bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of nitric oxide on chondrocyte migration, adhesion, and cytoskeletal assembly
Authors: Frenkel Sally R. , Clancy Robert M. , Ricci John L. , di Cesare Paul E. , Rediske John J. , Abramson Steven B.
Published: February 2007

Objective. The migration of cells of chondrocyte lineage is believed to play a role in cartilage growth and repair. The present study examined 1) whether chondrocytes are capable of migration in vitro; and 2) the effects of nitric oxide (NO) on chondrocyte migration, adhesion, and cytoskeletal assembly.

Methods. Chondrocyte migration was evaluated by 2 assays: 1) “centrifugal” migration within a 3‐dimensional collagen matrix (dot culture); and 2) directed migration under agarose in response to bone morphogenetic protein. To assess the effects of NO, chondrocytes were treated with either exogenous NO (S‐nitrosoglutathione [SNO‐GSH]) or a mixture of cytokines known to induce endogenous NO production. The effects of NO on chondrocyte adhesion to fibronectin‐coated surfaces, as well as on actin polymerization (determined by indirect immunofluorescence), were also examined.

Results. The capacity of chondrocytes to migrate was demonstrated both by the dot culture and by agarose methods. Both SNO‐GSH and endogenous NO induced by cytokines inhibited this migration. Exposure to NO also inhibited attachment of chondrocytes to fibronectin and disrupted assembly of actin filaments. These effects of SNO‐GSH and cytokine‐induced NO production were reversed in the presence of hemoglobin and the NO synthase inhibitor NG‐monomethyl arginine, respectively.

Conclusion. NO interferes with chondrocyte migration and attachment to fibronectin, an extracellular matrix protein, probably via effects on the actin cytoskeleton. These effects of NO may result in impairment of cartilage repair, by interfering with the extracellular matrix regulation of chondrocyte function.
Behçet‐type vasculopathy in a patient without the diagnostic features of Behçet disease
Authors: Golden Brian D. , Goel Archana , Mitnick Hal J.
Published: February 2007

Behçet's disease is a multisystem inflammatory disorder which may involve the vascular system. The vasculopathy of Behçet's disease is distinctive among the vasculitides in that it involves both arteries and veins, and vessels of all sizes. Most published diagnostic criteria for Behçet's disease include the classic triad of orogenital ulceration and ocular inflammation. In this report, we describe a patient who had a vasculopathy fitting the Behçet's disease type, but who lacked the other characteristic or diagnostic features of Behçet's disease. This case illustrates an unusual presentation and natural history of a complex vasculitic disease.
Shift toward T lymphocytes with a T helper 1 cytokine‐secretion profile in the joints of patients with rheumatoid arthritis
Authors: Dolhain Radboud J. E. M. , van der Heiden Annette N. , ter Haar Natalja T. , Breedveld Ferdinand C. , Miltenburg André M. M.
Published: February 2007

Objective. To investigate whether T cells in the inflamed joints of patients with rheumatoid arthritis (RA) preferentially produce the T helper 1 (Th1) cytokines, interferon‐γ (IFNγ) and interleukin‐2 (IL‐2), or the Th2 cytokine, IL‐4, when compared with corresponding peripheral blood—derived T cells.

Methods. Synovial fluid mononuclear cells (SFMC) and corresponding peripheral blood mononuclear cells (PBMC) from 10 patients with RA were analyzed, either directly or after in vitro stimulation, for the intracellular presence of Th1 and Th2 cytokines. The amount of secreted cytokine in the cell culture supernatants was measured by enzyme‐linked immunosorbent assay (ELISA).

Results. IFNγ‐containing cells were detected in the unstimulated SFMC, but not in the PBMC, of 3 patients with RA. Cells positive for IL‐2 or IL‐4 were not detected in the unstimulated samples. Following stimulation, the mean percentage of cells containing Th1 cytokines was significantly increased in the SFMC compared with the PBMC; no differences were found in the mean percentage of IL‐4—containing cells. A comparable shift toward Th1 cytokines was observed when the amount of secreted cytokine was determined by ELISA.

Conclusion. A shift toward T cells with a Th1 cytokine profile was observed in the joints of patients with RA. Since an imbalance between Th1 and Th2 cells is thought to be of pathogenic significance, this finding might have implications for the development of new therapies for RA.
Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A department of veterans affairs cooperative study
Authors: Clegg Daniel O. , Reda Domenic J. , Weisman Michael H. , Blackburn Warren D. , Cush John J. , Cannon Grant W. , Mahowald Maren L. , Schumacher H. Ralph , Taylor Thomas , Budiman‐Mak Elly , Cohen Miriam R. , Vasey Frank B. , Luggen Michael E. , Mejias Edwin , Silverman Stuart L. , Makkena Rama , Alepa F. Paul , Buxbaum Joel , Haakenson Clair M. , Ward Richard H. , Manaster B. J. , Anderson Robert J. , Ward John R. , Henderson William G.
Published: February 2007

Objective. To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active ankylosing spondylitis (AS) that is not controlled with nonsteroidal antiinflammatory drug therapy.

Methods. Two hundred sixty‐four patients with AS were recruited from 15 clinics, randomized (double‐blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on morning stiffness, back pain, and physician and patient global assessments.

Results. While longitudinal analysis revealed a trend favoring SSZ in the middle of treatment, no difference was seen at the end of treatment. Response rates were 38.2% for SSZ and 36.1% for placebo (P = 0.73). The Westergren erythrocyte sedimentation rate declined more with SSZ treatment than with placebo (P < 0.0001). AS patients with associated peripheral arthritis showed improvement that favored SSZ (P = 0.02). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints.

Conclusion. SSZ at a dosage of 2,000 mg/day does not seem to be more effective than placebo in the treatment of AS patients with chronic, longstanding disease. SSZ is well tolerated and may be more effective than placebo in the treatment of AS patients with peripheral joint involvement. This effect is more pronounced in treatment of the peripheral arthritis in this subgroup of AS patients.
Cumulative rate of relapse of lupus nephritis after successful treatment with cyclophosphamide
Authors: Ciruelo Elena , de la Cruz Javier , López Ignacio , Gómez‐reino Juan J.
Published: February 2007

Objective. To determine the cumulative rate of relapse of lupus nephritis that has been treated successfully with cyclophosphamide (CYC), and to estimate the association between time to relapse and demographic, clinical, laboratory, and treatment variables.

Methods. This was an observational study of 48 systemic lupus erythematosus (SLE) patients who were treated successfully with CYC between 1979 and 1993 and followed up thereafter at 3 university hospitals. Demographic and clinical variables, laboratory data during the first month of nephritis, and therapy‐related variables were recorded from charts. Renal biopsy specimens were retrieved and analyzed by a pathologist. Relapse of nephritis was the outcome of interest. Descriptive analysis of patients who did and those who did not have a relapse was performed by chi‐square test, Fisher's exact test, and Wilcoxon 2‐sample test. The cumulative rate of relapse was computed using the actuarial method. Univariate comparisons of time to relapse were computed by log‐rank test. Proportional hazards modeling was used to assess the combined effect of patient characteristics that have been hypothesized to be prognostic factors.

Results. Nephritis relapsed in 11 patients. Previous hematologic disorder, arthritis or arthralgia, and the use of CYC in oral form were more frequent in patients who had a relapse. The cumulative rate of relapse was 25% and 46% at 5 years and 10 years, respectively. A significant univariate difference in time to relapse was found when patients were stratified by time from diagnosis to initiation of CYC treatment (⩽ 5 months versus >5 months;P= 0.02). By multivariate analysis, age <29 years at nephritis onset (relative risk [RR] 6.29, 95% confidence interval [95% CI] 1.13–34.94,P= 0.03) and delay of >5 months from onset of nephritis to initiation of CYC therapy (RR 3.66, 95% CI 1.06–12.63,P= 0.04) were independently associated with time to relapse.

Conclusion. A selected population of SLE patients may have long‐term remission of renal disease following successful CYC therapy. Patients in whom CYC treatment is delayed or who are young at the time of nephritis onset are at increased risk of relapse.
Mannose‐binding protein genetic polymorphisms in black patients with systemic lupus erythematosus
Authors: Sullivan Kathleen E. , Wooten Candra , Goldman Daniel , Petri Michelle
Published: February 2007

Objective. To determine whether dysfunctional or deficient mannose‐binding protein (MBP) variants are found with increased frequency in black patients with systemic lupus erythematosus (SLE) compared with controls.

Methods. Allele‐specific polymerase chain reaction amplification of 4 different polymorphic sites was performed on samples from 92 black SLE patients and 86 geographically matched black controls.

Results. Two structural polymorphisms of MBP, associated with low serum levels of MBP, were found with significantly increased frequency in the SLE patient population compared with controls. In contrast, a promoter haplotype associated with particularly high serum levels of MBP was negatively associated with SLE.

Conclusion. Deficiencies of MBP predispose individuals to SLE.
Therapy for the maintenance of remission in sixty‐five patients with generalized Wegener's granulomatosis. Methotrexate versus trimethoprim/sulfamethoxazole
Authors: de Groot Kirsten , Reinhold‐Keller Eva , Tatsis Efstratios , Paulsen Jens , Heller Martin , Nölle Bernhard , Gross Wolfgang L.
Published: February 2007

Objective. To compare the efficacy of low‐dose intravenous (IV) methotrexate (MTX; 0.3 mg/kg once weekly), both with and without concomitant prednisone, versus daily oral trimethoprim/sulfamethoxazole (T/S; 160 mg of trimethoprim + 800 mg of sulfamethoxazole twice a day), with and without prednisone, in maintaining remission in patients with generalized Wegener's granulomatosis (WG).

Methods. In this study, 65 patients with generalized WG whose disease had entered remission with cyclophosphamide (CYC) and prednisone therapy were started on one of the following remission‐maintenance regimens: MTX alone (group A; n = 22), T/S alone (group B; n = 24), MTX plus concomitant prednisone (group C; n = 11), and T/S plus concomitant prednisone (group D; n = 8). Clinical, radiographic, and seroimmunologic data were evaluated to assess the efficacy of the 4 regimens and to seek possible predictive factors concerning outcome in each group.

Results. Partial or complete remission was maintained in 86% of the patients in group A, but in only 58% of those in group B (P < 0.05). In group C, 91% of patients remained in remission, which is in sharp contrast to group D, in which all patients experienced a relapse after a median of 14.5 months (P < 0.005). Side effects occurred twice as often with MTX (n = 12) as with T/S (n = 6) treatment and could usually be resolved by supplemental folinic acid. Two patients taking MTX and 3 patients taking T/S were withdrawn from the study medication because of side effects. In none of the patients were the adverse effects life threatening. No statistically significant factors predictive of poor outcome emerged in any group.

Conclusion. Low‐dose MTX was found to be superior to T/S for the safe and effective maintenance of remission in patients with generalized WG. The use of concomitant prednisone was not associated with a worse outcome with MTX treatment. Since T/S, especially with concomitant prednisone, seemed to increase the chance of relapse, neither T/S alone nor T/S plus prednisone can be recommended for the maintenance of remission in patients with generalized WG.
Hypercalcemia and systemic lupus erythematosus
Authors: Deftos Leonard J. , Burton Douglas W. , Baird Stephen M. , Terkeltaub Robert A.
Published: February 2007

Hypercalcemia is commonly caused by the increased production of parathyroid hormone—related protein (PTHrP) by a malignancy. In fact, the demonstration of increased PTHrP production in a patient with hypercalcemia is virtually pathognomonic of malignancy. We studied a patient with systemic lupus erythematosus (SLE), generalized lymphadenopathy, and hypercalcemia. Immunohistology of 2 biopsied lymph nodes revealed the abundant expression of PTHrP and the absence of malignant transformation. Although apparently rare, PTHrP production by nonmalignant lymphoid tissue may occur in SLE and should be considered in the differential diagnosis of hypercalcemia.
Disease patterns and tissue cytokine profiles in giant cell arteritis
Authors: Weyand Cornelia M. , Tetzlaff Naomi , Björnsson Johannes , Brack Alexander , Younge Brian , Goronzy Jörg J.
Published: February 2007

Objective. To determine whether clinical heterogeneity in patients with giant cell arteritis (GCA) is correlated with different patterns in the tissue‐specific inflammatory response.

Methods. Twenty‐three patients with typical histomorphologic findings of GCA were grouped according to the presence or absence of jaw claudication and/or visual abnormalities, fever, concomitant polymyalgia rheumatica (PMR), and histologic evidence of giant cell formation. The inflammatory response in temporal artery biopsy specimens was characterized by semiquantification of cytokine messenger RNA (mRNA) transcripts using reverse transcriptase‐polymerase chain reaction, followed by oligonucleotide hybridization with cytokine‐specific probes. Clinical patterns were then correlated with profiles of tissue cytokines.

Results. Inflammatory cytokines were expressed in all temporal artery tissues. In situ synthesis of interleukin‐2 (IL‐2), interferon‐γ (IFNγ), and IL‐1β mRNA, but not of IL‐10 and IL‐12 mRNA, distinguished different patterns of inflammation, and these patterns correlated with clinical manifestations of the disease. Patients with evidence of ischemic symptoms, indicated by jaw claudication and/or visual symptoms, typically expressed higher concentrations of IFNγ mRNA (P = 0.008) and IL‐1β mRNA (P = 0.02). Presence of fever was correlated with lower copy numbers of IFNγ (P = 0.02). Formation of giant cells in the granulomatous infiltrates was associated with the local synthesis of IFNγ mRNA (P = 0.003). Tissue from GCA patients with concomitant PMR contained higher levels of IL‐2 mRNA transcripts (P = 0.001).

Conclusion. Variations in the clinical presentation of GCA were correlated with cytokine mRNA expression in the affected temporal arteries. Differences in the effector functions of tissue‐infiltrating T cells distinguished disease patterns in which either local ischemic symptoms or systemic involvement was dominant, or in which there was co‐occurrence of PMR. Definition of different patterns of inflammation in GCA might, therefore, facilitate the design of differentiated therapeutic approaches.
Long‐term treatment of systemic lupus erythematosus with cyclosporin A
Authors: Caccavo Domenico , Laganà Bruno , Mitterhofer Anna P. , Ferri Giovanni M. , Afeltra Antonella , Amoroso Antonio , Bonomo Lorenzo
Published: February 2007

Objective. To evaluate the efficacy of long‐term treatment with cyclosporin A (CSA) in systemic lupus erythematosus (SLE).

Methods. Thirty patients with SLE whose condition was either poorly responsive or unresponsive to treatment with steroids and/or cytotoxic drugs were enrolled in a prospective, nonrandomized study of CSA. Patients with hypertension or hypercreatinemia were excluded. Disease activity was evaluated according to the systemic lupus activity measure. Assessments were made prior to study entry and after 6, 12, 18, and 24 months.

Results. Twenty‐seven patients completed at least 24 months of treatment with CSA. The mean disease activity score significantly decreased after 6 months of therapy (P < 0.01); this result was maintained throughout the study. A conspicuous steroid‐sparing effect was observed following administration of CSA (P < 0.01). Side effects included hypertrichosis (63% of patients), paresthesias (23%), gastrointestinal symptoms (20%), gingival hyperplasia (17%), hypertension (10%), tremors (7%), and nephrotoxicity (13%). No significant changes in serum creatinine levels were observed.

Conclusion. CSA represents a helpful second‐choice treatment for patients with active SLE. Administration of CSA necessitates expert and careful followup of patients.
Magnetic resonance imaging of the brain and cerebral proton spectroscopy in patients with systemic lupus erythematosus
Authors: Chinn R. J. S. , Wilkinson I. D. , Hall‐Craggs M. A. , Paley M. N. J. , Shortall E. , Carter S. , Kendall B. E. , Isenberg D. A. , Newman S. P. , Harrisonfrcp M. J. G.
Published: February 2007

Objective. To investigate the prevalence and extent of cerebral changes in patients with systemic lupus erythematosus (SLE) by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS).

Methods. SLE patients (47 women) and controls (25 women) underwent 1.5T MRI. A semiautomated segmentation technique calculated cerebrospinal fluid (CSF) and brain volumes. Proton MRS of the frontal and parieto‐occipital white matter yielded metabolite ratios of N‐acetyl groups (NA), choline, and creatine.

Results. Compared with the control group, the SLE patients more often had cerebral atrophy on MRI (32% versus 0%), confirmed by an increase in the CSF to intracranial volume ratio. The patients also had old infarcts and hemorrhages (8.5% versus 0%) and more small white matter lesions (23% versus 8% had > 5 such lesions). MRS showed relative reduction of NA peaks. Although no patient was studied when acutely ill, prior neurologic involvement was related to abnormal findings.

Conclusion. MRI and MRS are helpful in the investigation of cerebral complications of SLE. There are chronic changes which may be ischemic in nature. Their precise cause, consequences, and prevention are current challenges.
The relationship of socioeconomic status, race, and modifiable risk factors to outcomes in patients with systemic lupus erythematosus
Authors: Karlson Elizabeth W. , Daltroy Lawren H. , Lew Robert A. , Wright Elizabeth A. , Partridge Alison J. , Fossel Anne H. , Roberts W. Neal , Stern Steven H. , Straaton Karin V. , Wacholtz Mary C. , Kavanaugh Arthur F. , Grosflam Jodi M. , Liang Matthew H.
Published: February 2007

Objective. To study the relationship of race, socioeconomic status (SES), clinical factors, and psychosocial factors to outcomes in patients with systemic lupus erythematosus (SLE).

Methods. A retrospective cohort was assembled, comprising 200 patients with SLE from 5 centers. This cohort was balanced in terms of race and SES. Patients provided information on socioeconomic factors, access to health care, nutrition, self‐efficacy for disease management, health locus of control, social support, compliance, knowledge about SLE, and satisfaction with medical care. Outcome measures included disease activity (measured by the Systemic Lupus Activity Measure), damage (measured by the SLICC/ACR damage index), and health status (measured by the SF‐36).

Results. In multivariate models that were controlled for race, SES, center, psychosocial factors, and clinical factors, lower self‐efficacy for disease management (P ≤ 0.0001), less social support (P < 0.005), and younger age at diagnosis (P < 0.007) were associated with greater disease activity. Older age at diagnosis (P ≤ 0.0001), longer duration of SLE (P ≤ 0.0001), poor nutrition (P < 0.002), and higher disease activity at diagnosis (P < 0.007) were associated with more damage. Lower self‐efficacy for disease management was associated with worse physical function (P ≤ 0.0001) and worse mental health status (P ≤ 0.0001).

Conclusion. Disease activity and health status were most strongly associated with potentially modifiable psychosocial factors such as self‐efficacy for disease management. Cumulative organ damage was most highly associated with clinical factors such as age and duration of disease. None of the outcomes measured were associated with race. These results suggest that education and counseling, coordinated with medical care, might improve outcomes in patients with SLE.
Assessment of systemic lupus erythematosus disease activity by medical record review compared with direct standardized evaluation
Authors: Wluka Anita E. , Liang Matthew H. , Partridge Alison J. , Fossel Anne H. , Wright Elizabeth A. , Lew Robert A. , Karlson Elizabeth W.
Published: February 2007

Objective. Clinical studies of systemic lupus erythematosus (SLE) often necessitate assessment of previous disease activity, which is sometimes only possible by retrospective evaluation of information from the medical record. Using the Systemic Lupus Activity Measure (SLAM), the present study compared an assessment of disease activity obtained by chart abstraction with a direct clinical assessment.

Methods. A chart SLAM was obtained using information abstracted from the clinic notes of 46 patients with SLE who were being followed up at a referral center. Chart SLAM scores were compared with SLAM scores derived from an independent assessor's direct clinical evaluation.

Results. Direct SLAM and chart SLAM scores were correlated (r = 0.67 by Spearman's rank correlation, P = 0.0001). Chart review scores for disease activity tended to be lower, but to an inconsistent degree, reflecting both under‐ and overestimation of disease activity. The overall misclassification rate on a 3‐category scale (mild, moderate, or severe activity) was 59%.

Conclusion. Although chart SLAM scores were highly correlated with direct SLAM scores, misclassification of disease activity by chart review cannot be rectified. Thus, in research, medical record review should not be used as a proxy for the direct SLAM, nor should it be considered comparable with clinical assessments in the analysis of disease activity.
Accumulation of soluble fas in inflamed joints of patients with rheumatoid arthritis
Authors: Hasunuma Tomoko , Kayagaki Nobuhiko , Asahara Hiroshi , Motokawa Satoru , Kobata Tetsuji , Yagita Hideo , Aono Hiroyuki , Sumida Takayuki , Okumura Ko , Nishioka Kusuki
Published: February 2007

Objective. To examine the concentration of the soluble form of the Fas molecule (sFas) in the serum and synovial fluid of patients with rheumatoid arthritis (RA) and osteoarthritis (OA).

Methods. The concentration of sFas in the serum of 15 normal subjects and in the synovial fluid and serum of 45 RA patients and 13 OA patients was determined. The erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP) level, and the level of several cytokines in serum and synovial fluid were also determined.

Results. The synovial fluid concentration of sFas was higher in RA than in OA patients (P < 0.005). The synovial fluid level of sFas correlated weakly with serum levels of CRP (r = 0.541), the ESR (r = 0.499), and with synovial fluid levels of interleukin‐2 (IL‐2) receptor (r = 0.544), IL‐6 (r = −0.529), and intercellular adhesion molecule 1 (r = 0.514). Reverse transcription‐polymerase chain reaction analysis revealed that synovial cells and infiltrating mononuclear cells expressed sFas messenger RNA in RA patients.

Conclusion. Our data suggest that accumulation of sFas in the joint cavity of RA patients may inhibit apoptosis and exacerbate the inflammatory process.
Fas and Fas ligand expression in the salivary glands of patients with primary Sjögren's syndrome
Authors: Kong Liping , Ogawa Noriyoshi , Nakabayashi Toru , Liu George T. , D'Souza Errol , McGuff H. Stan , Guerrero Daniel , Talal Norman , Dang Howard
Published: February 2007

Objective. To assess the role of Fas‐mediated apoptosis in the salivary glands of patients with primary Sjögren's syndrome (SS).

Methods. Expression of Fas, Fas ligand (FasL), and bcl‐2 in salivary gland biopsy material was detected in situ by immunohistochemical staining and reverse transcriptase‐polymerase chain reaction. DNA fragmentation in apoptotic cells was assessed by the enzymatic incorporation of labeled nucleotides (digoxigenin‐dUTP).

Results. The acinar epithelial cells in SS were Fas+ and FasL+, and these cells died by apoptosis. The majority of infiltrating lymphocytes in SS were Fas+ and bcl‐2+, while few lymphocytes expressed FasL. In situ detection of apoptosis showed minimal cell death of lymphocytes, particularly in dense periductal foci. Lymphocytic cell death was significantly lower (P < 0.0001) in these foci compared with that in the interstitium.

Conclusion. Infiltrating lymphocytes in the focal lesions of the salivary glands of patients with SS are blocked in their ability to commit to apoptosis, even though they may express Fas. The presence of bcl‐2 in these cells may explain their inability to undergo apoptosis. The acinar epithelial cells, in contrast, may undergo Fas‐mediated apoptosis. These results suggest that the Fas death pathway may be an important mechanism leading to the glandular destruction found in SS.
Incidence and disease associations of a proteinase 3−antineutrophil cytoplasmic antibody idiotype (5/7 Id) whose antiidiotype inhibits proteinase 3−antineutrophil cytoplasmic antibody antigen binding activity
Authors: Strunz Hendryk P. , Csernok Elena , Gross Wolfgang L.
Published: February 2007

Objective. To evaluate the potential of a monoclonal proteinase 3‐antineutrophil cytoplasmic antibody (PR3‐ANCA) antiidiotype autoantibody (5/7 anti‐Id) as a candidate for specific immunotherapy in Wegener's granulomatosis (WG), and to estimate the immuno‐diagnostic value of the corresponding idiotype (5/7 Id).

Methods. We analyzed the incidence of 5/7 Id in patients with ANCA‐associated vasculitides (WG, microscopic polyangiitis, Churg‐Strauss syndrome), in disease controls (systemic lupus erythematosus patients), and in healthy donors. We then investigated the presence of 5/7 Id in relation to disease stage, clinical activity, and organ manifestations in 86 patients with WG. Finally, we investigated the ability of the 5/7 anti‐Id reagent to inhibit the binding of PR3‐ANCA to corresponding antigen in 19 WG patients.

Results. The incidence of 5/7 Id was significantly more frequent in WG patients (43 of 86; 50%). We did not find a significant correlation between the prevalence of idiotype expression and disease activity or organ manifestations. Further, we demonstrated in vitro suppression of PR3‐ANCA antigen binding activity by 5/7 anti‐Id in 11 of 19 WG patients who were positive for 5/7 Id.

Conclusion. This study shows that 5/7 Id is a common idiotype with a significantly increased incidence in WG and that 5/7 anti‐Id inhibits PR3‐ANCA antigen binding activity. Based on these observations, we conclude that 5/7 anti‐Id is a promising tool for the development of a specific immunotherapy for WG.
Systemic vasculitis and myelodysplastic syndromes. A report of two cases
Authors: Philippe Bruno , Couderc Louis‐Jean , Droz Dominique , Charlotte Frédéric , Choukroun Georges , Epardeau Bernard , Bletry Olivier , Caubarrere Isabelle , Varet Bruno , Hermine Olivier
Published: February 2007

Two cases of systemic vasculitis associated with myelodysplastic syndromes are reported. Vasculitis may develop either before or after the diagnosis of a hematologic disorder, and it responds to treatment with high‐dose corticosteroids.
High frequency of autoantibodies to insoluble cellular antigens in patients with chronic fatigue syndrome
Authors: Mikecz Anna Von , Konstantinov Konstantin , Buchwald Dedra S. , Gerace Larry , Tan Eng M.
Published: February 2007

Objective. To elucidate the humoral immune response in patients with chronic fatigue syndrome (CFS), by identification and characterization of autoantibodies.

Methods. Initial immunofluorescence histochemistry studies of sera using human HEp‐2 cell substrate were followed by antibody class subtyping and colocalization studies with reference antibodies. Association of CFS autoantigens with insoluble cellular components was determined by in situ extraction of soluble components and subsequent immunofluorescence histochemistry studies on the extracted cell substrate.

Results. Of 60 CFS patients, 41 (68%) were positive for antinuclear antibodies. Localization of nuclear staining was found at the nuclear envelope (52%), in reticulated speckles (25%), in nucleoli (13%), and in dense fine speckles (5%). Twenty‐eight CFS sera (47%) also had antibodies to cytoplasmic antigens. The major cytoplasmic staining pattern was of the intermediate filament type (35%). The observed nuclear envelope pattern of staining co‐localized with lamina‐associated polypeptide 2 (an integral nuclear membrane protein), the reticulated speckle pattern co‐localized with nonsmall nuclear RNP splicing factor SC‐35, and the intermediate filament pattern co‐localized with vimentin. The intermediate filament antigen was shown to be vimentin in immunoblotting experiments using recombinant human vimentin, and one of the nuclear envelope antigens was shown previously to be lamin B1. Fifty of the 60 CFS patients (83%) had antibodies to one or another of these antigens, all of which are relatively insoluble cellular antigens, whereas a control group of patients without chronic fatigue had a significantly lower frequency of such antibodies (17%).

Conclusion. The high frequency of autoantibodies to insoluble cellular antigens in CFS represents a unique feature which might help to distinguish CFS from other rheumatic autoimmune diseases.
In vitro apoptosis and expression of apoptosis‐related molecules in lymphocytes from patients with systemic lupus erythematosus and other autoimmune diseases
Authors: Lorenz Hanns‐Martin , Grünke Mathias , Hieronymus Thomas , Herrmann Martin , Kühnel Almuth , Manger Bernhard , Kalden Joachim R.
Published: February 2007

Objective. To analyze factors related to apoptosis in systemic lupus erythematosus (SLE) peripheral blood mononuclear cells (PBMC) and to compare the findings in SLE PBMC with those in normal donor PBMC or PBMC from patients with other autoimmune diseases.

Methods. PBMC from normal healthy donors or patients with SLE, mixed connective tissue disease (MCTD), rheumatoid arthritis (RA), or various vasculitides were isolated. The percentage of apoptosis after activation through different signaling pathways was quantified using propidium iodide staining. Protein expression of Fas/APO‐1 or bcl‐2, and messenger RNA (mRNA) expression of bcl‐2, bcl‐xL, bax, bak, Fas/APO‐1, Fas ligand (Fas‐L), c‐myc, mad, or max were determined.

Results. We confirmed previous findings of increased numbers of apoptotic cells in SLE PBMC compared with normal donor cells after in vitro incubation. After activation of PBMC with CD28 monoclonal antibody plus phorbol myristate acetate (CD28 MAb/PMA), staphylococcal enterotoxin B (SEB), or phytohemagglutinin (PHA), the percentage of apoptotic cells was unchanged (SEB) or diminished (CD28 MAb/PMA, PHA) in SLE cells, and the difference between normal donor and SLE cells was less pronounced. On the mRNA level, expression of apoptosis‐related gene products did not differ between SLE cells and normal donor cells. Expression of Fas/APO‐1 protein was increased in freshly isolated SLE T lymphocytes compared with normal donor T lymphocytes, whereas bcl‐2 protein was up‐regulated after a 3‐day culture period. Cellular activation further increased bcl‐2 protein levels, eliminating differences between normal donors and SLE patients. In RA cells, the percentage of apoptosis was similar to that in normal donor PBMC, whereas results using cells from patients with other autoimmune diseases (MCTD, Wegener's granulomatosis, Takayasu arteritis, polyarteritis nodosa) were comparable with those found using SLE PBMC. Addition of growth factors such as interleukin‐2 (IL‐2), IL‐4, or IL‐15 to culture medium decreased the percentage of in vitro apoptosis in both normal donor and SLE cells.

Conclusion. Based on these data, we conclude that accelerated in vitro apoptosis and increased Fas/APO‐1 and bcl‐2 protein expression in SLE are nonspecific for the disease, and might be explained at least in part by the increased in vivo activation levels of PBMC from patients with SLE, MCTD, or autoimmune vasculitides combined with in vitro incubation under “noninflammatory” conditions and growth factor withdrawal.
Oral L‐arginine supplementation and cutaneous vascular responses in patients with primary Raynaud's phenomenon
Authors: Khan Faisel , Litchfield Stuart J. , McLaren Margaret , Veale Douglas J. , Littleford Roberta C. , Belch Jill J. F.
Published: February 2007

Objective. To assess the effects of oral L‐arginine supplementation on cutaneous vascular responses in patients with primary Raynaud's phenomenon (RP).

Methods. Double‐blind, crossover comparison of placebo versus L‐arginine (8 gm/day for 28 days). Cutaneous vascular responses in the fingers were assessed during iontophoresis of acetylcholine and sodium nitroprusside, which are endothelium‐dependent and endothelium‐independent vasodilators.

Results. In comparison with control subjects, patients with primary RP had diminished endothelium‐dependent and ‐independent vasodilatation (P < 0.05, and P < 0.005, respectively, by analysis of variance). At the 3 doses used, vascular responses to acetylcholine were reduced by 71%, 64%, and 63%, respectively, and responses to sodium nitroprusside were reduced by 67%, 73%, and 66%, respectively. L‐arginine had no significant effect on cutaneous vascular responses to acetylcholine or sodium nitroprusside in control subjects or patients with primary RP.

Conclusion. Reduced vasodilator ability in primary RP is unlikely to be due to an impairment in the L‐arginine/nitric oxide pathway.
Development and initial validation of the vasculitis damage index for the standardized clinical assessment of damage in the systemic vasculitides
Authors: Exley A. R. , Bacon P. A. , Luqmani R. A. , Kitas G. D. , Gordon C. , Savage C. O. S. , Adu D.
Published: February 2007

Objective. To develop and validate the Vasculitis Damage Index (VDI) for the standardized clinical assessment of damage in the systemic vasculitides.

Methods. Using a nominal group consensus approach, the Birmingham Vasculitis Group generated guiding principles for assessment of damage in all systemic vasculitides. Damage was defined as irreversible change resulting from scars. Consensus principles were developed into the VDI, including guidelines for use, a list of items of damage, and a glossary.

Results. For 100 surviving patients with systemic vasculitis, the median VDI score at last observation was 3 (range 0–8). Within the Wegener's granulomatosis subgroup, the median VDI score for 12 non‐survivors was higher than for 47 survivors (non‐survivors median score 7, interquartile range 5–8 versus survivors median score 4, interquartile range 2–5; P = 0.003). VDI scores for 100 patients with systemic vasculitis increased from initial presentation to last observation by a median score of 3 (range 1–4; P < 0.001). The VDI assesses more items and is more sensitive to change than other indices of damage (P < 0.001). Using the VDI, trained observers can produce moderately consistent damage scores.

Conclusion. The VDI is a sensitive, reproducible, comprehensive, and credible clinical tool for quantifying damage. The data presented herein should enable further validation and testing of the VDI in specific vasculitic syndromes, and should facilitate the comparison of different therapies.
Monozygotic twins discordant for congenital complete heart block
Authors: Cooley Helen M. , Keech Catherine L. , Melny B. Joy , Menahem Samuel , Morahan Grant , Kay Thomas W. H.
Published: February 2007

Objective. Isolated congenital complete heart block (CCHB) occurs in 1/20,000 live births. More than 85% of mothers giving birth to affected infants are anti–Ro antibody positive, but only ˜ 1% of babies with anti–Ro‐positive mothers develop CCHB. We studied 2 sets of monozygotic twins discordant for CCHB.

Methods. Monozygosity was determined using placental examination and DNA microsatellite analysis. HLA typing was performed. Autoantibody studies were performed using counterimmunoelectrophoresis, immunoblotting, Ro 52 and Ro 60 enzyme‐linked immunosorbent assay (ELISA), and indirect immuno‐fluorescence (IIF) on Ro 60− and Ro 52−transfected HEp‐2 cells.

Results. Both sets of twins were monozygotic. They had similar birth weights. Twin 2 in the second set required a pacemaker at age 2 months. Both mothers were positive for anti–Ro 52 and anti–Ro 60 antibody, and neither had anti–La antibody on immunoblot. One set of twins was studied at birth. Similar titers of anti–Ro 52 and anti–Ro 60 antibody were found by IIF and ELISA.

Conclusion. There are no previous well‐documented reports of monozygotic twins discordant for CCHB. These cases demonstrate that there is still discordance in the development of CCHB despite identical genetics and environmental exposure to anti–Ro antibody.
Juvenile rheumatoid arthritis‐like polyarthritis in chromosome 22q11.2 deletion syndrome (digeorge anomalad/velocardiofacial syndrome/conotruncal anomaly face syndrome)
Authors: Sullivan Kathleen E. , McDonald‐McGinn Donna M. , Driscoll Deborah A. , Zmijewski Chester M. , Ellabban Abdou S. , Reed Lori , Emanuel Beverly S. , Zackai Elaine H. , Athreya Balu H. , Keenan Gregory
Published: February 2007

Objective. To investigate the association of polyarthritis and chromosome 22q11.2 deletions.

Methods. Eighty patients with chromosome 22q11.2 deletion syndrome followed up at The Children's Hospital of Philadelphia were examined for evidence of arthropathy or arthritis. Patients with chromosome 22q11.2 deletion syndrome and polyarthritis underwent laboratory evaluations of immunologic function to determine the relationship of their immunodeficiency to the polyarthritis.

Results. The prevalence of polyarthritis in patients with chromosome 22q11.2 deletion syndrome was markedly increased over the prevalence of polyarticular juvenile rheumatoid arthritis (JRA) in the general population. All 3 patients with polyarthritis had evidence of impaired T cell function. Two of the patients with polyarthritis also had IgA deficiency.

Conclusion. The chromosome 22q11.2 deletion syndrome represents a primary T cell disorder which can be associated with a JRA‐like polyarthritis. All 3 patients with polyarthritis had evidence of more extensive immunoregulatory derangements than those typically seen in patients with chromosome 22q11.2 deletion, and these derangements may have predisposed to the development of polyarthritis.
Incidence OF systemic sclerosis in allegheny county, Pennsylvania. A twenty‐year study of hospital‐diagnosed cases, 1963–1982
Authors: Steen Virginia D. , Oddis Chester V. , Conte Claudia G. , Janoski Janine , Casterline Gayle Ziegler , Medsger Thomas A.
Published: February 2007

Objective. To determine the incidence of hospital‐diagnosed systemic sclerosis (SSc) among residents of Pittsburgh and Allegheny County, PA, from 1963 through 1982.

Methods. Medical records from all Allegheny County hospitals were searched using International Classification of Diseases codes for patients diagnosed with SSc. Each case was reviewed and verified by a physician, according to specified criteria. Age‐adjusted incidence rates were computed for race and sex, and results were expressed as new cases per million population per year, with the 1970 Allegheny County population serving as the standard.

Results. Four hundred forty‐four cases of SSc were identified during this 20‐year survey, for a total annual incidence of 13.9 per million population. Overall, the incidence rate doubled during 1973–1982 compared with the first time interval of the study, with the greatest increase occurring in women. Among the younger population (ages 15–24), black women had the highest incidence of SSc (21.2 per million population). Overall, the female‐to‐male incidence ratio was 3:1, and was slightly higher (3.4:1) during the childbearing years (ages 15–44). Men under age 35 and children infrequently developed SSc.

Conclusion. The incidence of SSc reported in this study increased with time. Although this trend was most likely due to improved detection and medical record techniques, the incidence rate stability in men compared with women suggests that there may have been a true increase in the incidence of SSc in this population, particularly in women.
Increased rates of fibromyalgia following cervical spine injury. A Controlled study of 161 cases of traumatic injury
Authors: Buskila Dan , Neumann Lily , Vaisberg Genady , Alkalay Daphna , Wolfe Frederick
Published: February 2007

Objective. To study the relationship between cervical spine injury and the development of fibromyalgia syndrome (FMS).

Methods. One hundred two patients with neck injury and 59 patients with leg fractures (control group) were assessed for nonarticular tenderness and the presence of FMS. A count of 18 tender points was conducted by thumb palpation, and tenderness thresholds were assessed by dolorimetry at 9 tender sites. All patients were interviewed about the presence and severity of neck and FMS‐related symptoms. FMS was diagnosed using the American College of Rheumatology 1990 criteria. Additional questions assessed measures of physical functioning and quality of life (QOL).

Results. Although no patient had a chronic pain syndrome prior to the trauma, FMS was diagnosed following injury in 21.6% of those with neck injury versus 1.7% of the control patients with lower extremity fractures (P = 0.001). Almost all symptoms were more common and severe in the group with neck injury. FMS was noted at a mean of 3.2 months (SD 1.1) after the trauma. Neck injury patients with FMS (n = 22) had more tenderness, had more severe and prevalent FMS‐related symptoms, and reported lower QOL and more impaired physical functioning than did those without FMS (n = 80). In spite of the injury or the presence of FMS, all patients were employed at the time of examination. Twenty percent of patients with neck injury and 24% of patients with leg fractures filed an insurance claim. Claims were not associated with the presence of FMS, increased FMS symptoms, pain, or impaired functioning.

Conclusion. FMS was 13 times more frequent following neck injury than following lower extremity injury. All patients continued to be employed, and insurance claims were not increased in patients with FMS.
Human synovial mast cells. II. Heterogeneity of the pharmacologic effects of antiinflammatory and immunosuppressive drugs
Authors: de Paulis Amato , Ciccarelli Anna , Marinò Isabella , de Crescenzo Gennaro , Marinò Domenico , Marone Gianni
Published: February 2007

Objective. To evaluate the in vitro effects of 4 antiinflammatory and 5 immunosuppressive agents on the release of preformed and de novo‐synthesized mediators from human synovial mast cells (HSyMC) activated by immunologic and nonimmunologic stimuli.

Methods. The effects of antiinflammatory and immunosuppressive agents were evaluated on the in vitro release of histamine and tryptase and the de novo synthesis of prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) by HSyMC challenged with anti‐IgE and substance P.

Results. Nimesulide, a sulfonanilide nonsteroidal antiinflammatory drug (NSAID) chemically unrelated to other acidic NSAIDs (such as acetylsalicylic acid [ASA], diclofenac, and piroxicam) inhibited in a concentration‐dependent manner the release of preformed (histamine and tryptase) mediators from HSyMC challenged with anti‐IgE. In contrast, diclofenac and piroxicam had little or no effect on HSyMC activated by anti‐IgE. ASA, diclofenac, piroxicam, and nimesulide caused a concentration‐dependent inhibition of IgE‐mediated PGD2 release from HSyMC. Nimesulide, but not diclofenac or piroxicam, also inhibited the de novo synthesis of LTC4 by HSyMC challenged with anti‐IgE. Nimesulide, diclofenac, and piroxicam had no effect on HSyMC activated by substance P. Cyclosporin A (CSA) inhibited histamine release from HSyMC challenged with anti‐IgE, whereas cyclosporin H (CSH) had no effect. FK‐506 also inhibited histamine release from HSyMC activated by anti‐IgE, whereas rapamycin had no effect. Neither CSA, CSH, FK‐506, nor rapamycin inhibited the release of histamine from HSyMC induced by substance P. Methotrexate had no effect on the release of mediators from these cells, whereas adenosine (R‐phenylisopropyl adenosine and 5‐N‐ethylcarboxamide adenosine) enhanced histamine release from immunologically activated HSyMC in a concentration‐dependent manner.

Conclusion. Mast cells isolated from human synovia display 4 levels of pharmacologic heterogeneity with regard to 1) the inhibitory effects of 4 antiinflammatory drugs; 2) the capacity of different immunosuppressive drugs to exert antiinflammatory activity; 3) the inhibition of the release of different mediators; and 4) the capacity of antiinflammatory and immunosuppressive drugs to modulate HSyMC activated by different stimuli. This complexity of pharmacologic modulation of HSyMC in vitro might help explain the different activity of the compounds used to treat various pathophysiologic aspects of the inflammatory arthritides.
Mast cell responses in rheumatoid synovium. Association of the MCTC subset with matrix turnover and clinical progression
Authors: Gotis‐Graham Ian , McNeil H. Patrick
Published: February 2007

Objective. To determine the distribution of mast cell subsets and their density in synovium from normal subjects and from patients with osteoarthritis (OA) and rheumatoid arthritis (RA).

Methods. A sequential double‐immunohisto‐chemical staining technique was used to distinguish mast cells as positive for tryptase only (MCT) or for tryptase plus chymase (MCTC). Synovial tissue was obtained from RA patients (n = 16), OA patients (n = 18), and normal subjects (n = 15). Sections were analyzed to a depth of 1 mm from the synoviocyte lining layer by quantitative histomorphometry. Immunohisto‐chemical data were correlated with histologic findings and clinical indices of disease activity.

Results. In normal synovium, the majority of mast cells belonged to the MCTC subset, outnumbering MCT cells by 5:1. The mean density of mast cells was significantly increased in RA synovia (60.9 cells/mm2) compared with OA (21.7 cells/mm2) and with normal (9.4 cells/mm2) synovia. Selective expansion of the MCT subset accounted for the increased mast cell density in OA. In RA, both subsets expanded and were associated with infiltrating inflammatory cells or with regions of highly cellular fibrous tissue (mainly MCTC). An association was noted between clinical parameters of activity or progression of rheumatoid disease and the density of MCTC cells, especially the density in the superficial layer of synovium. In RA synovia, we found no evidence of the chymase only, or MCC, immunophenotype.

Conclusion. MCTC mast cells expand in RA but not OA, associate with regions of “active” fibrosis, and correlate with parameters of disease activity or progression of RA. These findings implicate the MCTC subset of mast cells in the pathologic mechanisms that mediate tissue damage in RA.