bluuebunny/crossref_metadata_2025 huggingface dataset:
Bone mineralization and bone mineral metabolism in children with juvenile rheumatoid arthritis
Authors: Pepmueller Peri Hickman , Cassidy James T. , Allen Susan H. , Hillman Laura S.
Published: February 2007

Objective. To identify mechanisms of the osteopenia associated with juvenile rheumatoid arthritis (JRA) by determining parameters of bone mineralization, and bone mineral content and density (BMC and BMD), in children with JRA.

Methods. BMC and BMD were measured by dual x‐ray absorptiometry in 41 children with JRA and 62 healthy children. Serum samples were analyzed for concentrations of minerals, vitamin D, parathyroid hormone, osteocalcin, bone‐specific alkaline phosphatase (BAP), procollagen I carboxy‐terminal propeptide, and tartrate‐resistant acid phosphatase (TRAP), and urinary excretion of deoxypyridinoline crosslinks and calcium.

Results. BMD was decreased at all sites in JRA patients. BMD, corrected for age, height, weight, and bone area, was decreased at cortical bone sites (1/3 radius, upper and lower extremities, and whole body). Low concentrations of osteocalcin and BAP suggested reduced bone formation, and low TRAP levels suggested decreased resorption. Clinical scales of disease severity were negatively correlated with measures of bone mass. Laboratory markers of disease severity were highly correlated with decreases in markers of bone formation, but not with those of resorption. Although laboratory findings were similar for children with oligoarticular and polyarticular disease, differences in bone mass were greater in children with polyarticular disease.

Conclusion. These data suggest an association between decreased bone mineralization in JRA and low bone formation that is related to disease severity. Efforts to stimulate bone formation, therefore, need to be considered clinically in prepubertal children with active JRA.
Anti‐endothelial cell IgG antibodies from patients with Wegener's granulomatosis bind to human endothelial cells in vitro and induce adhesion molecule expression and cytokine secretion
Authors: del Papa Nicoletta , Guidali Luisa , Sironi Marina , Shoenfeld Yehuda , Mantovani Alberto , Tincani Angela , Balestrieri Genesio , Radice Antonella , Sinico R. Alberto , Meroni Pier Luigi
Published: February 2007

Objective. To elucidate the role of antiendothelial cell antibodies (AECA) in vascular inflammation in patients with Wegener's granulomatosis (WG).

Methods. IgG fractions from 3 AECA‐positive WG patients, IgG from 3 AECA‐negative WG patients, and IgG from healthy donors were tested for their ability to: a) bind to endothelial cells and to display complement‐dependent or antibody‐dependent cellular cytotoxicity, b) modulate cell membrane expression of adhesion molecules, as evaluated by cytofluorometry and by immunoenzymatic assay, and c) induce the secretion of interleukin‐1β (IL‐1β), IL‐6, IL‐8, and monocyte chemotactic protein 1 (MCP‐1).

Results. We found that AECA IgG from WG patients do not display any significant cytotoxicity but are able to up‐regulate the expression of E‐selectin, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 and to induce the secretion of IL‐1β, IL‐6, IL‐8, and MCP‐1.

Conclusion. AECA in patients with WG could play a potential pathogenetic role by activating endothelial cells, and thus facilitating leukocyte recruitment and adhesion to endothelial surfaces, rather than by displaying a cytotoxic activity.
Aberrant expression pattern of the SS‐B/La antigen in the labial salivary glands of patients with Sjögren's syndrome
Authors: de Wilde P. C. M. , Kater L. , Bodeutsch C. , van den Hoogen F. H. J. , van de Putte L. B. A. , van Venrooij W. J.
Published: February 2007

Objective. Salivary glands of patients with Sjögren's syndrome (SS) have been shown to be a site of anti‐SS‐B/La antibody production. The present study investigated differences in the localization of the SS‐B/La antigen in labial salivary gland (LSG) tissue between SS and non‐SS patients, which may explain the local antigen‐driven anti–SS‐B/La response.

Methods. Distribution of SS‐B/La was studied immunohistologically in the LSG biopsy samples of 9 SS patients, 10 non‐SS patients, and in normal tissues obtained at autopsy within 2 hours after death, using a mouse monoclonal antibody directed to SS‐B/La. In 3 SS and 3 non‐SS patients, LSGs were also studied with affinity‐purified biotinylated human antibodies directed against SS‐B/La.

Results. In the non‐SS patients, SS‐B/La was primarily observed in the nucleoli of acinic cells of the LSGs. Patients with either primary SS or secondary SS showed an accumulation of SS‐B/La in the nucleoplasm of acinic cells. In the SS patients, SS‐B/La was also detected in the cytoplasm as a diffuse or perinuclear staining. Sometimes, SS‐B/La was found along the membrane of acinic cells as well. This aberrant nuclear and cytoplasmic distribution of SS‐B/La in SS patients correlated well with abnormalities in the composition of the plasma cell population in the LSGs, but not with a lymphocytic focus score > 1.

Conclusion. The accumulation and redistribution of SS‐B/La in the LSGs may play an important role in the local antigen‐driven anti–SS‐B/La response in SS, and can also be used to improve the diagnostic possibilities of the LSG biopsy.
Elevated serum level of soluble HLA class I antigens in patients with systemic lupus erythematosus
Authors: Tsuchiya Naoyuki , Shiota Michiko , Yamaguchi Akihiro , Ito Koji
Published: February 2007

Objective. To examine the clinical significance of serum soluble HLA class I antigens (sHLA class I) in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

Methods. Serum levels of sHLA class I were measured by enzyme‐linked immunosorbent assay, using a monoclonal antibody against monomorphic determinant of HLA class I (W6/32) and an enzyme‐labeled polyclonal antibody to human β2‐microglobulin.

Results. The serum sHLA class I concentration was 1.85 ± 1.15 μg/ml (mean ± SD) in 27 patients with SLE (P < 0.0001 versus normal controls, P = 0.0001 versus RA), 0.61 ± 0.34 μg/ml in 16 patients with RA (P = 0.02 versus normal controls), and 0.41 ± 0.20 μg/ml in normal controls. The HLA class I levels were significantly correlated with the SLE Disease Activity Index (r = 0.62, P = 0.0004) and with a reduction of CH50 levels (r = −0.60, P = 0.0007). A longitudinal analysis of patients with SLE indicated that serum sHLA class I levels fluctuated in conjunction with other disease activity markers.

Conclusion. Serum sHLA class I may be useful as a disease activity marker of SLE. The mechanism of secretion and the physiologic role of sHLA class I require further study.
Cellular adhesion molecules in rat adjuvant arthritis
Authors: Halloran Margaret M. , Szekanecz Zoltan , Barquin Nora , Haines G. Kenneth , Koch Alisa E.
Published: February 2007

Objective. To examine adhesion molecule expression during the progression of inflammation in a rheumatoid arthritis model of adjuvant‐induced arthritis (AIA) in rats.

Methods. Immunohistochemical analysis was used to determine the distribution of the following adhesion molecules: lymphocyte function–associated antigen 1 (LFA‐1; CD11a/CD18), Mac‐1 and p150/95 (CD11bc/CD18), intercellular adhesion molecule 1 (ICAM‐1), and CD44 in tissue sections from the ankle joints of rats with AIA. Control animals and those with AIA were killed at intervals over a 54‐day period after injection with mineral oil and Mycobacterium butyricum, respectively.

Results. CD44 and LFA‐1 were expressed on lymphocytes, macrophages, and synovial (ST) lining cells. CD44 expression on macrophages was found to be increased compared with control animals by day 18, and was significantly increased by day 41. CD44 expression on lymphocytes significantly increased earlier, on days 11–18. Increased LFA‐1 expression on macrophages occurred late, on day 41. LFA‐1 expression on lymphocytes was significantly increased on days 25, 47, and 54. ST lining cells exhibited two distinct periods of increased expression, one early, on days 11–25 and one later, on days 41–54. CD11b/c was expressed on macrophages and ST lining cells, showing a significant increase on AIA rat ST lining cells compared with control animals on day 4. No differences in ICAM‐1 expression on endothelial cells between rats with AIA and controls were found on any of the days examined.

Conclusion. CD44 expression is up‐regulated on macrophages and lymphocytes during the early development of AIA, while LFA‐1 expression is up‐regulated later in the development of AIA. The up‐regulation of CD44 and LFA‐1 at different times in the development of AIA suggests an important role for these adhesion molecules in establishing and sustaining an inflammatory response in the AIA joint.
Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin‐10 and interleukin‐4
Authors: van Roon Joel A. G. , van Roy Johanna L. A. M. , Gmelig‐Meyling Frits H. J. , Lafeber Floris P. J. G. , Bijlsma Johannes W. J.
Published: February 2007

Objective. Inflammation‐induced articular cartilage degradation is a major problem in rheumatoid arthritis (RA). Type 1 T cell activity (characterized by interferon‐γ/interleukin‐2 [IL‐2] production), and consequently, the production of the proinflammatory cytokines IL‐1 and tumor necrosis factor α (TNFα), have been reported to play a major role in cartilage damage. IL‐10 and IL‐4, both produced by type 2 T cells, are cytokines with the capacity to down‐regulate proinflammatory responses. The present study was undertaken to investigate the way in which these cytokines affect activated mononuclear cells (MNC) of RA patients in relation to human articular cartilage degradation in vitro.

Methods. MNC from synovial fluid and peripheral blood of RA patients were stimulated with bacterial antigen and treated with IL‐10 and/or IL‐4. Bacterial antigen is known to activate type 1 T cells and to induce proinflammatory IL‐1/TNFα–dependent cartilage damage. Cytokine production and effects of conditioned media, as well as effects of IL‐10 and IL‐4 on proteoglycan (PG) turnover (as a measure for cartilage damage), were determined.

Results. IL‐10 and IL‐4 inhibited proinflammatory cytokine production of stimulated RA MNC and completely reversed inhibition of cartilage PG synthesis induced by these stimulated RA MNC. IL‐10 was more potent than IL‐4 in this respect, and the combination of IL‐10 and IL‐4 had an additive effect. In addition, IL‐10 directly stimulated cartilage PG synthesis.

Conclusion. IL‐10 reverses the cartilage degradation induced by antigen‐stimulated MNC, and IL‐4 has an additive effect on this process. Furthermore, IL‐10 has a direct stimulatory effect on PG synthesis, and IL‐4, as a growth factor for type 2 T cells, can reduce the ratio of type 1 to type 2 T cell activity. These results provide evidence in favor of the use of a combination of the two cytokines in the treatment of RA.
Strong association of dermatomyositis‐specific Mi‐2 autoantibodies with a tryptophan at position 9 of the HLA‐DRβ chain
Authors: Mierau Rudolf , Dick Thomas , Bartz‐Bazzanella Peter , Keller Elisabeth , Albert Ekkehard D. , Genth Ekkehard
Published: February 2007

Objective. To characterize the clinical and immunogenetic features of patients with Mi‐2 autoantibodies.

Methods. Eighteen adult white patients with Mi‐2 antibodies were clinically characterized and compared with 41 Mi‐2–negative dermatomyositis (DM) patients. HLA class I and class II typing for DRB alleles was done by microcytotoxicity assay and for DQA and DQB alleles by polymerase chain reaction–based oligotyping.

Results. Seventeen of the 18 Mi‐2–positive patients had DM. Symptoms of scleroderma, lung involvement, and arthritis were less common in this group than in the Mi‐2–negative DM patients; the V‐sign rash and nailfold involvement were found more frequently. Mi‐2 antibodies were strongly associated with HLA‐DR7 (88% versus 24% in healthy controls), HLA–DQA1*0201 (86% versus 23%), and DR7 “homozygosity” (31% versus 0%). A tryptophan residue at position 9 of the HLA–DRβ chain was present in all Mi‐2–positive patients (100% versus 62%; homozygous in 81% versus 15%).

Conclusion. Our results reemphasize the specificity of Mi‐2 antibodies for DM, and extend previous reports that Mi‐2 antibody production is associated with certain HLA class II antigens. We propose β9‐Trp as a candidate epitope on the HLA–DRβ chain as a prerequisite for this type of autoimmune response.
Chronic intestinal pseudoobstruction associated with autoantibodies against proliferating cell nuclear antigen
Authors: Nojima Yoshihisa , Mimura Toshihide , Hamasaki Ken , Furuya Hiroko , Tanaka Go , Nakajima Atsushi , Matsuhashi Nobuyuki , Yazaki Yoshio
Published: February 2007

Autoantibodies against proliferating cell nuclear antigen (PCNA) have been detected almost exclusively in sera from patients with systemic lupus erythematosus (SLE). Because of the extremely low prevalence of anti‐PCNA, however, it has been difficult to establish its disease specificity and clinical associations. We present 2 cases in which patients with anti‐PCNA developed severe gastrointestinal dysfunction that led to chronic intestinal pseudoobstruction. Neither patient had manifestations suggestive of SLE. Although sclerodermatous skin changes were minimal or absent in these patients, physical and radiographic findings indicated that systemic sclerosis was a likely cause of the gastrointestinal dysfunction. The similarity of the clinical features in these patients implies that the unusual detection of this unique autoantibody may not be a coincidence.
Synergy between T cell receptor β gene polymorphism and HLA–DR4 in susceptibility to rheumatoid arthritis
Authors: Mu Hua , Charmley Patrick , King Mary‐Claire , Criswell Lindsey A.
Published: February 2007

Objective. To investigate the etiologic significance of germline polymorphisms in the T cell receptor β variable region 6S7 (TCRBV6S7) gene segment and adjacent loci in susceptibility to rheumatoid arthritis (RA).

Methods. Ten TCRB allelic polymorphisms were analyzed from 3 groups of white women: 112 with RA, 72 with systemic lupus erythematosus, and 70 healthy controls. All participants were also HLA typed.

Results. HLA–DR4+ RA patients showed significantly increased frequencies of TCRBV6S7*1, 13S5P*1 (an allelic variant of BV13S5 promoter), and 12S4*2, compared with healthy controls. The combination of DR4 with either BV6S7*1, 13S5P*1, or 12S4*2 conferred greater risk for RA than HLA–DR4 alone. Pairwise analyses showed a high degree of linkage disequilibrium (P = 10−5‐10−8) between these 3 TCRBV loci that span 47 kilobases (kb).

Conclusion. Our data suggest that a TCR gene segment in or linked to this 47‐kb region may be involved in genetic susceptibility to RA through an interaction with HLA–DR4.
Molecular detection of bacterial DNA in venereal‐associated arthritis
Authors: Li Feng , Bulbul Rula , Schumacher H. Ralph , Kieber‐Emmons Thomas , Callegari Peter E. , von Feldt Joan M. , Norden Daniel , Freundh Bruce , Wang Bin , Imonitie Victor , Chang Cheng Pei , Nachamkin Irving , Weiner David B. , Williams William V.
Published: February 2007

Objective. To evaluate the utility of polymerase chain reaction (PCR) amplification in detecting DNA from venereal‐associated microorganisms in the synovial fluid of patients with inflammatory arthritis.

Methods. Oligonucleotide primers were developed for nested PCR based on Chlamydia, Ureaplasma, and Neisseria DNA sequences. PCR products were detected by gel electrophoresis and dot‐blot hybridization. Primers specific for the target bacterial DNA were used to search for bacterial DNA in 61 synovial fluid specimens from patients with inflammatory arthritis, including several clinically associated with venereal infection.

Results. Five of the 61 synovial fluid specimens were positive for Neisseria gonorrhoeae DNA. Four of the 5 patients had clinical diagnoses of gonococcal arthritis; the other patient had an unexplained monarthritis. One specimen from a patient with a clinical diagnosis of gonococcal arthritis was negative for N gonorrhoeae. Three of the 61 specimens were positive for Chlamydia DNA. Two were derived from patients with clinical diagnoses of reactive arthritis or Reiter's syndrome, and 1 was from a patient with unexplained monarthritis. One of the 61 specimens was positive for Ureaplasma DNA; this sample was from a patient with a clinical diagnosis of Reiter's syndrome. In an additional patient with Reiter's syndrome, Ureaplasma DNA was also found in prostate biopsy tissue and a urine sample obtained after prostate massage (synovial fluid not available).

Conclusion. These data support the classification of these 3 venereal‐associated arthritides as infectious processes, and suggest that PCR for bacterial DNA is a useful method for detecting infectious agents in synovial fluid.
Risk of osteoarthritis associated with long‐term weight‐bearing sports: A radiologic survey of the hips and knees in female ex‐athletes and population controls
Authors: Spector Tim D. , Harris Pat A. , Hart Deborah J. , Cicuttini Flavia M. , Nandra Dalbir , Etherington John , Wolman Roger L. , Doyle David V.
Published: February 2007

Objective. To estimate the risk of osteoarthritis (OA) of the hip and knee due to long‐term weight‐bearing sports activity in ex–elite athletes and the general population.

Methods. A retrospective cohort study was conducted of 81 female ex–elite athletes (67 middle‐ and long‐distance runners, and 14 tennis players), currently ages 40–65, recruited from original playing records, and 977 age‐matched female controls, taken from the age–sex register of the offices of a group general practice in Chingford, Northeast London, England. The definition of OA included radiologic changes (joint space narrowing and osteophytosis) in the hip joints, patellofemoral (PF) joints, and tibiofemoral (TF) joints.

Results. Compared with controls of similar age, the ex‐athletes had greater rates of radiologic OA at all sites. This association increased further after adjustment for height and weight differences, and was strongest for the presence of osteophytes at the TF joints (odds ratio [OR] 3.57, 95% confidence interval [95% CI] 1.89–6.71), at the PF joints (OR 3.50, 95% CI 1.80–6.81), narrowing at the PF joints (OR 2.97, 95% CI 1.15–7.67), femoral osteophytes (OR 2.52, 95% CI 1.01–6.26), and hip joint narrowing (OR 1.60, 95% CI 0.73–3.48), and was weakest for narrowing at the TF joints (OR 1.17, 95% CI 0.71–1.94). No clear risk factors were seen within the ex‐athlete groups, although the tennis players tended to have more osteophytes at the TF joints and hip, but the runners had more PF joint disease. Within the control group, a small subgroup of 22 women who reported long‐term vigorous weight‐bearing exercise had risks of OA similar to those of the ex‐athletes. Ex‐athletes had similar rates of symptom reporting but higher pain thresholds than controls, as measured by calibrated dolorimeter.

Conclusion. Weight‐bearing sports activity in women is associated with a 2–3‐fold increased risk of radiologic OA (particularly the presence of osteophytes) of the knees and hips. The risk was similar in ex–elite athletes and in a subgroup from the general population who reported long‐term sports activity, suggesting that duration rather than frequency of training is important.
Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin a
Authors: Pasero Giampiero , Priolo Francesco , Marubini Ettore , Fantini Flavio , Ferraccioli Gianfranco , Magaro Mario , Marcolongo Roberto , Oriente Pasquale , Pipitone Vincenzo , Portioli Italo , Tirri Giuseppe , Trotta Francesco , Casa‐Alberighi Ornella Della
Published: February 2007

Objective. To evaluate the ability of low‐dose cyclosporin A (CsA) to control radiologic disease progression, and to assess the clinical efficacy and tolerability of CsA, compared with conventional disease‐modifying antirheumatic drugs (DMARDs), in patients with early active rheumatoid arthritis (RA).

Methods. In this long‐term, multicenter, prospective, open, blinded end point, randomized trial, 361 consenting patients with early (< 4 years since diagnosis) active RA were enrolled. Of the eligible patients, 167 were treated with CsA at 3 mg/kg/day, and 173 with DMARDs. The decision to use conventional antirheumatic drugs as controls was based on the fact that joint erosion could be expected to occur after 1 year regardless of the type of DMARD being used. The possibility of switching therapies in both groups was intended to keep the largest possible number of patients in the study.

Results. Blinded evaluation of hand and foot radiographs after 12 months of treatment showed that CsA led to a significant (P < 0.001) delay in the mean ± SD progression in the eroded joint count (1.3 ± 3.1 versus 2.4 ± 3.0 for the control group) and in the joint damage score (3.6 ± 8.9 versus 6.9 ± 9.1 for the control group), both measured by the Larsen‐Dale method. When only the patients without erosion at baseline were considered (37 in the CsA‐treated group and 54 in the control group), erosion appeared in only 10.8% of the CsA‐treated patients, but in 51.8% of the controls (P = 0.00005). Low‐dose CsA was as effective as traditional DMARDs in controlling clinical symptoms. Maintenance on the initially prescribed treatment regimen (“survival on treatment”) was also better at 12 months with CsA than with DMARDs (89.2% versus 77.5%; P = 0.002). The tolerability of CsA was acceptable.

Conclusion. These 12‐month results suggest that low‐dose CsA decreases the rate of further joint damage in previously involved joints as well as the rate of new joint involvement in previously uninvolved joints, in patients with early RA.
Acute febrile toxic reaction in patients with refractory rheumatoid arthritis who are receiving combined therapy with methotrexate and azathioprine
Authors: Blanco Ricardo , Martínez‐Taboada Victor M. , González‐Gay Miguel A. , Armona Jose , Fernández‐Sueiro Jose L. , Gonzaléz‐Vela M. Carmen , Rodríguez‐Valverde Vicente
Published: February 2007

Objective. To assess the frequency and clinical features of an acute febrile toxic reaction (AFTR) in patients with refractory rheumatoid arthritis (RA) receiving combined therapy with methotrexate (MTX) and azathioprine (AZA).

Methods. A cohort of 43 RA patients being treated with MTX/AZA combination therapy were studied. In all of them, RA had been refractory to single‐therapy disease‐modifying antirheumatic drugs. We analyzed the frequency and clinical features of AFTR, which consisted mainly of the development of fever, leukocytosis, and cutaneous leukocytoclastic vasculitis when AZA was added to the MTX regimen.

Results. Four of the 43 patients (9.3%) who had been receiving long‐term, well‐tolerated treatment with MTX (mean ± SD 375.5 ± 159.5 days, range 227–561 days) developed AFTR shortly (mean ± SD 25.7 ± 13.6 days, range 17–46 days) after the addition of AZA to the regimen. The AFTR resolved rapidly (3 ± 1.4 days) after discontinuation of AZA and MTX. In 2 cases, rechallenge with AZA and MTX was linked to a new flare of AFTR.

Conclusion. The knowledge of this side effect is particularly important because it mimics a severe infectious complication related to immunosuppressive therapy, and because rechallenge can produce severe toxicity. Most of the new combined therapies for RA do not seem to be more toxic than single‐drug treatment. Nevertheless, clinicians should be aware of a possible increase in side effects due to drug interactions or some other unidentified mechanism.
Depressive symptoms associated with scleroderma
Authors: Roca Robert P. , Wigley Fredrick M. , White Barbara
Published: February 2007

Objective. To examine the prevalence and correlates of depressive symptoms among patients with systemic sclerosis (SSc; scleroderma).

Method. Fifty‐four outpatients with scleroderma were administered the Beck Depression Inventory, the Neuroticism‐Extraversion‐Openness Personality Inventory, the Health Assessment Questionnaire, and the Psychosocial Adjustment to Illness Scale. In addition, patients underwent a comprehensive clinical assessment, and pulmonary function tests were obtained.

Results. Nearly half of the patients had mild depressive symptoms, and an additional 17% had symptoms in the moderate‐to‐severe range. Younger patients, those with digital ulceration, and those with more self‐rated functional impairment had more depressive symptoms, but there were few other relationships between depressive symptoms and either demographic or physician‐rated medical variables. In contrast, there were highly significant relationships between depression and aspects of personality, psychosocial adjustment to illness, and social support.

Conclusion. Depressive symptoms in patients with SSc are more strongly related to personality, self‐rated disability, and adequacy of emotional support than to objective medical indices of illness severity. Depression in scleroderma is a debilitating comorbid condition that should be recognized and treated in its own right.
Malignancy in systemic lupus erythematosus
Authors: Abu‐Shakra Mahmoud , Gladman Dafna D. , Urowitz Murray B.
Published: February 2007

Objective. To estimate the risk of cancer in patients with systemic lupus erythematosus (SLE).

Methods. Patients with SLE (n = 724) have been followed prospectively, for 24 years, at the University of Toronto Lupus Clinic. The diagnosis of cancer was confirmed by histologic or autopsy reports. Standardized rates of cancer and standardized incidence rates (SIR) (ratio of observed‐to‐expected cancers) were used to estimate the risk for cancers.

Results. Twenty‐four cancers were identified in 23 SLE patients (3.2%) during 7,233 patient‐years of followup. Compared with the Ontario population, the overall estimated risk for all cancers was not increased in the lupus cohort (SIR 1.08, 95% confidence interval 0.70–1.62). A 4.1‐fold increased risk for hematologic cancers was observed, due mainly to an increased risk of non‐Hodgkin's lymphoma. The risk for cancer was significantly lower in the SLE cohort compared with patients with rheumatoid arthritis (RA) and systemic sclerosis (SSc).

Conclusion. SLE is associated with a lower risk of all cancers compared with RA and SSc, but an increased risk for non‐Hodgkin's lymphoma compared with the general population.
Decrease in cellularity and expression of adhesion molecules by anti–tumor necrosis factor α monoclonal antibody treatment in patients with rheumatoid arthritis
Authors: Tak Paul P. , Taylor Peter C. , Breedveld Ferdinand C. , Smeets Tom J. M. , Daha Mohamed R. , Kluin Philip M. , Meinders A. Edo , Maini Ravinder N.
Published: February 2007

Objective. The effect of chimeric anti–tumor necrosis factor α (TNFα) monoclonal antibody (MAb) therapy on synovial inflammation was studied in order to address the hypothesis that anti‐TNFα therapy leads to down‐regulation of adhesion molecules and a decrease in inflammatory cell influx in synovial tissue (ST).

Methods. The immunohistologic features of synovial biopsy specimens, both before and 4 weeks after anti‐TNFα MAb (cA2) therapy, were studied in 14 patients with rheumatoid arthritis (RA). The patients either received a placebo (n = 2), or were given intravenous doses of cA2 at 10 mg/kg (n = 5) or 20 mg/kg (n = 7).

Results. A significant (P < 0.03) reduction in the mean scores for T cells and for the adhesion molecules, vascular cell adhesion molecule 1 and E‐selectin, was observed after therapy with 10 mg/kg or 20 mg/kg of cA2 in RA patients.

Conclusion. The reduced expression of adhesion molecules, and the decrease in cellularity of rheumatoid ST after cA2 administration support the hypothesis the antiinflammatory effect of anti‐TNFα therapy might be partly explained by down‐regulation of cytokine‐inducible vascular adhesion molecules in ST, with a consequent reduction of cell traffic into joints.
Dose‐range and dose‐frequency study of recombinant human interleukin‐1 receptor antagonist in patients with rheumatoid arthritis
Authors: Campion G. V. , Lebsack M. E. , Lookabaugh J. , Gordon G.
Published: February 2007

Objective. To preliminarily evaluate the safety and efficacy of different dose levels and dosing frequencies of recombinant human interleukin‐1 receptor antagonist (rHuIL‐1Ra) in the treatment of patients with rheumatoid arthritis (RA).

Methods. One hundred seventy‐five patients with active RA were enrolled in a randomized, double‐blind trial of rHuIL‐1Ra administered by subcutaneous injection. There were 9 treatment groups in the trial. During the initial 3‐week treatment phase, patients were treated with 20, 70, or 200 mg rHuIL‐1Ra, administered either once, 3 times, or 7 times per week, followed by a 4‐week maintenance phase, during which all patients received the treatment‐phase dose once per week. To maintain the blindness of the study, patients received daily injections of either rHuIL‐1Ra or placebo on the days rHuIL‐1Ra was not administered.

Results. Recombinant HuIL‐1Ra was well tolerated. The most frequent adverse event was injection‐site reactions, which were reported in 62% of patients and caused 8 patients (5%) to withdraw prematurely from the study. Five patients (3%) developed serious adverse reactions unrelated to dose or dosing frequency. Due to the lack of a placebo arm and to the multiple small treatment groups, a definitive statement regarding efficacy could not be made. However, by the end of the 3‐week treatment phase, daily dosing appeared more effective than weekly dosing when assessed by the number of swollen joints, the investigator and patient assessments of disease activity, pain score, and C‐reactive protein levels.

Conclusion. These preliminary data suggest that rHuIL‐1Ra may be safely administered by subcutaneous injection to RA patients. The frequency of dosing appears to be important in determining clinical response, with daily administration providing the most benefit. A placebo‐controlled trial is in progress to further assess the clinical usefulness and to better define appropriate doses of rHuIL‐1Ra in patients with RA.
Association of tumor necrosis factor microsatellite polymorphisms with HLA‐DRB1*04–bearing haplotypes in rheumatoid arthritis patients
Authors: Hajeer Ali H. , Worthington Jane , Silman Alan J. , Ollier William E. R.
Published: February 2007

Objective. To investigate 1) tumor necrosis factor (TNF) microsatellite allele frequencies in rheumatoid arthritis (RA), and 2) associations between TNF microsatellites and RA‐associated HLA specificities in order to build up extended HLA haplotypes.

Methods. Eighty‐five caucasoid patients with RA and 109 healthy caucasoid controls were typed for TNF microsatellites a‐d using fluorescent‐labeled primers and semiautomated genotyping. A further 56 RA patients who were selected for having certain HLA‐DRB1 types were also typed for these TNF microsatellites. Linkage disequilibria between TNF and HLA alleles were calculated, and extended haplotypes were established.

Results. The TNFa6 allele frequency was significantly increased in the RA patients compared with the controls (P = 0.0019, odds ratio [OR] 2.5, 95% confidence interval [95% CI] 1.3–4.6), an increase that was further evident in patients who were HLA–DRB1*0401 homozygous (P =0.0003, OR 7.3, 95% CI 2.2–24.4). This increase was found to be due to association with HLA–DRB1*0401. No TNF microsatellite allele was found to be associated with HLA‐DRB1*0404. Three HLA extended haplotypes were identified in the RA group: 1) HLA–DRB1*0401;TNFd4;TNFa6;TNFb5;HLA–B44;HLA–Cw5;HLA–A2, 2) HLA–DRB1*0301;TNFd2;TNFa2;TNFb3;HLA–B8;HLA–CW7;HLA–A1, and 3) TNFd5;TNFc2;TNFa2;TNFb1;HLA–B62;HLA–Cw3.

Conclusion. TNF microsatellites found to be associated with RA do not appear to be independent of class II HLA associations.
Comprehensive noninvasive assessment of cardiac involvement in limited systemic sclerosis
Authors: Candell‐Riera Jaume , Armadans‐Gil Lluís , Simeón Carmen‐Pilar , Castell‐Conesa Joan , Fonollosa‐Pla Vicent , García‐Del‐Castillo Herminio , Vaqué‐Rafart Josep , Vilardell Miquel , Soler‐Soler Jordi
Published: February 2007

Objective. To assess cardiovascular abnormalities in patients with limited systemic sclerosis (SSc), using noninvasive cardiac techniques.

Methods. Sixty‐three patients with limited SSc were prospectively evaluated with Doppler echocardiography and thallium‐201 perfusion scintigraphy after a cold‐stress test and radionuclide ventriculography.

Results. In the patients with limited SSc, there was a significantly high prevalence of abnormal left‐ and right‐diastolic function parameters (P = 0.001 and P = 0.0002, respectively), thickening of papillary muscles (46%; P = 0.003), and mild mitral regurgitation (49%; P < 0.0001), compared with controls. Systolic pulmonary arterial hypertension was detected in 9 patients (14%), and pericardial effusion in 11 patients (18%). In 64% of patients with limited SSc, an ischemic response was detected on the thallium cold‐stress scan; similarly, an ischemic response was detected in 57% of patients with primary Raynaud's phenomenon (P < 0.0001 versus controls).

Conclusion. Although the frequency of cardiovascular symptoms was low in patients with limited SSc, a significant rate of cardiovascular abnormalities was found by noninvasive cardiac techniques.
Early expression of E‐selectin, tumor necrosis factor α, and mast cell infiltration in the salivary glands of patients with systemic sclerosis
Authors: Hebbar Mohamed , Gillot Jean‐Michel , Hachulla Eric , Lassalle Philippe , Hatron Pierre‐Yves , Devulder Bernard , Janin Anne
Published: February 2007

Objective. To assess the predictive value of early endothelial E‐selectin and tumor necrosis factor α (TNFα) expression, as well as mast cell infiltration, in the subsequent progression to systemic sclerosis (SSc) in patients with Raynaud's phenomenon (RP) and abnormal nailfold capillaroscopic findings.

Methods. Clinical criteria were evaluated, and immunostaining was performed on lip biopsy samples from 22 patients with RP and abnormal capillaroscopic results. None of these patients initially fulfilled the American College of Rheumatology criteria for SSc.

Results. E‐selectin, TNFα, and mast cell infiltration were found in 9, 10, and 8 of 11 patients, respectively, whose disease progressed to SSc, and in 0, 2, and 1 of 11 patients, respectively, whose disease did not progress to SSc (P < 0.001, P < 0.01, and P < 0.01, respectively).

Conclusion. E‐selectin, TNFα, and mast cell infiltration are detectable in the very early stages of SSc, prior to the onset of skin changes.
Sicca syndrome associated with hepatitis C virus infection
Authors: Jorgensen Christian , Legouffe Marie‐Christine , Perney Pascal , Coste Joliette , Tissot Barbara , Segarra Christiane , Bologna Christophe , Bourrat Laurent , Combe Bernard , Blanc François , Sany Jacques
Published: February 2007

Objective. To determine the prevalence of hepatitis C virus (HCV) infection in patients with sicca syndrome, and to determine the clinical, immunologic, and genetic characteristics of sicca syndrome associated with HCV.

Methods. We conducted a prospective study in a university hospital immunology–rheumatology department. Sixty‐two consecutive patients with sicca syndrome according to the European criteria for Sjögren's syndrome were included. HCV infection was diagnosed in patients with positive recombinant immunoblot assay findings and the presence of viral RNA in serum and saliva. Rheumatoid factor (RF), cryoglobulins, antinuclear antibodies, and anti–SS‐A/SS‐B antibodies were sought. HLA typing was performed on all patients.

Results. The prevalence of HCV infection in patients with sicca syndrome was 19%. The incidence of neurologic involvement was significantly increased in patients with sicca syndrome associated with HCV infection (24% versus 4%; P < 0.03), as was elevations in transaminase levels (87.5% versus 16%; P < 0.0001). RF and cryoglobulins were more frequent in HCV‐positive sicca syndrome patients (62% versus 30%; P < 0.03, and 56% versus 10%; P < 0.001, respectively). In contrast, anti–SS‐A/SS‐B antibodies were present in 38% of HCV‐negative sicca syndrome patients, but in only 1 HCV‐positive sicca syndrome patient (P < 0.01). No significant difference in HLA type was observed. Viral RNA was present in the saliva of 83% of HCV‐positive sicca syndrome patients, but in none of the HCV‐negative sicca syndrome patients.

Conclusion. We observed a high prevalence of HCV infection in our patients with sicca syndrome. HCV‐positive sicca syndrome patients had specific clinical characteristics and were seronegative for SS–A/SS‐B antibodies. Moreover, HCV RNA was present in the saliva of patients with HCV‐associated sicca syndrome.
Reactive arthritis in patients attending an urban sexually transmitted diseases clinic
Authors: Rich Eric , Hook Edward W. , Alarcón Graciela S. , Moreland Larry W.
Published: February 2007

Objective. To assess the prevalence, clinical manifestations, associated genital infections, and HLA associations of reactive arthritis (ReA) among patients attending an urban sexually transmitted diseases (STD) clinic.

Methods. Using a standardized questionnaire, 271 consecutive adults, primarily black, with possible or proven Chlamydia trachomatis genital infection were screened for symptoms of ReA. A followup questionnaire was administered 6 weeks later by mail. Patients who reported at least 1 symptom were evaluated by a rheumatologist. HLA–B typing was performed on patients with objective ReA features.

Results. Nine of 217 patients (4.1%) with genital infection/inflammation had objective ReA features. Chlamydial or nongonococcal STD syndromes were diagnosed in 8 of these 9 patients (88%). Genital infection/inflammation was asymptomatic in 78% of patients with ReA features. HLA–B27 or other B7–cross‐reactive group antigens were not associated with the occurrence of ReA.

Conclusion. Nongonococcal genital infections, often asymptomatic, can trigger a relatively mild ReA in a larger number of exposed patients than previously thought, irrespective of the individual's HLA status.
Familial aggregation of primary Raynaud's disease
Authors: Freedman Robert R. , Mayes Maureen D.
Published: February 2007

Objective. To determine the occurrence of familial aggregation of primary Raynaud's disease.

Methods. Twenty‐three patients with primary Raynaud's disease and their first‐degree relatives were assessed by questionnaire and, when possible, by physical examination. The same procedures were performed on the patients' spouses and the spouses' first‐degree relatives, who served as the control group.

Results. The prevalence of Raynaud's disease was significantly higher in the families of the probands than in the control families when assessed by questionnaire (26.1% versus 5.5%; P < 10−5), and by physical examination (11.2% versus 2.8%; P = 0.015).

Conclusion. These findings demonstrate that there is significant familial aggregation of primary Raynaud's disease.
Leukocyte infiltration in synovial tissue from the shoulder of patients with polymyalgia rheumatica. Quantitative analysis and influence of corticosteroid treatment
Authors: Meliconi Riccardo , Pulsatelli Lia , Uguccioni Mariagrazia , Salvarani Carlo , Macchioni Pierluigi , Melchiorri Cinzia , Focherini Maria Cristina , Frizziero Luigi , Facchini Andrea
Published: February 2007

Objective: To investigate the immunologic features of synovitis in patients with polymyalgia rheumatica (PMR) and to assess the modifications induced by corticosteroid.

Methods. Arthroscopic biopsies of shoulder synovium were obtained from 12 patients with untreated PMR and from 7 patients with PMR that had been treated. Immunohistochemistry was performed on frozen sections utilizing a panel of monoclonal antibodies and computerized image analysis.

Results. Synovitis was present in 10 of 12 (83%) untreated patients and in only 2 of 7 (29%) treated patients. The synovitis was characterized by vascular proliferation and leukocyte infiltration. Infiltrating cells consisted predominantly of macrophages and T Lymphocytes. Almost all T lymphocytes were CD45RO positive. A few neutrophils, but no B cells, natural killer cells, or γ/δ T cells were found. Intense expression of HLA class II antigens (DR moreso than DP moreso than DQ) was found in the lining layer cells as well as in macrophages and lymphocytes. DR, but not DP or DQ, was expressed by the endothelium of a few vessels. Class II antigen expression correlated with the number of macrophages and lymphocytes. Macrophage infiltration of arteriole walls was observed in 1 untreated patient without giant cell arteritis (GCA). In untreated patients, there was a positive correlation between the percentage of infiltrating T cells and the duration of disease. Steroid therapy was associated with a significant reduction in the number of blood vessels and of HLA class II expression. One treated patient who no longer had symptoms of PMR still had active synovitis: a relapse occurred 4 months after the biopsy.

Conclusion. Our findings support the hypothesis that synovitis is a major cause of the musculoskeletal symptoms of PMR. There are immunologic similarities with the vascular inflammation observed in GCA. Corticosteroids act on both the vascular and cellular components of synovitis.
Effect of classification on the incidence of polyarteritis nodosa and microscopic polyangiitis
Authors: Watts Richard A. , Jolliffe Victoria A. , Carruthers David M. , Lockwood Martin , Scott David G. I.
Published: February 2007

Objective. Polyarteritis nodosa (PAN) has been used as a generic term for systemic vasculitis. The distinction between classic PAN and microscopic polyangiitis (MPA) has not always been made. The aims of this study were to compare the American College of Rheumatology (ACR) criteria for PAN with the Chapel Hill Consensus Conference (CHCC) definitions of classic PAN and MPA, and to estimate the annual incidence of PAN and MPA.

Methods. The 1990 ACR criteria and CHCC definitions for systemic vasculitis were applied to an unselected cohort of 130 patients with systemic vasculitis attending a single district hospital in the UK between February 1, 1988 and January 31, 1994.

Results. Eight patients who met the ACR criteria for PAN and who also met the CHCC definition of MPA but not classic PAN were identified. A further 5 patients met the CHCC definition of MPA but not the ACR criteria for any other type of systemic vasculitis. No patient who met the CHCC definition of classic PAN was identified. The annual incidence of MPA was calculated to be 3.6/million (95% confidence interval 1.7–6.9), and the annual incidence of PAN (ACR criteria) was 2.4/million (95% confidence interval 0.9–5.3).

Conclusion. Classic PAN as defined by the CHCC is rare, because small vessel involvement is excluded from this definition.
Antibiotic prophylaxis and treatment of reactive arthritis. Lessons from an animal model
Authors: Zhang Yong , Gripenberg‐Lerche Christel , Söderström Karl‐ove , Toivanen Auli , Toivanen Paavo
Published: February 2007

Objective. To study the effect of antibiotic prophylaxis and treatment of reactive arthritis (ReA), using an experimental model.

Methods. Yersinia enterocolitica O:8, when injected intravenously into Lewis rats, causes a sterile arthritis closely resembling human ReA in 70% of the animals. Arthritis develops in 1–2 weeks; in some of the animals it remains chronic, and exacerbations occur. This model was applied to study the effect of a 7‐day treatment with ciprofloxacin, using 2 different dosages (20 or 100 mg/kg/day) and 4 different schedules for initiation of treatment. The effects were evaluated by determining the daily arthritis score, the number of rats developing arthritis, and fecal excretion of Yersinia. In addition, weight gain was monitored. At autopsy (35 or 60 days after inoculation with bacteria), samples were obtained for determination of Yersinia‐specific antibodies in the serum. At the same time, samples were collected from mesenteric lymph nodes, lung, spleen, and liver for bacterial cultures, and from the ankle joints for histologic evaluation. In a separate experiment, ciprofloxacin concentrations in samples from serum and mesenteric lymph nodes were analyzed by high performance liquid chromatography.

Results. A 7‐day course with 100 mg/kg/day of ciprofloxacin, started on day 3 after bacterial inoculation, completely prevented the development of ReA and eliminated Yersinia during the 60‐day experiment. If a dosage of 20 mg/kg/day was used, development of acute arthritis was prevented, but some of the animals had positive fecal cultures at the end of experiment. If antibiotic treatment was started on day 5, the preventive effect was still observed, but was less pronounced. If the treatment was started at the peak of the development of arthritis, no effect on arthritis was observed.

Conclusion. These results indicate that if any effect of antibiotic treatment in Yersinia‐triggered ReA is to be expected, the treatment must be started early and given in sufficient dosage. However, antibiotic treatment has no effect on fully developed arthritis.
Progression of rheumatoid arthritis following bone marrow transplantation. A case report with a 13‐year followup
Authors: McKendry Robert J. R. , Huebsch Lothar , Leclair Benoit
Published: February 2007

The progression of rheumatoid arthritis (RA) is documented in a patient receiving a sex‐mismatched, allogeneic bone marrow transplant (BMT) for gold‐induced marrow aplasia. DNA typing confirmed a high probability of a full donor engraftment (complete chimerism). Although the RA was in complete remission 2 years post‐BMT, clinical, laboratory, histologic, and radiologic evidence of the recurrence of synovitis from 3–13 years post‐BMT is presented. Implications of these observations for theories of the pathogenesis of RA and the future of immunotherapies are discussed.
Degenerative joint disease in the guinea pig. Use of magnetic resonance imaging to monitor progression of bone pathology
Authors: Watson Paul J. , Hall Laurance D. , Malcolm Archie , Tyler Jenny A.
Published: February 2007

Objective. The suitability of magnetic resonance imaging (MRI) for serial monitoring of bone pathology in the guinea pig stifle joint, an in vivo model of osteoarthritis, was investigated.

Methods. MR images were compared with histologic features and radiographs of 1‐mm‐thick sections to determine the MR correlates of the bone changes. Ten guinea pigs were then imaged on 7 occasions over the first year of life, enabling serial measurements of subchondral bone thickness, subchondral pseudocysts, and osteophytes.

Results. The signal intensity of trabecular bone in MR images accurately reflected the degree of osteopenia and trabecular thinning noted around the cruciate ligament insertions. The extent of subchondral sclerosis and the development of marginal osteophytes were also accurately represented. Serial observations revealed that MRI can detect highly significant progression of lytic bone lesions, subchondral sclerosis, and osteophyte size over periods of 6 weeks.

Conclusion. MRI is not only a reliable technique for the assessment of bone pathology but is also a useful tool for monitoring the progression of bone damage in osteoarthritis.