bluuebunny/crossref_metadata_2025 huggingface dataset:
Kidney Biopsy in Systemic Lupus Erythematosus. II. Survival Analyses According to Biopsy Results
Authors: McLaughlin John , Gladman Dafna D. , Urowitz Murray B. , Bombardier Claire , Farewell Vernon T. , Cole Edward
Published: February 2007

Renal biopsy specimens from 123 patients with systemic lupus erythematosus (SLE) seen between 1970 and 1984 were assessed according to the World Health Organization classification and according to the presence of proliferative, active, or chronic renal lesions. Survival analysis was used to study the determinants of mortality. Survival rates were higher for patients with minimal lesions, intermediate for patients with focal or diffuse proliferative nephritis, and low for patients with glomerular sclerosis. The presence of proliferative and chronic lesions was associated with a higher risk of dying. Renal biopsy results are helpful in predicting prognosis for all‐cause mortality in patients with SLE.
Effect of an Extract of the Chinese Herbal Remedy Tripterygium Wilfordii Hook F on Human Immune Responsiveness
Authors: Tao Xuelian , Davis Laurie S. , Lipsky Peter E.
Published: February 2007

Tripterygium wilfordii Hook F (TWH) is a vine‐like plant that grows in a wide area of south China. An alcohol extract of this plant known as T2 has been suggested to be effective in the treatment of rheumatoid arthritis (RA). To examine the mechanism by which this herbal remedy might be effective in RA, the capacity of T2 to alter human immune responsiveness in vitro was investigated. Human peripheral blood mononuclear cells were obtained from normal adults and separated into purified populations of monocytes, T cells, and B cells. T2 at 0.1–1 μg/ml inhibited antigen‐ and mitogen‐stimulated proliferation of T cells and B cells, interleukin‐2 (IL‐2) production by T cells, and immunoglobulin production by B cells. T2 did not affect IL‐2 receptor expression by T cells, IL‐1 production by monocytes, or the capacity of monocytes to present antigen. Inhibition could not be accounted for by nonspecific toxicity. These results support the conclusion that T2 exerts a powerful suppressive effect on human immune responses. This action might account for its therapeutic effectiveness in RA.
Fibromyalgia and Parvovirus Infection
Authors: Leventhal Lawrence J. , Naides Stanley J. , Freundlich Bruce
Published: February 2007

An infectious cause of fibromyalgia (FM) has been hypothesized based upon the observed similarity of this entity and chronic fatigue syndrome. Three patients developed symptoms of FM after documented episodes of acute parvovirus B19 infections. B19 antibody determinations were obtained approximately 1 month after the symptoms began; both IgM and IgG titers were positive at that time. All 3 patients met criteria for FM. Polysomnography performed on 2 of the patients revealed profound alpha‐wave intrusion throughout non–rapid eye movement sleep. A more careful search for viral infections in FM patients whose symptoms appear following a „flu‐like”︁ illness appears warranted.
A Case of Sjögren's Syndrome With Repeatedly Negative Findings on Lip Biopsy
Authors: Katz James , Yamase Harold , Parke Ann
Published: February 2007

We report a case of Sjögren's syndrome characterized by keratoconjunctivitis sicca, parotid swelling, reduced salivary flow, and abnormalities on nuclear scanning. Two labial gland biopsies showed complete atrophy. Biopsy of an enlarged submandibular gland revealed lymphoid follicles and glandular replacement consistent with the diagnosis of Sjögren's syndrome. This case supports the concept that a negative finding on labial biopsy does not rule out a diagnosis of Sjögren's syndrome.
In Vitro Effect of Nonsteroidal Antiinflammatory Drugs on Proteoglycanase and Collagenase Activity in Human Osteoarthritic Cartilage
Authors: Vignon Eric , Mathieu Pierre , Louisot Pierre , Richard Michel
Published: February 2007

The effects of several nonsteroidal antiinflammatory drugs, used at concentrations achievable in synovial fluid, on human osteoarthritic (OA) cartilage metalloprotease activity in vitro was studied. Acetaminophen and ketoprofen had no effect; sodium salicylate, indomethacin, and diclofenac slightly decreased proteoglycanase activity. Piroxicam and tenoxicam suppressed proteoglycanase activity by 48.2% and 68.3%, respectively, and suppressed collagenase activity by 19.1% and 36.8%, respectively. Use of these NSAIDs may help to decrease cartilage catabolism in patients with OA.
Biannual Radiographic Assessments of Hands and Feet in a Three‐Year Prospective Followup of Patients with Early Rheumatoid Arthritis
Authors: Heijde Désirée M. F. M. Van Der , Leeuwen Miek A. Van , Riel Piet L. C. M. Van , Koster Anja M. , Hof Martin A. Van't , Rijswijk Martin H. Van , Putte Levinus B. A. Van De
Published: February 2007

In a prospective followup study of 147 patients with rheumatoid arthritis of recent onset, we assessed the progression of radiographic evidence of joint damage on films of the patients' hands and feet obtained biannually. Patients were receiving first‐line and second‐line treatment. Ninety patients were followed up for 3 years, and 57 were followed up for only 2 years. Radiographic damage was determined by a modification of the method described by Sharp, and to ensure comparability of findings, we determined the percentage of damage per joint group (actual score divided by the maximum possible score). After 3 years, radiographic damage was present in 70% of the patients, all of whom could be identified after 1 year of study. Overall, 18—20% of the joints of the hands and feet were affected after 3 years, with relatively little abnormality per joint (˜8% of maximum possible score). During the entire followup, more foot joints than hand joints were affected. The rate of progression in the first year was significantly higher than in the second and third years of study, indicating a flattening of the curve of radiographic progression of joint damage.
Activation of Synovial Fluid T Lymphocytes by 60‐Kd Heat‐Shock Proteins in Patients with Inflammatory synovitis
Authors: Pope Richard M. , Lovis Rosa M. , Gupta Radhey S.
Published: February 2007

Objective. Synovial fluid lymphocytes from patients with rheumatoid arthritis and with other forms of inflammatory synovitis demonstrate enhanced proliferative responses to Mycobacterium tuberculosis antigens, in particular, the 65‐kd heat‐shock protein. There is a high degree of homology between the human and the mycobacterial 60‐kd family of heat‐shock proteins. These studies were performed to determine if the enhanced response to the mycobacterial 65‐kd heat‐shock protein was due to cross‐reactivity of an immune response generated against the human homolog.

Methods. These studies were performed by in vitro culture of isolated synovial fluid mononuclear cells with crude and purified antigens.

Results. The synovial fluid lymphocytes of a majority of patients with rheumatoid arthritis recognized the mycobacterial 65‐kd heat‐shock protein, as evidenced by T cell proliferation. In contrast, only 18% of all samples tested responded to a highly purified recombinant human 60‐kd heat‐shock protein. With only one exception, proliferative responses to the mycobacterial antigen were stronger than those to the human homolog. The proliferative responses generated against mycobacterial 65‐kd heat‐shock proteins from different sources were highly correlated.

Conclusion. The findings suggest that the enhanced proliferative response to the mycobacterial 65‐kd heat‐shock protein noted in most patients with rheumatoid arthritis and other forms of inflammatory synovitis is not due to cross‐reactivity of an immune response directed against the human heat‐shock protein.
Activation of the Alternative Complement Pathway Accompanies Disease Flares in Systemic Lupus Erythematosus During Pregnancy
Authors: Buyon Jill P. , Tamerius John , Ordorica Steve , Young Bruce , Abramson Steven B.
Published: February 2007

Objective. To assess the activity of systemic lupus erythematosus (SLE) during pregnancy and to distinguish it from preeclampsia.

Methods. We prospectively measured the complement activation products Ba, Bb, SC5b—9, and C4d, as well as the conventional complement determinants C3, C4, and CH50, during pregnancy in 14 patients with SLE and 10 women with preeclampsia.

Results. Four of the 14 SLE patients were considered to have disease flares, 3 occurring in the second trimester and 1 postpartum. In these patients, significant abnormalities of Ba, Bb, SC5b—9, and CH50 were noted. In contrast, measures of C4d did not distinguish between pregnant patients who had flares and those whose SLE remained stable. Although decreased values of C3 were rarely seen in the patients with stable disease, normal values of C3 during lupus pregnancy were not reliably associated with stable disease. Three of 10 non‐SLE patients with preeclampsia had elevated levels of Ba; however, in each case, the CH50 level was close to or within the normal range. This was in sharp contrast to the findings observed in the 4 patients with active SLE, in whom high levels of plasma Ba were always associated with low CH50 values. Moreover, the ratio of CH50 to Ba was significantly lower in the patients with lupus flares than in the non‐SLE patients with preeclampsia.

Conclusion. While a decline in the CH50 level alone could otherwise be attributed to decreased synthesis of complement components, these data demonstrate that ongoing activation of the alternative complement pathway can accompany disease flares in pregnant women with SLE.
Expression of Cell‐Adhesion Molecules in the Salivary Gland Microenvironment of Sjögren's Syndrome
Authors: Clair E. William S.T. , Angellilo John C. , Singer Kay H.
Published: February 2007

Objective. The potential role of cell adhesion molecules in the pathogenesis of Sjögren's syndrome (SS) was assessed by examining their expression in salivary gland (SGL) tissue.

Methods. Intercellular adhesion molecule type 1 (ICAM‐1), lymphocyte function‐associated antigen type 1 (LFA‐1), LFA‐3, CD2, and CD44 expression were determined using indirect immunofluorescence techniques.

Results. In inflamed labial SGL tissue, ICAM‐1 expression was evident on infiltrating LFA‐1+/CD2+/LFA‐3+ mononuclear cells, and to a limited extent on SGL acinar epithelial cells adjacent to sites of intense inflammation.

Conclusion. In SS, the SGL microenvironment is characterized by only a modest up‐regulation of ICAM‐1 expression on epithelial cells, despite the presence of T cells bearing an activated phenotype.
Antibodies to Carbonic Anhydrase in Systemic Lupus Erythematosus and Other Rheumatic Diseases
Authors: Itoh Yasuhiko , Reichlin Morris
Published: February 2007

Objective. Autoantibodies to CA were demonstrated in the sera of patients with systemic lupus erythematosus (SLE) and some other rheumatic diseases. This study was undertaken to define the isoform and species specificity of these reactions, as well as to develop a method for detecting immune complexes.

Methods. Antibodies to CA were sought by enzyme‐linked immunosorbent assay (ELISA) and by Western immunoblotting.

Results. An increased prevalence of CA autoantibodies was detected, by both methods, in patients with SLE, scleroderma, and polymyositis, compared with controls. In SLE patients, CA autoantibodies occurred preferentially in those with anti—U1 RNP or anti‐U1 RNP and Ro/SS‐A. Some sera reacted with only the CA 1 or CA II isoform, while ˜50% of sera that were CA positive reacted with both isoforms. The autoantibodies reacted preferentially with the human enzymes, rather than the bovine CA, both on Western blot and by ELISA. Selected IgG F(ab')2 fragments from anti‐CA—containing sera specifically inhibited the enzyme activity of CA, and the CA inhibitor acetazolamide partially inhibited the binding of anti‐CA to CA. Thus, at least a part of autoanti‐CA is directed toward the active site of CA. Finally, CA molecules were detected as immune complexes in sera from selected anti‐CA‐positive patients.

Conclusion. Autoantibodies to CA represent a previously unrecognized autoantibody to an abundant intracellular protein of the human erythrocyte.
Molecular Genetic Analysis of HLA—DR and HLA—DQ Genes Among Anti—U1‐70‐kd Autoantibody Positive Connective Tissue Disease Patients
Authors: Kaneoka Hidetoshi , Hsu Kou‐Ching , Takeda Yoshihiko , Sharp Gordon C. , Hoffman Robert W.
Published: February 2007

Objective. We have recently found that the presence of autoantibodies against the 70‐kd polypeptide of U1 RNP (U1‐70‐kd) is associated with HLA—DR4 and DR2. To further characterize this association, we performed a molecular genetic analysis of HLA—DR and DQ genes among patients with autoantibodies against U1‐70‐kd.

Methods. The polymerase chain reaction (PCR), sequence‐specific oligonucleotide hybridization, and solid‐phase direct DNA sequencing of PCR‐amplified DNA were utilized to analyze HLA—DRB1, DRB5, DQA1, and DQB1 genes.

Results. A comprehensive analysis of HLA—DRB1, DRB5, DQA1, and DQB1 from 27 patients and controls identified shared amino acids FDYFYQA (Phe, Asp, Tyr, Phe, Tyr, Gln, Ala) at positions 26, 28, 30—32, 70, and 73 of HLA—DRB1 on disease‐associated haplotypes.

Conclusion. A common cluster of shared amino acids, or a shared epitope, identified within HLA—DRB1 among anti—U1—70‐kd autoantibody positive connective tissue disease patients may be important in regulating an autoimmune response to the U1—70‐kd antigen.
Antibiotic Treatment of Venereal Disease and Reiter's Syndrome in a Greenland Population
Authors: Bardin Thomas , Enel Catherine , Cornelis FrançOis , Salski Chris , Jorgensen Christian , Ward Richard , Lathrop G. Mark
Published: February 2007

Objective. To assess the effects of antibiotic treatment of urethritis or cervicitis on the incidence of recurrences of articular symptoms in Reiter's syndrome patients.

Methods. Retrospective evaluation of the medical charts of 109 patients living in Greenland.

Results. Thirty‐seven percent of the episodes of genitourinary tract inflammation that were not treated or were treated with penicillin were followed by arthritis, compared with 10% of those treated with tetracycline or erythromycin.

Conclusion. Antibiotics active against Chlamydia trachomatis reduced the risk of postvenereal arthritis in the population studied.
Interactions Between Anticollagen Antibodies and Chondrocytes
Authors: Takagi Toshitaka , Jasin Hugo E.
Published: February 2007

Objective. To investigate the interactions between anticollagen antibodies and living chondrocytes.

Methods. Mouse monoclonal anti—type II collagen (anti‐CII) antibodies, rabbit anti‐human CII, and rat anti‐CII, anti‐CIV, anti‐CV, anti‐CVI, and anti‐CIX were studied in vitro to determine their ability to bind to the plasma membrane of living bovine chondrocytes.

Results. Mouse monoclonal anti‐CII, rabbit anti‐CII, and rat anti‐CII, anti‐CV, anti‐CVI, and anti‐CIX were shown to bind in vitro to the plasma membrane of bovine chondrocytes. Antibody binding was not observed with anti‐CIV, or with chondrocytes previously incubated with bacterial collagenase. A significant increase in chondrocyte caseinase and collagenase secretion was observed following sequential incubation with the monoclonal antibodies and a source of activating cytokines.

Conclusion. These results suggest that collagen autoantibodies may exert some of their pathogenic effects on cartilage through interactions with resident chondrocytes, leading to modulation of the rate of secretion of cartilage matrix—degrading enzymes.
A revised estimate of twin concordance in systemic lupus erythematosus
Authors: Deafen Dennis , Escalante Agustin , Weinrib Lisa , Horwitz David , Bachman Barbara , Roy‐Burman Pradip , Walker Ann , Mack Thomas M.
Published: February 2007

Objective. Based on a small clinical series and previously published case reports, concordance for systemic lupus erythematosus (SLE) among monozygous (MZ) twins has been reported to be as high as 69%. Using a larger and less biased sample, we provide another estimate of this percentage.

Methods. We established a registry of twins with SLE, based upon self‐reports and information provided by the patients' physicians. We used DNA fingerprinting to validate the reported zygosity in a sample of these twins.

Results. Of 107 twin pairs meeting the American College of Rheumatology 1982 revised criteria for the diagnosis of SLE, 24% of 45 MZ pairs and 2% of 62 dizygous (DZ) pairs were concordant. The frequency distributions of diagnostic criteria and disease symptoms in the SLE patients were similar to those in other published reports of SLE patients. Zygosity was confirmed by DNA fingerprinting in a subsample of 15 self‐described MZ twins and 7 self‐described DZ twins. AH individuals had correctly predicted their zygosity.

Conclusion. MZ concordance for SLE is similar to that for other autoimmune diseases and is much lower than previously believed.
Extracorporeal photochemotherapy for the treatment of systemic lupus erythematosus. A Pilot study
Authors: Knobler Robert M. , Graninger Winfried , Graninger Wolfgang , Lindmaier Andreas , Trautinger Franz , Smolen Joseph S.
Published: February 2007

Objective. To investigate the effectiveness and feasibility of extracorporeal photochemotherapy (ECP) in the treatment of an autoimmune disease with known cutaneous photosensitivity.

Methods. Ten patients with systemic lupus erythematosus (SLE) were treated with ECP in an open clinical trial. The efficacy of treatment was analyzed by means of established disease activity scores.

Results. Eight patients completed the trial. In 7 of the 8, there was a significant response to the treatment, with no or minor side effects. The clinical activity score in the group of 8 patients decreased from a median of 7 (range 4–9) to a median of 1 (range 0–5) (P < 0.05). Laboratory abnormalities did not change significantly, but were mild at the outset.

Conclusion. ECP led to clinical improvement of SLE without side effects. The effectiveness of this method should be investigated further in controlled clinical trials.
Basic calcium phosphate crystals stimulate cell proliferation and collagenase message accumulation in cultured adult articular chondrocytes
Authors: Mitchell Peter G. , Struve Janine A. , Mccarthy Geraldine M. , Cheung Herman S.
Published: February 2007

Objective. To investigate BCP (basic calcium phosphate) crystal—stimulated mitogenesis and collagenase gene transcription in primary cultures of porcine chondrocytes.

Methods. The role of protein kinases in BCP crystal—stimulated DNA synthesis was investigated using thymidine incorporation, kinase inhibitors, and protein kinase C (PKC) assays. Northern blot analysis was used to determine the levels of collagenase c‐fos and c‐jun message.

Results. BCP crystals stimulated chondrocyte proliferation in a PKC‐dependent manner. Increased levels of collagenase message were preceded by an increased accumulation of c‐fos, but not c‐jun.

Conclusion. BCP crystals could contribute to the abnormal chondrocyte proliferation and collagenase secretion observed in some rheumatic diseases.
Use of short‐term efficacy/toxicity tradeoffs to select second‐line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials
Authors: Felson David T. , Anderson Jennifer J. , Meenan Robert F.
Published: February 2007

Objective. Preferred drugs for rheumatoid arthritis (RA) should be those that have maximal efficacy with the least toxicity. We evaluated the efficacy and toxicity tradeoffs for drugs frequently used in the treatment of RA.

Methods. We updated 2 metaanalyses of published clinical trials, by adding trials published through 1990 and trials of azathioprine (AZA). We tested 3 different definitions of efficacy, each plotted against 3 different toxicity measures, for antimalarial drugs, methotrexate (MTX), auranofin, injectable gold, D‐penicillamine, sulfasalazine (SSZ), AZA, and placebo. Efficacy measures included composite efficacy (a combination of joint count, grip strength, and erythrocyte sedimentation rate), tender joint count alone, and a measure based on how many patients dropped out due to inefficacy. Toxicity measures were the proportion dropping out due to toxicity, the same dropouts with side effects weighted for severity using a modification of a published toxicity index, and the proportion with severe toxicities (defined as a score of at least 7 of 10 on the toxicity index). The latter were usually organ toxicities (e.g., cytopenias and renal involvement).

Results. All 9 efficacy/toxicity tradeoff plots suggested that MTX and antimalarial drugs had the highest efficacy relative to toxicity. MTX scored among the most efficacious of the drugs and, of these, had the least toxicity. Antimalarial drugs, though showing only moderate efficacy, had the lowest toxicity rate of all the drugs. SSZ scored close to MTX but was, in general, slightly more toxic.

Conclusion. In the short‐term context of clinical trials, antimalarial drugs and MTX have the best efficacy/toxicity tradeoffs and may, therefore, be the preferred drugs.
Treatment of systemic sclerosis with recombinant interferon‐γ. A phase I/II clinical trial
Authors: Freundlich Bruce , Jimenez Sergio A. , Steen Virginia D. , Medsger Thomas A. , Szkolnicki Michelle , Jaffe Howard S.
Published: February 2007

Objective. A phase I/II trial to examine the safety and efficacy of interferon‐γ (IFNγ) therapy for patients with systemic sclerosis (SSc).

Methods. An 18‐week open‐label study was performed. Eighteen patients with rapidly progressive SSc were enrolled, 14 of whom completed at least 16 weeks of the study. These 14 patients had a mean age of 40 years and had been diagnosed as having SSc an average of 10.1 months prior to study entry. Recombinant IFNγ was injected intramuscularly 3 times weekly for 18 weeks. Six patients received a 0.1 mg/m2 dose, while 8 patients received a 0.5 mg/2 dose. Patients who completed the 18‐week trial were offered maintenance therapy at a dose of up to 0.5 mg/m2. The effects of IFNγ on skin involvement were assessed by 2 methods: 1) evaluation of skin thickness, by scoring 15 zones according to a 0 (normal skin) to 3 (hidebound skin) scale; and 2) determination of the total body surface area involved, by using 2‐dimensional body diagrams to indicate areas affected, and then having a second, “blinded,” assessor calculate the area score with a planimeter.

Results. The mean skin thickness score decreased from a baseline of 25.9 to 19.1 (P < 0.03), and the mean area scores declined from 33.1 to 19.6 (P < 0.02) after 18 weeks of IFNγ treatment. Ten patients had a >25% decrease in area score. Five patients had a ⩾70% decrease in area score, and 3 of them have not experienced disease recurrence for 6 to 17 months after discontinuation of IFNγ. Five patients withdrew before the study ended. Three of these patients developed renal crisis, which may reflect the severity of the SSc in the study group, although an adverse effect of IFNγ in SSc cannot be excluded.

Conclusion. IFNγ was associated with a beneficial effect on the skin involvement in most of this series of patients with rapidly progressive SSc. A placebo‐controlled study will be necessary to confirm these results.
Light microscopic characterization of the fibroblast‐like synovial intimal cell (synoviocyte)
Authors: Wilkinson Linda S. , Pitsillides Andrew A. , Worrall Jennifer G. , Edwards Jo C. W.
Published: February 2007

Objective. To reassess synovial intimal cell populations by light microscopy.

Methods. Non‐inflamed, rheumatoid and osteoarthritic synovia were analyzed as tissue sections and cytospin preparations by a series of combined immunohistochemical and cytochemical staining techniques.

Results. Two populations of intimal cells were identified. The first carried macrophage markers. The second showed high uridine diphosphoglucose dehydrogenase (UDPGD) activity, minimal cytoplasmic CD68, absent non‐specific esterase (NSE) activity, and absent leukocyte and endothelial antigens. The majority of these cells showed a high content of prolyl hydroxylase.

Conclusion. Combined cytochemical staining for NSE and UDPGD activity allows effective separation of intimal cell populations. We suggest that the cells of high UDPGD activity are the fibroblast‐like or type B synovial intimal cells defined by electron microscopy. High UDPGD activity probably reflects a preferential ability to synthesize glycosaminoglycans, including hyaluronan.
The development of monoclonal antibodies to the human mitochondrial 60‐kd heat‐shock protein, and their use in studying the expression of the protein in rheumatoid arthritis
Authors: Sharif Mohammed , Worrall Jennifer G. , Singh Bhag , Gupta Radhey S. , Lydyard Peter M. , Lambert Claude , McCulloch John , Rook Graham A.
Published: February 2007

Objective. To assess the claim that the human 60‐kd heat‐shock protein (HSP) is highly expressed in the joints of patients with rheumatoid arthritis (RA), but is not readily detected in normal tissues.

Methods. Monoclonal antibodies were raised against the human 60‐kd mitochondrial heat‐shock protein (P1 protein; hsp60), and their specificity was established. They were then applied to synovial tissue.

Results. HSP was expressed similarly in normal, osteoarthritic, and RA synovium. Low levels of hsp60 were detected in synovial fluid by immunoprecipitation.

Conclusion. Minor differences in the distribution of hsp60 in synovium from RA joints were attributable to increased cellularity and to the disorganization of the tissue architecture.
Auranofin‐induced vasomotor reaction
Authors: Proudman S. M. , Cleland L. G.
Published: February 2007

Vasomoto reactions after administraton of gold sodium thiomalate (GST)are well recognized, ut such reacti9os have not bn reported to ccur in assocation woth oral gold treatment. We descrbe a woman with rheumatoid arthritis who exprienced typical nitritoid reactions after treatment with GST, and later, with auranofin.
Rheumatoid synovium is enriched in CD45RBdim mature memory T cells that are potent helpers for B cell differentiation
Authors: Thomas Ranjeny , McIlraith Melissa , Davis Laurie S. , Lipsky Peter E.
Published: February 2007

Objective. To delineate the phenotype and function of synovial T cells in rheumatoid arthritis (RA).

Methods. T cells from normal subjects or from RA peripheral blood (PB), synovial fluid (SF), or synovial tissue (ST) were analyzed phenotypically and functionally.

Results. RA SF and ST T cells were found to be markedly enriched in CD45RAdim, CD45RO+, CD45RBdim mature memory cells, whereas in the PB, CD45RAbright naive T cells were more frequent than CD45RO+ memory T cells, and only a minority were CD45RBdim. SF and ST T cells proliferated less well and produced less interleukin‐2 in response to mitogenic stimuli than did PB T cells. However, synovial T cells effectively promoted the production of Ig from normal B cells. Moreover, PB and synovial T cells differed in their capacity to down‐regulate immunoglobulin production. Anti‐CD3—stimulated PB T cells suppressed Ig production unless their proliferation was prevented with mitomycin C. In contrast, synovial T cells were potent helpers of B cell Ig production regardless of antecedent treatment with mitomycin C. To examine the relationship between the CD45RBdim phenotype and B cell help, CD45RBdim T cells were sorted from PB. As opposed to the findings with synovial T cells, suppression by control PB CD45RBdim T cells was observed, but only when large numbers were employed. B cell Ig production was enhanced after treatment of PB CD45RBdim T cells with mitomycin C. In contrast, healthy control sorted CD45RBbright or sorted CD4+, CD45RO+, CD45RBbright T cells did not support Ig secretion. After treatment with mitomycin C, both of these populations were more effective helpers of Ig production.

Conclusion. RA synovium is enriched in differentiated CD45RBdim memory T cells with potent helper activity and diminished capacity to down‐regulate B cells, strongly implying an active role for these cells in the production of Ig in the synovium, and thus in the propagation of disease.
ATP‐induced chondrocalcinosis
Authors: Ryan Lawrence M. , Kurup Indira V. , Derfus Beth A. , Kushnaryov Vladimir M.
Published: February 2007

Objective. To determine whether adult articular cartilage mineralizes in the presence of ATP.

Methods. Intact adult porcine articular cartilage and monolayers of chondrocytes were cultured in physiologic media containing ATP, and mineralization was measured as retention of 45Ca. Cartilage was analyzed by electron microscopy.

Results. Articular cartilage sequestered 45Ca when incubated with 100 γM ATP. Use of the ATP analog α,β‐methylene ATP did not promote mineralization and addition of pyrophosphatase inhibited mineralization, indicating that hydrolysis of ATP to AMP and inorganic pyrophosphate is necessary for the process to occur. Mineral was concentrated in articular cartilage vesicles in the perichondral area.

Conclusion. Adult articular cartilage mineralizes in the presence of ATP, in a manner similar to that found with isolated matrix or articular cartilage vesicles. This supports the notion that these structures have a role in chondrocalcinosis.
Independent regulation of plasminogen activator inhibitor 2 and plasminogen activator inhibitor 1 in human synovial fibroblasts
Authors: Hamilton John A. , Cheung Daisy , Filonzi Enrico L. , Piccoli Diana S. , Wojta Johann , Gallichio Marisa , McGrath Katherine , Last Karena
Published: February 2007

Objective. To study the plasminogen activator inhibitor(s) (PAI) produced in vitro by human synovial fibroblast‐like cells.

Methods. Human synovial cell explant cultures were established using cells from nonrheumatoid donors. PAI‐2 and PAI‐1 antigens were measured by enzyme‐linked immunosorbent assay, and messenger RNA (mRNA) levels were determined by Northern blot.

Results. The synovial fibroblasts produced both PAI‐2 and PAI‐1. Interleukin‐1 (IL‐1) increased PAI‐2 but decreased PAI‐1 formation, both at the protein and the mRNA levels. Using cyclooxygenase inhibitors, evidence was obtained that an endogenous cyclooxygenase product(S) in the IL‐1—treated cultures inhibited formation of both PAIs; exogenous prostaglandin E2 (10−7M) reversed the effect of cyclooxygenase inhibition. The glucocorticoid dexamethasone (10−6 to 10−7M) inhibited IL‐1—stimulated PAI‐2 formation but reversed the suppressive effect of IL‐1 on PAI‐1 production.

Conclusion. PAI‐2 formation and PAI‐1 formation can be regulated independently in human synoviocytes, illustrating the complexity of the modulation of the net PA activity expressed by these cells.
Local Proliferation of Fibroblast‐Like Synoviocytes Contributes to Synovial Hyperplasia
Authors: Qu Zhenhong , Garcia Cesar Hernandez , O'Rourke Leslie M. , Planck Stephen R. , Kohli Manoj , Rosenbaum James T.
Published: February 2007

Objective. To test the hypothesis that local proliferation contributes significantly to the hyperplasia of rheumatoid synovium.

Methods. Immunohistologic and chemical staining was used to identify 3 markers of cell proliferation: proliferating cell nuclear antigen, c‐myc proto‐oncogene, and nucleolar organizer regions. Synovium from 21 patients with rheumatoid arthritis, 34 with degenerative joint disease, and 7 with joint trauma was examined.

Results. All 3 markers indicated substantial, active proliferation of synovial lining cells in synovium with hyperplasia. Proliferating cells showed type I procollagen immunoreactivity but were negative for CD68, a monocyte/macrophage marker. Proliferation was greater in rheumatoid arthritis than in the other conditions evaluated.

Conclusion. In situ proliferation of fibroblast‐like synoviocytes in the synovium lining contributes considerably to the increase in cell numbers in rheumatoid synovium.
Development and validation of the european league against rheumatism response criteria for rheumatoid arthritis: Comparison with the preliminary american college of rheumatology and the world health organization/international league against rheumatism criteria
Authors: van Gestel A. M. , Prevoo M. L. L. , van't Hof M. A. , van Rijswijk M. H. , van de Putte L. B. A. , van Riel P. L. C. M.
Published: February 2007

Objective. To validate the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR), and the World Health Organization (WHO)/International League Against Rheumatism (ILAR) response criteria for rheumatoid arthritis (RA).

Methods. EULAR response criteria were developed combining change from baseline and level of disease activity attained during followup. In a trial comparing hydroxychloroquine and sulfasalazine, we studied construct (radiographic progression), criterion (functional capacity), and discriminant validity.

Results. EULAR response criteria had good construct, criterion, and discriminant validity. ACR and WHO/ILAR criteria showed only good criterion validity.

Conclusion. EULAR response criteria showed better construct and discriminant validity than did the ACR and the WHO/ILAR response criteria for RA.
The epidemiology of Wegener's granulomatosis. Estimates of the five‐year period prevalence, annual mortality, and geographic disease distribution from population‐based data sources
Authors: Cotch Mary Frances , Hoffman Gary S. , Yerg Diane E. , Kaufman Gerald I. , Targonski Paul , Kaslow Richard A.
Published: February 2007

Objective. To estimate the prevalence, annual mortality, and geographic distribution of Wegener's granulomatosis.

Methods. Analysis of national vital statistics data and hospitalization data from a national survey and from all New York State inpatient facilities.

Results. Between 1979 and 1988, 1,784 death certificates in the United States listed Wegener's granulomatosis as a cause of death. Nationally, an estimated 10,771 hospitalizations included Wegener's granulomatosis among the discharge diagnoses. In New York State, there were 978 hospitalizations among 571 individuals with Wegener's granulomatosis.

Conclusion. The prevalence of Wegener's granulomatosis in the United States is approximately 3.0 per 100,000 persons. Clear differences in the geographic distribution of Wegener's granulomatosis are apparent when analyses consider rates of disease in individual counties. Contrary to previous reports, associations between disease exacerbations and season were not apparent.
Complete remission of multicentric reticulohistiocytosis with combination therapy of steroid, cyclophosphamide, and low‐dose pulse methotrexate. Case report, review of the literature, and proposal for treatment
Authors: Liang George C. , Granston Arthur S.
Published: February 2007

We describe a patient with multicentric reticulohistiocytosis in whom complete remission was achieved by sequential combination therapy with steroid, methotrexate, and cyclophosphamide. We reviewed all cases of complete or near‐complete remissions of multicentric reticulohistiocytosis reported in the English‐language literature and propose a new drug regimen for this rare but potentially disabling disease.
Activation of recombinant human neutrophil procollagenase in the presence of doxycycline results in fragmentation of the enzyme and loss of enzyme activity
Authors: Smith Gerald N. , Brandt Kenneth D. , Hasty Karen A.
Published: February 2007

Objective. To determine if reduction of collagenase activity in vitro by doxycycline (doxy) is related to activation of the proenzyme, and to determine how exogenous Ca++ and Zn++ affect the reduction.

Methods. Recombinant human neutrophil pro‐collagenase was activated with trypsin or APMA. Activity was assayed on a small peptolide substrate or on 14C‐acetylated collagen fibers. The molecular weight of the proenzyme, active enzyme, and enzyme fragments was determined by Western blotting, using a polyclonal antiserum raised against the recombinant proenzyme. Similar experiments were performed in the presence of EDTA, EGTA, 1,10‐phenanthroline, or doxy. The effects of exogenous Ca++ and Zn++ were also tested.

Results. Doxy inhibited activity of the enzyme against both substrates. If the drug was present during activation, the yield of activity was lower than when it was added after activation of the proenzyme. Western blotting showed that activation in the presence of doxy resulted in the appearance of lower molecular weight fragments and accumulation of less active enzyme. APMA generated prominent 28‐ and 26‐kd fragments, while trypsin cleavage yielded 40‐ and 30‐kd fragments. Fragmentation of the enzyme also occurred in the presence of EDTA or EGTA, but not 1,10‐phenanthroline. It was prevented by Ca++ concentrations greater than 50 mM, but was not altered by addition of Zn++ in concentrations as high as 500 μM. Inhibition of collagenase activity by doxy could be overcome by 100 mM Ca++, but addition of Zn++ had no effect.

Conclusion. These data suggest that doxy alters the conformation of procollagenase or collagenase by binding enzyme‐associated Ca++, rendering the proteins more susceptible to proteolysis and resulting in irreversible loss of enzyme protein.
Specificity of a porcine 127‐kd nucleotide pyrophosphohydrolase for articular tissues
Authors: Cardenal Antonio , Masuda Ikuko , Haas Arthur L. , McCarty Daniel J.
Published: February 2007

Objective. To determine the tissue specificity of a porcine 127‐kd nucleotide pyrophosphohydrolase (NTPPHase) found in vesicles derived from hyaline articular cartilage (ACV).

Methods. Homogenates of porcine brain, lung, liver, kidney, urinary bladder, pancreas, spleen, skin, vena cava, marrow, bone (cells), tendon (Achilles), ligament (anterior cruciate), elastic cartilage, meniscus, and hyaline cartilage were analyzed for NTPPHase activity (thymidine monophosphate paranitrophenyl ester substrate) and by Western blot using polyclonal antibodies against 127‐kd NTPPHase and against recombinant PC‐1, another ecto‐NTPPHase.

Results. All tissues contained NTPPHase activity; the highest specific activity was found in hyaline articular cartilage, the lowest in brain. ACV‐associated 127‐kd NTPPHase was expressed in cartilage, ligament, and tendon. PC‐1 was also expressed in those tissues and in skin, kidney, bone cells, and (probably) in liver and muscle.

Conclusion. The 127‐kd NTPPHase appears to be highly specific for articular tissues.
Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis
Authors: Gutierrez‐Ureña Sergio , Molina Jose F. , García Cesar O. , Cuéllar Marta L. , Espinoza Luis R.
Published: February 2007

Objective. To assess the frequency of methotrexate (MTX)‐induced pancytopenia in rheumatoid arthritis (RA).

Methods. A MEDLINE literature search was conducted to identify articles published during the last 15 years (1980–1995) that presented data on MTX‐associated pancytopenia. Two case reports of our own experience are also presented. In addition, articles that examined risk factors associated with MTX‐related pancytopenia were identified.

Results. A total of 70 patients with pancytopenia related to MTX therapy were identified (68 reported in the literature, 2 from our own experience). Sixty‐one of the patients were described in published case reports, 7 patients were from 5 long‐term prospective studies. In many of these cases, predisposing factors for the development of pancytopenia were described. The 5 long‐term prospective studies reported toxicity data on patients who had been treated with MTX for at least 13 weeks. A total of 511 patients were included in the prospective trials, yielding an overall incidence of pancytopenia of 1.4% (7 of 511). Of the 70 cases reported, 12 patients died (17%). Most of them had impaired renal function, hypoalbuminemia, concurrent infection, and/or concomitant medication with more than 5 drugs. The minimal cumulative MTX dose leading to fatal pancytopenia was 10 mg, observed in one of our patients.

Conclusion. Pancytopenia is not an uncommon side effect of low‐dose pulse MTX therapy in RA. It can lead to serious complications, including death.
Laboratory tests as predictors of disease exacerbations in systemic lupus erythematosus. Why some tests fail
Authors: Esdaile John M. , Abrahamowicz Michal , Joseph Lawrence , MacKenzie Todd , Li Yin , Danoff Deborah
Published: February 2007

Objective. To evaluate whether changes in laboratory test values are either simultaneous with or precede disease exacerbations in patients with systemic lupus erythematosus (SLE).

Methods. At 9, 6, and 3 months preceding a flare in disease activity (defined as a rise of ⩾ points in the modified SLE Disease Activity Index), laboratory tests were performed to measure patients' hematocrit levels, white blood cell, lymphocyte, and platelet counts, erythrocyte sedimentation rate, C1q binding, DNA binding, and levels of C3 and C4. Flares were classified as either present or absent, and were divided into renal, vasculitic, central nervous system, skin, serosal, and musculoskeletal subgroups. The predictive patterns were (1) the simultaneous change in the test value from the mean of 9, 6, and 3 months preceding a flare to the time of the flare; (2) the gradual change, following a linear time trend, in test results for the same time points; and (3) the change from the mean of 9 and 6 months to 3 months preceding a flare, as a measure of predictive ability. These analyses used repeated‐measures analysis of variance models. Multiple linear regression was used to study the cross‐sectional association of average‐overtime differences in test results with patients' flare subgroup.

Results. Among 202 patients with SLE (median followup 86.5 months), 83 flares occurred in 53 patients. Of 189 statistical contrasts performed, only 14 were significant (versus 10 expected), and the differences were of minor importance. Nonetheless, evaluation of all test results over each patient's observed disease course revealed significant differences between selected test values in association with specific types of flare.

Conclusion. Fluctuations in laboratory test values are poor predictors of disease exacerbations in SLE. Cross‐sectional evaluation of some test results revealed differences at the time of flare for those patients who were destined to have different types of flares, because these values differed over the entire study period. This pattern explains the frequent cross‐sectional association of disease activity with laboratory test results, and the inconsistent association of flares with recent changes in test values.
Interleukin‐10 functions as an antiinflammatory cytokine in rheumatoid synovium
Authors: Isomäki Pia , Luukkainen Reijo , Saario Riitta , Toivanen Paavo , Punnonen Juha
Published: February 2007

Objective. Interleukin‐10 (IL‐10) is an antiinflammatory cytokine that has been shown to play a role in rheumatoid arthritis (RA). We therefore investigated the effects of IL‐10 on the function and phenotype of synovial fluid mononuclear cells (SFMC) derived from patients with RA. In addition, we studied the production of IL‐10 in rheumatoid joints, and the role of endogenous IL‐10 in the regulation of SFMC function.

Methods. The presence of IL‐10 in rheumatoid joints was studied using IL‐10–specific enzyme‐linked immunosorbent assay (ELISA) and reverse transcriptase–polymerase chain reaction (RT‐PCR) techniques. The effects of recombinant human IL‐10 or neutralizing anti–IL‐10 monoclonal antibodies (MAbs) on both cytokine production and phenotype of SFMC were evaluated using cytokine‐specific ELISAs and flow cytometry. The effect of IL‐10 on proliferation of SFMC was determined by incorporation of tritiated thymidine.

Results. IL‐10 was detected by ELISA in 22 of 23 SF samples, and was spontaneously produced by cultured SFMC. IL‐10 messenger RNA was detectable in all 8 SFMC samples, as determined by RT‐PCR. Neutralization of endogenously produced IL‐10 by anti–IL‐10 MAbs resulted in increased production of IL‐1β, tumor necrosis factor α (TNF α), and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) by SFMC, and in enhanced proliferation of SFMC. In particular, the production of TNF α was dramatically increased by anti–IL‐10 MAbs. Moreover, the expression of HLA–DR molecules by SF macrophages was increased, and the expression of CD16 was decreased by anti–IL‐10 MAbs. In contrast, addition of recombinant IL‐10 significantly decreased the production of IL‐1β, TNF α, and GM‐CSF by SFMC, and decreased spontaneous and IL‐2–induced proliferation of SFMC. Finally, IL‐10 decreased HLA–DR expression and increased the expression of the Fcγ receptors, CD16 and CD64, by SF macrophages.

Conclusion. These data indicate that endogenously produced IL‐10 functions as an immunoregulatory molecule in rheumatoid synovium. Importantly, exogenous IL‐10 has potent antiinflammatory effects on SFMC, suggesting that IL‐10 may be useful in the treatment of patients with RA.
High frequencies of identical T cell clonotypes in synovial tissues of rheumatoid arthritis patients suggest the occurrence of common antigen‐driven immune responses
Authors: Ikeda Yoko , Masuko Kayo , Nakai Yuta , Kato Tomohiro , Hasunuma Tomoko , Mizushima Yutaka , Nishioka Kusuki , Yamamoto Kazuhiko , Yoshino Shin‐Ichi
Published: February 2007

Objective. To investigate T cell antigen receptor (TCR) clonotypes in rheumatoid arthritis (RA) lesions.

Methods. Reverse transcriptase–polymerase chain reaction with TCR Vβ family–specific primers and subsequent single‐strand conformation polymorphism (SSCP) analysis were performed. Direct nucleotide sequencing was also conducted.

Results. A distinct clonal expansion of T cells was observed in the synovium. Furthermore, identical bands in samples of different areas of the same lesion were obtained by SSCP analysis. Nucleotide sequencing revealed that T cell clonotypes of identical mobility on SSCP analysis had the same nucleotide sequence and thus were identical clones. In 6 RA patients, 60–100% of the expanded T cell clonotypes had identical migration patterns in 2 different samples, indicating that this percentage represents commonly existing T cell clonotypes in the affected joint. Furthermore, the Jβ2.1 gene segment was used predominantly by the TCR Vβ clonotypes that commonly expanded in the different portions of the same joint.

Conclusion. These results suggest that the immune response in RA is not random, but rather is driven by common stimuli.
High seroprevalence of anti–HTLV‐I antibody in rheumatoid arthritis
Authors: Eguchi Katsumi , Origuchi Tomoki , Takashima Hiroyuki , Iwata Kokichi , Katamine Shigeru , Nagataki Shigenobu
Published: February 2007

Objective. To investigate the association between human T lymphotropic virus type I (HTLV‐I) infection and rheumatoid arthritis (RA) in Nagasaki, an area highly endemic for HTLV‐I infection.

Methods. Sera from 113 female patients with RA and 19,796 female blood donors were screened for anti–HTLV‐I antibodies with a gelatin particle agglutination kit and confirmed using an immunoblotting kits.

Results. The age‐adjusted summary odds ratio of HTLV‐I infection among RA patients, as compared with blood donors, was 2.8 (95% confidence interval [95% CI] 1.8–4.6). The etiologic fraction, i.e., the proportion of RA in the study population that is attributable to HTLV‐I infection, was estimated to be 13.2% (95% CI 5.1–21.2). There was no significant difference in the clinical and laboratory findings between HTLV‐I–infected and HTLV‐I–uninfected RA patients.

Conclusion. These epidemiologic findings support the idea that HTLV‐I infection is a risk factor for RA, and suggest that ∼13% of the cases of RA in females living in Nagasaki are associated with HTLV‐I infection.