bluuebunny/crossref_metadata_2025 huggingface dataset:
The centromere kinesin‐like protein, CENP‐E. An autoantigen in systemic sclerosis
Authors: Rattner Jerome B. , Rees Jennifer , Arnett Frank C. , Reveille John D. , Goldstein Rose , Fritzler Marvin J.
Published: February 2007

Objective. Autoantibodies directed against centromere proteins (CENPs) are a serologic feature in some patients with systemic sclerosis (SSc). Previous studies have focused on autoantibodies to CENPs A, B, and C. CENP‐E is a recently described 312‐kd protein that also localizes to the centromere. Therefore, we studied the presence of autoantibodies to recombinant CENP‐E in patients with SSc.

Methods. Sixty sera from patients with the SSc spectrum of diseases were screened for the presence of autoantibodies against CENP‐E, by indirect immunofluorescence and immunoblotting using recombinant CENPE protein. HLA class II alleles were determined by DNA oligotyping.

Results. Among the SSc sera, 15 of 60 (25%) demonstrated antibody reactivity with recombinant CENP‐E, and 14 of these 15 sera (93%) had antibodies directed against another CENP. Anti–CENP‐E was seen in 13 of 30 sera with anti‐CENP (43%). All patients with anti–CENP‐E had a limited form of SSc, known as the CREST variant (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias). When patients with anti‐CENPs A, B, or C were compared with patients with anti–CENP‐E, no unique clinical features in the anti–CENP‐E positive group were identified. Ninety‐three percent of the patients with anti–CENP‐E had HLA–DQB1 alleles that had polar amino acids at position 26 (primarily DQB1*05), similar to patients with other CENP autoantibodies.

Conclusion. Antibodies to CENP‐E are common in patients with SSc, and are seen in higher frequency in sera from patients with a limited form, or CREST variant, of the disease.
Increased prevalence of systemic sclerosis in a native american tribe in oklahoma. Association with an amerindian HLA haplotype
Authors: Arnett Frank C. , Howard Robert F. , Tan Filemon , Moulds Joann M. , Bias Wilma B. , Durban Egon , Cameron H. Daniel , Paxton Gabe , Hodge Trevor J. , Weathers Paul E. , Reveille John D.
Published: February 2007

Objective. To investigate a high prevalence of systemic sclerosis (SSc; scleroderma) in a well‐defined population of 21,255 Choctaw Indians residing in 8 southeastern Oklahoma counties who were “users” of Indian Health Services.

Methods. A case–control study of 12 SSc cases and 48 matched non‐SSc controls (4 per case) was conducted to investigate potential occupational, residential, and infectious exposures, as well as genetic factors which might predispose to SSc. HLA class II alleles were determined by DNA oligotyping, and class I and III alleles were defined serologically.

Results. The prevalence of SSc in full‐blooded Choctaws was at least 8/1,704, or 469/100,000 (95% confidence interval [95% CI] 203–930) over the 4‐year interval 1990–1994 and was significantly higher than that among non‐full‐blooded Choctaws (6/19,551, or 31/100,000) (P= 0.00001, odds ratio [OR] = 15.4, 95% CI 4.9–49.8). The overall prevalence of SSc in Oklahoma Choctaws (66/100,000) also was significantly higher than that in other Native Americans in Oklahoma (9.5/100,000) (P= 10−6, OR = 6.95, 95% CI 33–13.7), who showed a prevalence similar to that reported for whites (2.1–25.3/100,000). Among the SSc cases, there was striking homogeneity of disease expression with the majority exhibiting diffuse scleroderma, pulmonary fibrosis, and autoantibodies to topoisomerase I. No environmental exposures were found to be in excess among cases versus controls. The strongest risk factor for SSc in cases (100%) versus controls (54%) was an HLA haplotype bearing the allelesB35, Cw4, DRB1*1602 (DR2), DQA1*O501, andDQB1*0301 (DQ7)(P= 0.002,Pcorr= 0.036, OR = 21, 95% CI 2.9–437). Survey of another group of Choctaws residing in another state revealed no cases of SSc despite a high frequency of the same HLA haplotype.

Conclusion. Full‐blooded Choctaw Native Americans living in southeastern Oklahoma have the highest prevalence of SSc yet found in any population. A major risk factor for disease is a uniquely Amerindian HLA haplotype; however, additional genes and/or an as‐yet‐unidentified environmental exposure seem likely.
Use of a radiolabeled monoclonal antibody against e‐selectin for imaging of endothelial activation in rheumatoid arthritis
Authors: Chapman Peter T. , Jamar François , Keelan Edward T. M. , Peters A. Michael , Haskard Dorian O.
Published: February 2007

Objective. To determine the potential of 111Inlabeled anti–E‐selectin monoclonal antibody (MAb) to image localized endothelial activation in rheumatoid arthritis (RA).

Methods. Fourteen patients with RA were studied after intravenous administration of 111In‐labeled F(ab′)2 fragments of MAb against the cytokine‐inducible endothelial cell activation antigen E‐selection (MAb 1.2B6). To compare uptake of 1.2B6 with that of nonspecific immunoglobulin 111In‐labeled polyclonal human immunoglobulin (HIG) was separately administered to 6 of these patients and the relative uptake of each tracer was determined.

Results. Prominent and discrete uptake of the radiolabeled MAb 1.2B6 was clearly visible in inflamed joints of all patients. Compared with 111In‐HIG, 111In‐1.2B6 provided superior images in terms of sensitivity and image intensity. Furthermore, the distribution of uptake in inflamed joints was different for the 2 tracers, with 1.2B6 showing a more focal localization in synovium.

Conclusion. This study demonstrates that it is possible to objectively assess E‐selectin expression on activated endothelium in vivo in patients with RA, using a radiolabeled MAb. This technique has considerable potential for monitoring disease activity and response to therapy in inflammatory diseases.
Cytokine messenger rna expression in the labial salivary glands of patients with Sjögren's syndrome
Authors: Ohyama Yukiko , Nakamura Seiji , Matsuzaki Goro , Shinohara Masanori , Hiroki Akiko , Fujimura Takao , Yamada Akira , Itoh Kyogo , Nomoto Kikuo
Published: February 2007

Objective: To characterize the initiation and progress of localized autoimmune damage in Sjögren's syndrome (SS), an autoimmune disease that is also considered to be a lymphoaggressive disorder, by examining the pattern of cytokine production at the site of autoimmune damage.

Methods. Using a polymerase chain reaction–based method, cytokine messenger RNA (mRNA) expression in the labial salivary glands of 15 patients with SS was investigated. In addition, the infiltrating lymphocytes in the labial salivary glands were examined immunohistochemically.

Results. Messenger RNAs of Th1 cytokines, such as interleukin‐2 (IL‐2) and interferon‐γ, were consistently detected in all patients, while Th2 cytokine mRNAs, such as IL‐4 and IL‐5, were detected in some cases, in association with strong B cell accumulation in the labial salivary glands. Other cytokine mRNAs produced by a variety of cell types, including ILIO, IL‐6, and transforming growth factor β (TGFβ), were also consistently detected in all patients, while IL‐12 mRNA was detected in some of the patients.

Conclusion. These results suggest that Th1 cytokines, as well as IL‐10, IL‐6, and TGFβ, are essential in the induction and/or maintenance of SS, while Th2 cytokines are involved in the progression of the disease process, especially local B cell activation.
Juvenile rheumatoid arthritis in rochester, minnesota 1960–1993. Is the epidemiology changing?
Authors: Peterson Lynne S. , Mason Tom , Nelson Audrey M. , O'Fallon W. Michael , Gabriel Sherine E.
Published: February 2007

Objective. To examine trends in the incidence and prevalence of juvenile rheumatoid arthritis (JRA) in Rochester, Minnesota, over 33 years.

Methods. The diagnostic retrieval system of the Rochester Epidemiology Project was utilized to screen medical records of all Rochester residents with any potential diagnoses of JRA from 1978 to 1993 (based on the American College of Rheumatology 1977 revised criteria). In addition, all cases of JRA from our previously identified cohort from 1960–1979 were verified, and the 2 data sets were combined, resulting in an incidence cohort spanning 33 years (1960–1993).

Results. Of the 1,240 medical records screened, we identified 65 cases of JRA diagnosed between 1960 and 1993 (48 females, 17 males). The average followup for cases was 12.7 years (range 0–34 years) for a total of 833 person‐years of observation. A bimodal distribution of age at diagnosis was observed, with peaks between 0 and 4 years and 9 and 15 years. Seventy‐two percent of patients had pauciarticular‐onset, 17% had polyarticular‐onset, and 11% had systemic‐onset disease. Progression of pauciarticular to polyarticular disease occurred in 11% of the cases. The overall age‐ and sex‐adjusted incidence rate was 11.7 per 100,000 population (95% confidence intervals 8.7, 14.8). The incidence rate per 100,000 population was 15.0, 14.1, and 7.8 for the time periods 1960–1969, 1970–1979, and 1980–1993, respectively (P = 0.024). A 3‐year, centered, moving average, which was used to display time trends in incidence, suggested a cyclical pattern, with incidence peaks in 1967, 1975, and 1987.

Conclusion. An overall decrease in the incidence rate over the last decade was observed, most marked in the pauciarticular‐ and systemic‐onset subtypes. This decrease, along with the observed cyclical pattern, suggest that environmental factors may influence disease frequency.
Which is the active moiety of sulfasalazine in ankylosing spondylitis? A randomized, controlled study
Authors: Taggart Allister , Gardiner Philip , McEvoy Frances , Hopkins Robbie , Bird Howard
Published: February 2007

Objective. To compare the efficacy of sulfasalazine (SSZ) with its two moieties, 5‐aminosalicylic acid (ASA) and sulfapyridine (SP), in patients with active ankylosing spondylitis (AS).

Methods. A 26‐week randomized, observer‐blinded, 2‐center, controlled study of treatment with either SSZ, ASA, or SP was conducted in 90 patients with active AS. Patients were evaluated at baseline and at monthly intervals, using several clinical and laboratory measures of disease activity. A global assessment of treatment efficacy was made by both patients and observers at the end of the study period.

Results. There were no significant changes in any of the parameters of disease activity in the ASA treatment group. Levels of serum IgG, IgA, and IgM fell significantly during treatment with SP, but none of the other changes reached statistical significance. Plasma viscosity and IgG and IgA levels fell significantly during treatment with SSZ, as did nocturnal spinal pain and overall spinal pain. Patients and observers reported a favorable outcome after treatment with SSZ or SP significantly more often than with ASA treatment.

Conclusion. SP appears to be the active moiety in AS, although there was a trend suggesting a better outcome in the SSZ group compared with the SP group, perhaps suggesting the importance of a common sulfonamide structure for efficacy.
Computed tomography of the knee joint as an indicator of intraarticular tophi in gout
Authors: Gerster Jean C. , Landry Michel , Duvoisin Bertrand , Rappoport Georges
Published: February 2007

Objective. To evaluate the utility of computed tomography (CT) of the knee joint for detecting intraarticular tophaceous deposits.

Methods. A prospective study of 16 patients with gout affecting the knee was conducted. A condition for inclusion in the study was the presence of needle‐shaped crystals with negative birefringence in the knee joint synovial fluid. Conventional radiography and CT were performed in each case.

Results. Intraarticular opacities in the capsule and the synovium, consistent with the presence of tophaceous deposits, were found in 5 of the 16 patients (9 knee joints). The mean duration of gout was longer in the patients with intraarticular tophi than in those without tophi, and 2 of the patients with tophi had poor tolerance to antihyperuricemic therapy.

Conclusion. Intraarticular opacities considered to represent tophi were observed in approximately one‐third of the patients. The presence of tophi correlated with a longer duration of the disease and a poor tolerance to medication. We therefore suggest that CT of the knees could be useful in the assessment and followup of certain patients with gout.
Antibodies to β2‐glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus
Authors: Tsutsumi Akito , Matsuura Eiji , Ichikawa Kenji , Fujisaku Atsushi , Mukai Masaya , Kobayashi Seiichi , Koike Takao
Published: February 2007

Objective. To investigate whether anticardiolipin antibodies (aCL) in patients with systemic lupus erythematosus (SLE) bind to β2‐glycoprotein I (β2GPI), and to search for a relationship between the presence of IgG and/or IgM anti‐β2GPI antibody and clinical manifestations in SLE patients.

Methods. IgG and IgM anti‐β2GPI in 308 Japanese SLE patients were measured using phospholipid‐independent enzyme immunoassays. Relationships to clinical histories and to various laboratory data were examined.

Results. The values of anti‐β2GPI and aCL, as measured by conventional enzyme immunoassay, showed a strong correlation, but the anti‐β2GPI assay was more useful in distinguishing β2GPI‐dependent aCL from β2GPI‐independent aCL. The presence of IgG anti‐β2GPI was associated with an increased frequency of a history of thrombosis. Comparisons of various laboratory data suggested that the titer of anti‐β2GPI may fluctuate with disease activity.

Conclusion. The results suggest that pathogenic aCL is directed against structurally altered β2GPI and that enzyme immunoassay for anti‐β2GPI may prove useful in evaluating the risk of thrombosis and monitoring the clinical course in patients with SLE.
Renal biopsy findings and followup of renal function in rheumatoid arthritis patients treated with cyclosporin A. An update from the international kidney biopsy registry
Authors: Rodríguez F. , Krayenbühl J. C. , Harrison W. B. , Førre Ø. , Dijkmans B. A. C. , Tugwell P. , Miescher P. A. , Mihatsch M. J.
Published: February 2007

Objective. To review data from the International Kidney Biopsy Registry, which describes the occurrence of cyclosporin A (CSA)–induced nephropathy, and to discuss the potential risk factors for its development.

Methods. The report examines data on a total of 60 first and 14 second renal biopsies performed in rheumatoid arthritis (RA) patients treated with CSA for up to 87 months.

Results. Five of the 60 patients with RA included in the Biopsy Registry had findings consistent with CSA‐induced nephropathy at first biopsy. One further patient had such findings at second biopsy. Of the 22 patients who started CSA at dosages < 4 mg/kg/day and subsequently received dosages no higher than 5 mg/kg/day, none developed CSA‐induced nephropathy. Continuous assessment of renal function did not show any evidence of deterioration over time in patients maintained on low‐dose CSA.

Conclusion. The data indicate that in RA patients being treated according to current dosing recommendations, the risk of developing CSA‐induced nephropathy is low.
Interrelationship of major histocompatibility complex class II alleles and autoantibodies in four ethnic groups with various forms of myositis
Authors: Arnett Frank C. , Targoff Ira N. , Mimori Tsuneyo , Goldstein Rose , Warner Noranna B. , Reveille John D.
Published: February 2007

Objective. To examine interrelationships among myositis subsets, autoantibodies, and major histocompatibility complex (MHC) class II alleles across ethnic lines, and to localize genetic susceptibility (presence of HLA–DR versus DQ) to myositis within the MHC class II region.

Methods. MHC class II alleles (HLA–DRB1, DQA1, and DQB1, detected by DNA oligotyping) and myositis‐specific autoantibodies (MSA) were determined in 224 patients with various myositis syndromes, including 89 whites, 89 African‐Americans, 25 Mexican‐Americans, and 21 Japanese.

Results. Anti–Jo‐1 (histidyl–transfer RNA [tRNA] synthetase) and other MSAs (anti–PL‐12, anti–PL‐7, anti‐OJ, anti‐EJ, anti‐KJ, anti‐tRNA, and anti–signal recognition particle) were equally distributed among the races, but occurred more often in patients with polymyositis (PM) than in those with dermatomyositis (DM) or other myositis syndromes. MSA frequencies were significantly positively associated with anti–Ro (SS‐A) (P = 0.002), and significantly negatively associated with anti–U1 RNP (P = 0.003). Frequencies of the HLA–DRB1*0301 (DR3), DQA1*0501, and DQB1*0201 (DQ2) alleles (and haplotype) were each increased in white patients with myositis, especially those with PM, but most strikingly in those with MSAs. However, in the other ethnic groups, except the Japanese group, only frequencies of HLA–DQA1*0501 and the structurally similar DQA1*0401 alleles were significantly increased. The presence of HLA–DQA1*0501 or *0401 was most significantly associated with anti–Jo‐1, anti–PL‐12, and other MSAs, compared with myositis patients without MSAs (P = 0.0008, Pcorr = 0.01, odds ratio [OR] = 3.7), and with normal, ethnically matched controls (P = 3 × 10−7, Pcorr = 1 × 10−6, OR = 6.5). Among MSA‐positive patients who were negative for HLA–DQA1*0501 and *0401, including Japanese patients, the HLA–DQA1*0101 and *0103 alleles predominated. In addition, there appeared to be a negative association of the HLA–DR2 alleles (DRB1*1501 and *1503) with PM (P = 0.007, Pcorr not significant, OR = 0.39), but not with DM or myositis overall.

Conclusion. By transracial gene mapping, genetic susceptibility to anti–Jo‐1 and other MSAs in patients with myositis can be localized within the MHC region to the HLA–DQA1 locus.
Treatment of psoriatic arthritis with extracorporeal photochemotherapy and conventional psoralen–ultraviolet A irradiation
Authors: Vahlquist Carin , Larsson Marianne , Ernerudh Jan , Berlin Gösta , Skogh Thomas , Vahlquist Anders
Published: February 2007

Objective. To study the use of combined photopheresis and psoralen–ultraviolet A irradiation (PUVA) in the treatment of psoriatic arthritis.

Methods. Eight patients with psoriasis and sero‐negative arthritis received photopheresis for 12 weeks, followed by photopheresis plus PUVA for another 12 weeks. Clinical and laboratory examinations were performed every 3 months for up to 1 year after therapy.

Results. Four patients experienced a marked improvement of joint symptoms that lasted for ≥12 months post‐therapy (74% decrease in the Ritchie articular index; P < 0.01). Prior to therapy, these patients had a higher CD4:CD8 ratio than the poor responders. Only minor laboratory changes occurred.

Conclusion. A more extensive trial of photopheresis plus PUVA in psoriatic arthritis is warranted.
Chronic arthropathy and musculoskeletal symptoms associated with rubella vaccines. A review of 124 claims submitted to the national vaccine injury compensation program
Authors: Weibel Robert E. , Benor David E.
Published: February 2007

Objective. To report the outcome of 124 claims of chronic arthropathy associated with rubella vaccine submitted to the National Vaccine Injury Compensation Program.

Methods. Medical records and testimony were reviewed separately by physicians and Special Masters to determine the clinical diagnosis and eligibility for compensation under the Program.

Results. Among the 124 subjects with chronic arthropathy, the onset occurred between 1 week and 6 weeks after the rubella vaccination in 72, and <1 week or >6 weeks after the vaccination in 52. Various conditions developed in the 2 onset groups (1–6 weeks postvaccination, <1 week or >6 weeks postvaccination), including, respectively, unspecified arthritis (n = 29, n = 1), specified arthritis (n = 11, n = 19), arthralgia (n = 24, n = 7), fibromyalgia (n = 4, n = 11), and multiple symptoms with minimal arthralgia or myalgia (n = 4, n = 14). Concordance of medical recommendations by Program physicians and Special Masters' decisions in 56 completed claims was 91%, with awards mainly to patients with chronic unspecified arthritis and arthralgia.

Conclusion. The Program and the US Court of Federal Claims have accepted a causal relationship between currently used rubella vaccine in the US and some chronic arthropathy with an onset between 1 week and 6 weeks after vaccine administration.
The spindle kinesin‐like protein HsEg5 is an autoantigen in systemic lupus erythematosus
Authors: Whitehead Clark M. , Winkfein Robert J. , Fritzler Marvin J. , Rattner J. B.
Published: February 2007

Objective. Autoantibodies directed against the mitotic spindle apparatus (MSA) have been shown to target an antigen referred to as NuMA (nuclear mitotic apparatus). In this study, we identified a second MSA antigen as the spindle kinesin‐like protein HsEg5. We studied the frequency of antibodies to HsEg5 in human sera that demonstrate the MSA pattern of staining, the frequency of autoantibodies to HsEg5 in patients with systemic lupus erythematosus (SLE), and the clinical features of patients with antibodies to HsEg5.

Methods. A prototype serum from an SLE patient was used to isolate a 4.8‐kilobase complementary DNA (cDNA) from a HeLa cDNA library. Western blot, immunoprecipitation, and sequence analysis revealed that the antigen was an ∼130‐kd protein, HsEg5. The frequency of autoantibodies to recombinant HsEg5 in 51 sera that demonstrated an MSA pattern of staining on HEp‐2 and HeLa cells was detected by immunoblotting 2 constructs of the cDNA. The clinical features of patients with antibodies directed against HsEg5 was obtained by retrospective chart review.

Results. The antigen responsible for the MSA‐35 pattern was identified as the human kinesin‐like protein HsEg5. Seven of 51 sera (14%) that demonstrated an MSA pattern of staining reacted with recombinant HsEg5. Six of 7 of the HsEg5‐positive patients (86%) had SLE, and 1 had Sjögren's syndrome. The indirect immunofluorescent staining pattern of sera that reacted with HsEg5 could be distinguished from the other sera that reacted with NuMA. In an unselected cohort of 52 SLE patients, 3 (6%) had autoantibodies reactive with the recombinant HsEg5.

Conclusion. Autoantibodies to MSA fall into 2 major classes: those reactive with NuMA and those reactive with HsEg5. Autoantibodies to HsEg5 are found in a lower frequency than NuMA in sera that demonstrate the MSA pattern of staining and appear to be specifically associated with SLE. HsEg5 can be distinguished from NuMA by indirect immunofluorescence and Western blotting.
Two major autoantigen—Antibody systems of the mitotic spindle apparatus
Authors: Andrade Luis E. C. , Chan Edward K. L. , Peebles Carol L. , Tan Eng M.
Published: February 2007

Objective. To characterize human autoantigen‐antibody systems related to the mitotic poles and spindles.

Methods. Thirty‐seven human sera with autoantibodies staining mitotic poles and spindles in indirect immunofluorescence (IIF) studies were further characterized by immunofluorescence on mitotic cells and by immunoblotting and immunoprecipitation. Clinical diagnoses meeting the American College of Rheumatology criteria were based on chart review and interview with the corresponding physicians.

Results. Two autoantibody systems reactive with mitotic poles and spindles were defined. Type 1 nuclear mitotic apparatus (NuMA‐1) antibodies were identified in the serum of 30 patients. Interphase cells showed a fine, speckled, nuclear staining, while mitotic cells had bright staining of the rim of the centrosomes and light staining of the spindles proximal to the centrosomes. In telophase, the staining shifted from the centrosomes to the reforming nuclei. On immunoblotting, anti—NuMA‐1 sera reacted with a 210‐kd protein. The reactivity of these sera was identified (with the aid of reference antibodies) as the previously described NuMA antigen—antibody system. Clinical information was available for only 17 of the 30 patients with anti—NuMA‐1; of these, 17 (53%) had clinical and lip biopsy findings that met the criteria for Sjögren's syndrome. NuMA‐2 antibodies were found in the sera of 7 patients. Interphase cells showed no nuclear or cytoplasmic staining, but mitotic cells had brightly stained poles and spindles. At anaphase/telophase, staining shifted to the midbody and the intercellular bridge. Anti—NuMA‐2 sera immunoprecipitated a protein of 116 kd. This group of patients was more heterogeneous and had both systemic and organ‐specific autoimmune diseases.

Conclusion. NuMA protein (here called NuMA‐1) and a 116‐kd protein (here called NuMA‐2) are the major targets of the autoimmune response in the mitotic apparatus, since most of the selected sera (based on IIF staining of the mitotic spindles and poles) recognized 1 of these 2 antigens.
Identification of autoantibodies to the I protein of the heterogeneous nuclear ribonucleoprotein complex in patients with systemic sclerosis
Authors: Montecucco Carlomaurizio , Caporali Roberto , Cobianchi Fabio , Biamonti Giuseppe
Published: February 2007

Objective. To assess the presence of autoantibodies to the I protein (polypyrimidine‐tract binding protein) of the heterogeneous nuclear RNPs (hnRNP) in different connective tissue diseases. Antibodies to other hnRNP proteins (A1, A2, and B) have been previously found in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD).

Methods. Sera from 101 patients with various connective tissue diseases and 25 normal controls were investigated by enzyme‐linked immunosorbent assay and immunoblotting, for their reactivity to highly purified recombinant hnRNP I. Moreover, reactivity to cellular hnRNP I protein was investigated by immunoblotting using a partially purified preparation of hnRNP proteins (including A1, A2, B, and I), and by indirect immunofluorescence. For the analysis of the fluorescence pattern, affinity‐purified antibodies to hnRNP I, obtained from a selected patient, were tested on HEp‐2 cells.

Results. By immunoblotting, antibodies reacting to recombinant hnRNP I were found in 22 of 40 patients with systemic sclerosis (SSc), 3 of 32 with RA, 0 of 23 with SLE, and 0 of 6 with MCTD. Antibodies to recombinant hnRNP I were more frequently found in patients with pre‐SSc or limited SSc (15 of 24) than in those with intermediate or diffuse SSc (7 of 16). In indirect immunofluorescence studies, affinity‐purified anti—hnRNP I autoantibodies gave a diffuse nucleoplasmic staining. Using an hnRNP preparation from nuclear extracts, anti—hnRNP I reactivity was detectable in SSc sera, while it was not detectable in RA, SLE, and MCTD sera reacting with hnRNP A/B proteins.

Conclusion. Human autoimmune sera show distinct patterns of anti‐hnRNP reactivity, i.e., anti‐A/B in SLE and RA sera, and anti‐I in SSc sera. This suggests that A/B proteins and the I protein may be involved in different dynamic hnRNP complexes that elicit different autoimmune responses. From a clinical perspective, anti—hnRNP I antibodies are frequently associated with pre‐SSc features, suggesting an early appearance of these antibodies during the course of the disease.
Adherence of synovial cells on EDA‐containing fibronectin
Authors: Hino Kazuo , Maeda Toshinaga , Sekiguchi Kiyotoshi , Shiozawa Kazuko , Hirano Hisanobu , Sakashita Eiji , Shiozawa Shunichi
Published: February 2007

Objective. To investigate the role of EDA‐containing fibronectin (EDA+ FN), a splice variant of FN detectable in association with cellular transformation, in the adherence of synovial cells (SC) on rheumatoid cartilage surface.

Methods. The number of SC adherent on cartilage slices or on culture plates containing either EDA+ FN or plasma FN (pFN) was enumerated under a phase‐contrast microscope. The portion of the FN molecule responsible for adherence of SC onto EDA+ FN was investigated by inhibition studies using antibodies or peptide fragments.

Results. SC adhered more strongly on the surfaces containing EDA+ FN than on those containing pFN (P < 0.01). When monoclonal antibodies against the EDA or the carboxyl‐terminal heparin‐binding (Hep2) domains were used, adhesion of SC onto EDA+ FN was reduced to a level comparable with that onto pFN. FN fragments containing Hep2 or heparan sulfate inhibited the adhesion of SC onto EDA+ FN. Treatment of SC with heparitinase, but not heparinase, reduced the adhesion of SC onto EDA+ FN.

Conclusion. EDA+ FN enhances adherence of SC on the matrix via the Hep2 region of EDA+ FN.
The presence of interleukin‐13 in rheumatoid synovium and its antiinflammatory effects on synovial fluid macrophages from patients with rheumatoid arthritis
Authors: Isomäki Pia , Luukkainen Reijo , Toivanen Paavo , Punnonen Juha
Published: February 2007

Objective. To study the production of interleukin‐13 (IL‐13) in rheumatoid synovium and the effects of recombinant IL‐13 on the phenotype and function of synovial fluid (SF) macrophages and T cells derived from patients with rheumatoid arthritis (RA).

Methods. The presence of IL‐13 in SF was studied using an IL‐13—specific enzyme‐linked immunosorbent assay (ELISA); the production of IL‐13 was studied in SF mononuclear cells (SFMC) by reverse transcriptase—polymerase chain reaction. The effects of recombinant IL‐13 on cytokine production by and phenotype of SFMC were evaluated using cytokine‐specific ELISAs and flow cytometry, respectively. The effect of IL‐13 on the proliferation of SFMC was determined by 3H‐thymidine incorporation. The production and the effects of IL‐13 were compared with those of IL‐4.

Results. IL‐13 was present in 27 of 28 SF samples, and IL‐13 messenger RNA (mRNA) was detectable in SFMC. Importantly, IL‐13 levels were significantly higher than those of IL‐4, and IL‐13 protein and mRNA were expressed in several samples, although IL‐4 synthesis was undetectable. Recombinant IL‐13 significantly reduced the production of IL‐1β and tumor necrosis factor α and the expression of CD16 and CD64 by SF macrophages, whereas the expression of HLA—DR and CD23 was increased. These effects on SF macrophages were similar to those observed with IL‐4, but in contrast to IL‐4, IL‐13 had no growth‐promoting effect on SF T cells.

Conclusion. IL‐13 is consistently present in rheumatoid synovium. The ability of exogenous IL‐13 to decrease the production of proinflammatory cytokines by SFMC suggests that it may have therapeutic potential in the treatment of patients with RA.
Patterns of expression of tumor necrosis factor α, tumor necrosis factor β, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondylarthropathy
Authors: Grom Alexei A. , Murray Kevin J. , Luyrink Lorie , Emery Helen , Passo Murray H. , Glass David N. , Bowlin Terry , Edwards Carl
Published: February 2007

Objective. To assess the expression of tumor necrosis factor α (TNF α), TNF β, and their receptors in synovia of patients with juvenile rheumatoid arthritis (JRA) and juvenile spondylarthropathy (JSpA), and to determine similarities with and differences from adult RA.

Methods. Twenty‐eight synovial tissue samples from patients with JRA, 6 from patients with JSpA, and 6 from patients with RA, selected for the presence of inflammatory infiltrates, were analyzed for the expression of TNF α, TNF β, and their receptors (p55 and p75 TNFR), utilizing the dual approach of reverse transcriptase—polymerase chain reaction and immunohistochemistry analysis.

Results. The presence of both TNF α and TNF β expression was demonstrated in most JRA and JSpA tissues, although samples from patients with pauci‐articular JRA had somewhat lesser amounts of these cytokines. TNF β expression correlated significantly with the occurrence of lymphocytic aggregates in tissues. Staining with monoclonal antibodies specific for the p55 and p75 receptors revealed that a diverse range of cell types expressed the receptors, with the most intense p55 staining on vascular endothelial cells. In the vast majority of synovial tissues, far greater numbers of cells expressed the p55 form of the receptor than the p75 form.

Conclusion. JRA and JSpA synovia are characterized by the presence of TNF α, TNF β, and cells expressing TNFR. These findings provide further evidence that TNF, through autocrine/paracrine mechanisms, may amplify local inflammation, leading to joint destruction. The prominence of TNF β in the synovium in particular subgroups of JRA patients and in JSpA patients may be a distinguishing feature of these diseases.
Distinct immunologic features of finnish Sjögren's syndrome patients with HLA alleles DRB1*0301, DQA1*0501, and DQB1*0201. Alterations in circulating T cell receptor γ/δ subsets
Authors: Kerttula Tuija O. , Collin Pekka , Polvi Anne , Korpela Markku , Partanen Jukka , Mäki Markku
Published: February 2007

Objective. To determine whether there were differences in the circulating T lymphocyte subsets or clinical features of patients with primary Sjögren's syndrome (SS) who were positive for different HLA alleles.

Methods. Two‐ and three‐color flow cytometry analyses were performed, using a whole blood lysing method.

Results. Patients with SS who had the HLA alleles DRB1*0301, DQA1*0501, and DQB1*0201 had lower levels of circulating Vδ1‐positive T cell receptor γ/δ (TCRγ/δ) cells and higher levels of circulating CD45RO‐positive TCRγ/δ cells compared with patients with SS who did not have these alleles. The patient subgroup with these alleles also had higher levels of anti—SS‐A/Ro and anti—SS‐B/La.

Conclusion. These results indicate that patients with primary SS may be immunologically divided into subgroups according to their HLA status. These immunologic changes in SS may also be typical of other autoimmune disorders in patients with the HLA—DR3 haplotype.
Elevated levels of 92‐kd type IV collagenase (matrix metalloproteinase 9) in giant cell arteritis
Authors: Sorbi D. , French D. L. , Nuovo G. J. , Kew R. R. , Arbeit L. A. , Gruber B. L.
Published: February 2007

Objective. To determine if circulating gelatinase activity and matrix metalloproteinase 9 (MMP‐9) (gelatinase B, or 92‐kd type IV collagenase) antigenic levels are elevated in sera of patients with giant cell arteritis (GCA), and to ascertain if MMP‐9 messenger RNA (mRNA) is deposited in situ at sites of disease involvement.

Methods. Serum samples were collected from 12 patients with GCA and 12 healthy volunteers. Vascular tissue was obtained at the time of temporal artery biopsy. Type IV collagenase activity was determined by gelatin substrate zymography and the quantitative biotinylated gelatin substrate degradation assay. A double‐sandwich immunoassay utilizing 2 different isotypes of monoclonal antibodies generated against MMP‐9 was used for measuring serum MMP‐9 antigenic levels. Finally, to localize sites of MMP‐9 mRNA transcription in inflamed arteries, the method of reverse transcriptase in situ polymerase chain reaction (RTisPCR) was utilized.

Results. Serum gelatinase activity and MMP‐9 titers were significantly increased in patients with GCA (mean ± SEM 198.9 ± 36.9 μg gelatin/hour/ml serum, versus 21.2 ± 4.0 in controls; P = 0.0006). The differences in antigenic MMP‐9 levels were even more prominent (3005.4 ± 900.6 ng/ml and 31.6 ± 9.8 ng/ml in GCA and control sera, respectively; P = 0.007). By RTisPCR, MMP‐9 mRNA was mainly detected in cytoplasm of cells resembling smooth muscle cells and fibroblasts in regions of fragmented elastic tissue in the lamina media.

Conclusion. Gelatinase activity, and specifically MMP‐9 levels, are substantially elevated in sera of patients with GCA. Detection of MMP‐9 mRNA in the lamina media of inflamed vasculature suggests that degradation of intercellular matrix, particularly elastic fibers, may play a key role in the pathogenesis of GCA. Further studies are needed to determine if the circulating MMP‐9 level could be utilized as a clinical marker of disease activity.
HLA—DRB1 genes and disease severity in rheumatoid arthritis
Authors: Reveille John D. , Alarcón Graciela S. , Fowler Sarah E. , Pillemer Stanley R. , Neuner Rosemarie , Clegg Daniel O. , Mikhail Isis S. , Trentham David E. , Leisen James C. C. , Bluhm Gilbert , Cooper Sheldon M. , Duncan Howard , Tuttleman Marilyn , Heyse Stephen P. , Sharp John T. , Tilley Barbara ,   For the MIRA trial group
Published: February 2007

Objective. To examine the effect of alleles encoding the “shared”/“rheumatoid” epitope on rheumatoid arthritis (RA) disease severity in patients who participated in the minocycline in RA (MIRA) trial.

Methods. Of 205 patients with a week‐48 visit, blood was available for typing of HLA‐DRB1 and HLA‐DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosions were used to assess disease severity and new erosions at the last visit served as a proxy for progression.

Results. At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebotreated, but not the minocycline‐treated, patients. A treatment group/HLA‐DR4 epitope interaction was demonstrated in multivariate analyses. Approximately two‐thirds of African‐American patients did not have the rheumatoid epitope.

Conclusion. HLA‐DRB1 oligotyping may be useful in predicting the progression of disease in some Caucasian patients. Our study corroborates the infrequency of the epitope among African‐American patients with RA.
Gamma‐linolenic acid treatment of rheumatoid arthritis. A randomized, placebo‐controlled trial
Authors: Zurier Robert B. , Rossetti Ronald G. , Jacobson Eric W. , Demarco Deborah M. , Liu Nancy Y. , Temming Joseph E. , White Bernadette M. , Laposata Michael
Published: February 2007

Objective. To assess the clinical efficacy and adverse effects of γ‐linolenic acid (GLA), a plant seed oil‐derived unsaturated fatty acid that suppresses inflammation and joint tissue injury in animal models, in the treatment of active rheumatoid arthritis (RA).

Methods. Fifty‐six patients with active RA were randomized to treatment groups in a 6‐month, double‐blind trial of GLA versus placebo. This was followed by a 6‐month, single‐blind trial during which all patients received GLA. Patients were treated with 2.8 gm/day of GLA as the free fatty acid or with sunflower seed oil (placebo) administered in identical capsules.

Results. Treatment with GLA for 6 months resulted in statistically significant and clinically relevant reductions in the signs and symptoms of disease activity in patients with RA. Overall meaningful responses (at least 25% improvement in 4 measures) were also better in the GLA treatment group (14 of 22 patients versus 4 of 19 in the placebo group; P = 0.015). During the second 6 months, both groups exhibited improvement in disease activity. Thus, patients taking GLA during the entire study showed progressive improvement during the second 6 months. In this group, 16 of 21 patients showed meaningful improvement at 12 months compared with study entry.

Conclusion. GLA at doses used in this study is a well‐tolerated and effective treatment for active RA. GLA is available as a component of several plant seed oils and is usually taken in far lower doses than were used in this trial. It is not approved in the United States for the treatment of any condition, and should not be viewed as therapy for any disease. Further controlled studies of its use in RA are warranted.
Low‐dose corticosteroids in rheumatoid arthritis. A meta‐analysis of their moderate‐term effectiveness
Authors: Saag Kenneth G. , Criswell Lindsey A. , Sems Kelly M. , Nettleman Mary D. , Kolluri Sheela
Published: February 2007

Objective. To perform a systematic literature review and meta‐analysis of the effectiveness of low‐dose corticosteroids in the treatment of rheumatoid arthritis (RA).

Methods. After identifying all relevant studies meeting preselected inclusion criteria, we performed 2 meta‐analyses. First, we compared the effectiveness of prednisone to placebo and active drug controls (aspirin, chloroquine, or deflazacort) using standard meta‐analysis methods for continuous data. Then, to compare the relative effectiveness of prednisone to second‐line agents, we used methods similar to prior meta‐analyses of second‐line agents for RA treatment. Outcomes assessed were the number of tender and swollen joints, grip strength, and the erythrocyte sedimentation rate (ESR).

Results. Very few studies directly assessed the effectiveness of corticosteroids for RA treatment, and many were of poor methodologic quality. Only 9 of 34 studies identified by our search met criteria for inclusion. The results of our standard meta‐analysis indicated that corticosteroids appeared to be more effective than either placebo or active drug controls in improving most conventional outcome measures (effect size 0.90 for the number of tender joints, 1.05 for the number of swollen joints, and 1.20 for the ESR). In our second comparative meta‐analysis, corticosteroids were nearly equivalent to second‐line agents previously examined in meta‐analyses (combined effect size 0.82).

Conclusion. Based on the limited data available, during moderate‐term treatment periods averaging slightly over 7 months, corticosteroids appeared to be as effective or more effective than alternative therapies in improving several common RA disease activity measures.
Ribosomal P autoantibodies in systemic lupus erythematosus. Frequencies in different ethnic groups and clinical and immunogenetic associations
Authors: Arnett Frank C. , Reveille John D. , Moutsopoulos Haralampos M. , Georgescu Liviu , Elkon Keith B.
Published: February 2007

Objective. To determine the frequencies and clinical associations of antiribosomal P antibodies (anti‐P) in a large multiethnic cohort of patients with systemic lupus erythematosus (SLE), and to assess whether anti‐P was associated with any major histocompatibility complex (MHC) class II alleles or shared amino acid sequences.

Methods. Sera from 394 SLE patients were studied for anti‐P using an enzyme‐linked immunosorbent assay, and MHC class II alleles (HLA‐DRB1, DQA1, and DQB1) were determined by DNA oligotyping.

Results. Anti‐P antibodies were found in 13‐20% of patients in the majority of ethnic groups, but were perhaps more frequent in Chinese patients (36%) and less common in Bulgarian patients (6%). Neuropsychiatric lupus (psychosis and/or depression) was significantly associated with anti‐P. The HLA‐DR2, DQ6 haplotypes DRB1*1501 or *1503, DQA1*0102, and DQB1*0602 were increased in anti‐P‐positive whites, blacks, and Mexican Americans. The HLA‐DQB1*0602 allele showed the strongest association with anti‐P when these 3 ethnic groups were combined and compared with both race‐matched anti‐P—negative SLE patients and normal controls. The HLA‐DQ8 specificity (DQB1*0302) was increased both in whites and in Mexican‐Americans with anti‐P who were negative for HLA‐DQB1*0602, and perhaps also increased in Greeks, but not in blacks, in whom HLA‐DQB1*0301 was increased. A shared amino acid sequence in HLA‐DQB1 (at position 26 of leucine and position 30 of tyrosine) was strongly associated with anti‐P positivity (70%) versus anti‐P negativity (42%) across ethnic lines.

Conclusion. The anti‐P response in SLE patients, occurring in ∼ 15% of patients, was strongly influenced by certain MHC class II alleles and was correlated with diffuse neuropsychiatric dysfunction.
Impaired recovery and cytolytic function of CD56+T and non—T cells in systemic lupus erythematosus following in vitro polyclonal T cell stimulation. Studies in unselected patients and monozygotic disease‐discordant twins
Authors: Stohl William , Elliott Julie E. , Hamilton Ann S. , Deapen Dennis M. , Mack Thomas M. , Horwitz David A.
Published: February 2007

Objective. To determine whether there is impaired generation and cytolytic function of CD56+ T cells and non‐T cells in human systemic lupus erythematosus (SLE).

Methods. Peripheral blood mononuclear cells (PBMC) were obtained from 73 patients with SLE, 39 normal controls, and 9 pairs of monozygotic (MZ) twins discordant for SLE. PBMC were stimulated with anti‐CD3 monoclonal antibody, maintained in interleukin‐2, and assayed for percentages of total CD56+ cells and CD56+ T cells by flow cytometry, and for cytolytic activity against 51Cr‐labeled Daudi target cells.

Results. Despite normal total cell expansion, the percentages of recovered CD56+ T cells and total CD56+ cells were 1.6‐fold and 1.8‐fold lower, respectively, in patients with SLE compared with normal controls (P = 0.011 and P < 0.001, respectively). Cytolytic activities of isolated total CD56+ cells and CD56+ T cells and were also reduced in patients with SLE compared with normal controls (P = 0.033). These defects associated with SLE were independent of disease activity and immunosuppressive medications, and they reflected impaired maturation of cytolytic effector cells rather than a deficiency in precursor cell number. In MZ twins discordant for SLE, recovered percentages of CD56+ cells and cytolytic responses were very low in 4 of 8 and 6 of 9 co‐twins with SLE, respectively. Cell‐mixing experiments with the PBMC of the MZ twins demonstrated that the E+ cell fractions (containing all T cells and CD56+ non‐T cells) from the co‐twins with SLE had decreased ability to generate cytolytic activity compared with the corresponding E+ cell fractions from the healthy co‐twins. However, recovered percentages of CD56+ cells and non‐T cells and cytolytic responses were also depressed in 4 of 8 and 4 of 9 healthy co‐twins, respectively.

Conclusion. Impaired CD56+ T cell and non‐T cell responses are a feature of SLE and may antedate the onset of clinical disease.
Recombinant human osteogenic protein 1 is a potent stimulator of the synthesis of cartilage proteoglycans and collagens by human articular chondrocytes
Authors: Flechtenmacher Johannes , Huch Klaus , Thonar Eugene J.‐M. A. , Mollenhauer Juergen A. , Davies Sherri R. , Schmid Thomas M. , Puhl Wolfhart , Sampath T. Kuber , Aydelotte Margaret B. , Kuettner Klaus E.
Published: February 2007

Objective. To study the effects of recombinant human osteogenic protein‐1 (rHuOP‐1; bone morphogenetic protein‐7) on proteoglycan and collagen synthesis by human articular chondrocytes.

Methods. Articular chondrocytes from fetal, adolescent, and adult human donors were cultured in alginate beads for 4 days in a mixture of Ham's F‐12, Dulbecco's modified Eagle's medium, 10% fetal bovine serum (FBS), then for an additional 3‐10 days in the presence and absence of rHuOP‐1, with and without FBS. Chondrocyte synthetic activity was measured as the amount of incorporation of 35S‐sulfate into proteoglycans and 3H‐proline into hydroxyproline. Sieve chromatography and sodium dodecyl sulfate‐polyacrylamide gel electrophoresis were performed to identify specific proteoglycans and collagens.

Results. Recombinant human OP‐1 markedly stimulated the synthesis of proteoglycans (mostly aggrecan) and collagens (predominantly type II) by all chondrocyte preparations. This did not require the presence of FBS and was associated with continued expression of the chondrocyte phenotype.

Conclusion. Recombinant human OP‐1 is a more potent stimulator of the synthesis of cartilage‐specific molecules by human articular chondrocytes than are other factors tested for comparison, including TGFβ1 and activin A.