone mass, has not been investigated in long‐term studies. This prospective, randomized study was undertaken to compare disease activity and bone mass during long‐term treatment with prednisone versus chloroquine in this patient population.

Methods.Patients with active RA diagnosed at age ≥ 60 were randomized to receive prednisone (15 mg/day for 1 month, with the dosage tapered as low as possible thereafter) (n = 28) or chloroquine (n = 28). Patients who did not show a response received other second‐line drugs as an adjunct to prednisone or as a replacement for chloroquine. Bone mass was measured by dual‐energy x‐ray absorptiometry. The study duration was 2 years.

Results.During the 2 years, treatment with other second‐line drugs was needed for 12 patients in the prednisone group (43%) and 8 in the chloroquine group (29%). Functional capacity and disease activity improved significantly in both groups and did not differ significantly between the groups, except for a greater improvement in the prednisone group at 1 month. Radiographic scores for joint destruction progressed similarly in both groups. There was a nonsignificant excess bone loss of 1.8% in the spine and 1.5% in the hip in the prednisone group, compared with the chloroquine group.

Conclusion.Neither treatment was entirely satisfactory since a significant number of patients needed an additional second‐line drug over the 2‐year period.
Severe anemia as the presenting manifestation of giant cell arteritis
Authors: Michael Weiss L. , Gonzalez Emilio , Miller Stephen B. , Agudelo Carlos A.
Published: February 2007

Giant cell (temporal, cranial) arteritis (GCA) is usually confirmed in patients presenting with classic features. Those who present with atypical features often undergo prolonged evaluations until a diagnosis is established. Severe anemia as an initial manifestation of GCA has rarely been described. We describe herein 2 patients with biopsy‐proven GCA who presented with severe anemia and significant weight loss, which corrected after corticosteroid therapy.
Racial differences in the incidence of gout
Authors: Hochberg Marc C. , Thomas John , Johniene Thomas D. , Mead Lucy , Levine David M. , Klag Michael J.
Published: February 2007

Objective. To estimate the incidence of and examine risk factors for the development of gout in black and white male physicians.

Methods. Data from 2 cohorts of former medical students, 352 black men in the Meharry Cohort Study and 571 white men in the Johns Hopkins Precursors Study, were analyzed. Cases of gout were identified by self‐report. Baseline variables and incident hypertension were examined as risk factors for the development of gout in both cohorts.

Results. The incidence of gout was 3.11 and 1.82 per 1,000 person‐years in the black men and the white men, respectively (P< 0.05); the cumulative incidence was 10.9% and 5.8%, respectively (P= 0.04). The relative risk (RR) for gout among the black men was 1.69 (95% confidence interval [95% CI] 1.02–2.80). This excess risk persisted after adjustment for baseline systolic blood pressure (adjusted RR = 1.96 [95% CI 1.14–3.38]). Incident hypertension was independently associated with the development of gout in univariate analysis (RR = 3.78 [95% CI 2.18–6.58]); when this variable was included as a time‐dependent covariate in a Cox model, the excess risk for gout in black men was reduced and no longer significant (adjusted RR = 1.30 [95% CI 0.77–2.19]).

Conclusion. The approximately 2‐fold excess risk for gout among black men is explained, in part, by a greater risk of incident hypertension.
American college of rheumatology preliminary definition of improvement in rheumatoid arthritis
Authors: Felson David T. , Anderson Jennifer J. , Boers Maarten , Bombardier Claire , Furst Daniel , Goldsmith Charles , Katz Linda M. , Lightfoot Robert , Paulus Harold , Strand Vibeke , Tugwell Peter , Weinblatt Michael , James Williams H. , Wolfe Frederick , Kieszak Stephanie
Published: February 2007

Objective. Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials.

Methods. Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3‐step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement.

Results. The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acutephase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo‐treated patients as being improved.

Conclusion. We present a definition of improvement which we hope will be used widely in RA trials.
Fibromyalgia in women
Authors: Mountz James M. , Bradley Laurence A. , Modell Jack G. , Alexander Ronald W. , Triana‐Alexander Mireya , Aaron Leslie A. , Stewart Katharine E. , AlarcóN Graciela S. , Mountz John D.
Published: February 2007

Objective. To determine if regional cerebral blood flow (rCBF) in the left and right hemithalami or the left and right heads of the caudate nucleus is abnormal in women with fibromyalgia (FM).

Methods. Resting‐state rCBF in the hemithalami and left and right heads of the caudate nucleus of 10 untreated women with FM and 7 normal control women was measured by single‐photon–emission computed tomography. Pain threshold levels at tender and control points also were assessed in both the women with FM and the controls.

Results. The rCBF in the left and right hemithalami and the left and right heads of the caudate nucleus was significantly lower in women with FM than in normal controls (P = 0.01, P = 0.003, P = 0.01, and P = 0.02, respectively). Compared with controls, the women with FM also were characterized by significantly lower cortical rCBF (P = 0.001) and lower pain threshold levels at both tender points (P = 0.0001) and control points (P = 0.0001).

Conclusion. The findings of low rCBF and generalized low pain thresholds support the hypothesis that abnormal pain perception in women with FM may result from a functional abnormality within the central nervous system.
High level of interleukin‐10 production by the activated t cell population within the rheumatoid synovial membrane
Authors: Cohen Shara B. A. , Katsikis Peter D. , Chu Cong‐Qiu , Thomssen Henrike , Webb LOUISE M. C. , Maini Ravinder N. , Londei Marco , Feldmann Marc
Published: February 2007

Objective. To characterize the cytokine profile of the activated T cell population derived from the synovial membrane of rheumatoid arthritis (RA) patients.

Methods. Interleukin‐2 (IL‐2) was used to select for in vivo–activated T cells from the synovial membrane of 2 patients with RA, and the cells were cloned nonspecifically. The cytokine production profile of these clones was compared with that of clones derived from peripheral blood monocytes (PBM) by stimulating all clones for 24 hours with immobilized anti‐CD3 (coated at 10 μg/ml) or phorbol‐12‐myristate‐13‐acetate (10 ng/ml) plus soluble anti‐CD3 (1 μg/ml). Interferon‐γ (IFNγ), IL‐4, and IL‐10, the cytokines that discriminate between Th1 and Th2 cells and are involved in immunoregulation, were assayed by enzyme‐linked immunosorbent assay.

Results. There was a difference in the cytokines produced by the clones derived from the rheumatoid membranes compared with clones derived from the periphery. Clones derived from both membranes and PBM were mostly IFNγ‐producers, i.e., either a Th0 or a Th1 profile. There was a high proportion of IFNγ/high IL‐10‐producing cells derived from the joint, but not from the periphery. Of clones derived from the synovial membrane of each of 2 RA patients, 100% and 50% produced both 1–10 ng/ml IFNγ and >7 ng/ml IL‐10, compared with <7% of clones derived from normal or RA peripheral blood. In addition, when autologous membrane and PBM were compared, the mean concentration of IL‐10 produced by the clones derived from the synovial membrane sample was significantly different from those produced by clones derived from peripheral blood (P < 0.02).

Conclusion. The cytokine profile of the T cell clones that were obtained from the RA joint after expansion with IL‐2 is distinct from that of the T cells that are predominant in PBM. This supports the concept that the T cell subsets that accumulate in the joint are not a random sample. The high level of IL‐10 production by clones derived from the synovium suggests that this cytokine may be a major contributor to the endogenous immunosuppression that occurs in RA.
Autoepitopes of the 52‐kd ss‐a/ro molecule
Authors: Kato Tomohiro , Sasakawa Hiroko , Suzuki Satoshi , Shirako Manami , Tashiro Fumio , Nishioka Kusuki , Yamamoto Kazuhiko
Published: February 2007

Objective. This study was undertaken to clarify the mechanisms responsible for the generation of anti–52‐kd SS‐A/Ro autoantibodies and to elucidate why, as has recently been reported, anti–52‐kd autoantibodies preferentially recognize the denatured form rather than the native 52‐kd molecule.

Methods. Using a series of truncated 52‐kd auto‐antigens, produced as β‐galactosidase fusion proteins in Escherichia coli, the B cell epitope distribution was probed with 18 anti‐Ro–positive sera by immunoblotting and by enzyme‐linked immunosorbent assay.

Results. Nearly all the antigenicity of the molecule was found to be linked to its leucine zipper region. In a further study using 9 of the 18 sera, the antigenicity of the molecule was found to be mainly formed by multiple conformational epitopes, and one of these epitopes appeared to be universally recognized by all the sera tested.

Conclusion. The recognition of multiple epitopes indicates that the Ro 52‐kd antigen itself drives the autoimmunity to this molecule. Further, the concentration of the antigenicity at the leucine zipper region may explain why anti–52‐kd antibodies preferentially recognize the denatured protein rather than its native form.
End‐stage liver disease developing with the use of methotrexate in heterozygous α1‐antitrypsin deficiency
Authors: Hilsden Robert J. , Urbanski Stefan J. , Swain Mark G.
Published: February 2007

We report a case of cirrhosis developing in a man who was heterozygous for α1‐antitrypsin deficiency and who was receiving methotrexate for severe rheumatoid arthritis. The α1‐antitrypsin phenotype PiMZ has been associated with cryptogenic cirrhosis. Our patient had no biochemical or histologic evidence of chronic liver disease during the first year of receiving methotrexate. We postulate that the PiMZ state may result in enhanced susceptibility to methotrexate‐induced hepatic toxicity and should be screened for if liver function abnormalities occur during methotrexate therapy.
Levels of circulating collagenase, stromelysin‐1, and tissue inhibitor of matrix metalloproteinases 1 in patients with rheumatoid arthritis: relationship to serum levels of antigenic keratan sulfate and systemic parameters of inflammation
Authors: Manicourt Daniel‐Henri , Fujimoto Noboru , Obata Ken'ichi , Thonar Eugene j.‐ M. A.
Published: February 2007

Objective. To measure serum levels of matrix metalloproteinase–1 (MMP‐1), matrix metalloproteinase–3 (MMP‐3), and tissue inhibitor of MMP–1 (TIMP‐1) in patients with rheumatoid arthritis (RA) and in agematched control subjects, and to determine how these correlate with serum levels of antigenic keratan sulfate (KS) and other biochemical and clinical indicators of disease activity.

Methods. Immunoassays were used to measure levels of MMP‐1, MMP‐3, TIMP‐1, and antigenic KS. Radiologic and functional joint scores were based upon Steinbrocker's criteria. Erythrocyte sedimentation rates (ESR) and levels of C‐reactive proteins (CRP) were measured.

Results. In RA patients, levels of MMP‐3 and TIMP‐1 were significantly increased, and strongly correlated with the ESR and CRP levels but not with radiologic or functional joint scores. Levels of antigenic KS were significantly lower in RA patients and correlated negatively with systemic parameters of inflammation and serum levels of TIMP‐1.

Conclusions. The increase in serum levels of MMP‐3 and TIMP‐1 appears to reflect systemic inflammation in RA. The inverse correlation between serum levels of TIMP‐1 and antigenic KS suggests that an upregulation of TIMP‐1 synthesis might be responsible for the apparent suppression of cartilage aggrecan catabolism in patients with severe inflammatory changes.
Differential effects of interleukins 10 and 4 on the production of interleukin‐6 by blood and synovium monocytes in rheumatoid arthritis
Authors: Chomarat Pascale , Banchereau Jacques , Miossec Pierre
Published: February 2007

Objective. To determine how the antiinflammatory cytokines interleukin‐10 (IL‐10) and IL‐4 affect the production of IL‐6 in rheumatoid arthritis (RA) and to assess the contribution of IL‐10 production.

Methods. IL‐6 production was measured by enzyme‐linked immunosorbent assay (ELISA) in the supernatants of cultured RA synovium pieces (from 23 patients), purified RA synovial tissue monocyte/macrophages, and RA blood monocytes, in the presence of IL‐10 and IL‐4. IL‐10 was also detected by ELISA in culture supernatants and in RA sera.

Results. The production of IL‐6 by RA synovium was strongly inhibited by IL‐4 (46.6%; P = 0.0001) and was inhibited to a lower extent by IL‐10 (25.3%; P = 0.03). Likewise, the spontaneous production of IL‐6 by RA synovial tissue monocyte/macrophages was decreased by the addition of IL‐4 (48.8%) and IL‐10 (23.7%). This inhibition of IL‐6 production was significantly lower (P < 0.03) than that observed with RA blood monocytes (83.0% for IL‐10 and 85.2% for IL‐4). Interestingly, and in contrast to RA blood monocytes, RA synovial tissue monocyte/macrophages produced spontaneously high levels of IL‐10, which were inhibited by IL‐4 and interferon‐γ.

Conclusion. The ability of IL‐10 and IL‐4 to suppress IL‐6 production was dependent on 1) differences in the state of differentiation of blood and synovial tissue monocytes, and 2) local production of cytokine inside the synovium.