bluuebunny/crossref_metadata_2025 huggingface dataset:
HLA–DR4 subtypes in new zealand polynesians. predominance of dw13 in the healthy population and association of dw15 with rheumatoid arthritis
Authors: Tan Paul L. J. , Farmiloe Sarah , Roberts Maurice , Geursen Arie , Skinner Margot A.
Published: February 2007

Objective. To analyze HLA–DR4 alleles in New Zealand Polynesians with rheumatoid arthritis (RA).

Methods. Thirty Polynesians and 30 Caucasians with RA, as well as 65 Polynesian and 60 Caucasian healthy blood donors, were DR4 subtyped using the polymerase chain reaction and sequence‐specific oligonucleotide probes.

Results.The frequency of DR4 (DRB1*04) was increased in both Polynesian (P <0.001) and Caucasian (P <0.005) RA patients compared with race‐matched controls. Dw4 (DRB1*0401) was detected in 15 of 30 Caucasian patients but only 2 of 30 Polynesian patients (P <0.001). In Polynesians, RA was associated with Dw15 (DRB1*0405), which was present in 11 of 30 patients and 3 of 65 controls (P < 0.001). Dw13 (DRB1*0403) was the most frequent DR4 allele in healthy Polynesians, but was not significantly associated with RA.

Conclusion. The predominance of the Dw13 subtype in Polynesians may explain in part the low prevalence of RA in this population. The association of Dw15 with RA in Polynesians supports the hypothesis that the third hypervariable region of DRβ determines susceptibility to RA.
Release of cartilage macromolecules into the synovial fluid in patients with acute and prolonged phases of reactive arthritis
Authors: Saxne Tore , Glennås Anne , Kvien Tore K. , Melby Kjetil , Heinegård Dick
Published: February 2007

Objective. Extensive changes in articular cartilage metabolism occur during the acute phase of reactive arthritis, as indicated by altered release of cartilage macromolecules into synovial fluid (SF) demonstrated immunochemically. Nevertheless, permanent cartilage lesions are rare in this disease. To monitor specific events during the evolution of reactive arthritis, we investigated the content of cartilage macromolecules in sequentially obtained SF samples from 22 patients.

Methods. Two groups of proteoglycan epitopes, the glycosaminoglycan‐rich region of aggrecan (referred to as proteoglycan) and its hyaluronan‐binding region (HABr), as well as one matrix protein, cartilage oligomeric matrix protein (COMP), were quantified by immunoassay.

Results. SF proteoglycan concentrations, which were initially elevated, decreased significantly with prolonged arthritis, whereas COMP levels changed less markedly and levels of HABr remained stable. There was a positive correlation between SF and serum concentrations of COMP in samples obtained during the early phase of the disease.

Conclusion. Cartilage involvement in reactive arthritis is transient, in contrast to findings in rheumatoid arthritis. Reactive arthritis should therefore be a suitable model for studies of repair processes in cartilage, which will facilitate understanding of the pathophysiology of cartilage involvement in arthritis.
Production of monocyte chemotactic protein–1 in human type B synoviocytes. synergistic effect of tumor necrosis factor α and interferon‐γ
Authors: Hachicha Mohamed , Rathanaswami Palaniswami , Schall Thomas J. , Mccoll Shaun R.
Published: February 2007

Objective. Since local secretion of chemotactic factors could contribute substantially to the homing of monocytes to the rheumatoid synovium, we investigated the ability of type B, or “fibroblast‐like,” synoviocytes isolated from the synovial tissue of patients with rheumatoid arthritis to synthesize and secrete the novel cytokine monocyte chemotactic protein 1 (MCP‐1).

Methods. Synthesis and secretion of MCP‐1 was determined by immunoprecipitation following metabolic labeling of MCP‐1 with 35S‐cysteine. MCP‐1 gene regulation was assessed by Northern blot analysis.

Results. Unstimulated type B synoviocytes released little or no MCP‐1, although low levels of MCP‐1 messenger RNA (mRNA) were detected. However, incubation of these cells with tumor necrosis factor α (TNFα) resulted in a time‐ and dose‐dependent release of MCP‐1 into the supernatant, and expression of MCP‐1 mRNA. Use of cycloheximide and actinomycin D confirmed that TNFα was inducing MCP‐1 expression at both the transcriptional and translational levels. Treatment of the synoviocytes with interferon‐γ (IFNγ) also stimulated an increase in both the steady‐state levels of MCP‐1 mRNA, as well as MCP‐1 protein synthesis and secretion. In addition, TNFα and IFNγ in combination exerted a synergistic effect on both MCP‐1 mRNA accumulation and protein secretion.

Conclusion. These studies demonstrate that the MCP‐1 gene is regulated by TNFα and IFNγ in type B synoviocytes and indicate that these cells may play an important role in the recruitment of inflammatory cells to the rheumatoid synovial environment, via the production of novel chemotactic cytokines such as MCP‐1.
Transforming growth factor β exerts opposite effects from interleukin‐1β on cultured rabbit articular chondrocytes through reduction of interleukin‐1 receptor expression
Authors: Réadini F. , Mauviel A. , Pronost S. , Loyau G. , Pujol J.‐P.
Published: February 2007

Objective. The aim of the study was to determine whether transforming growth factor β (TGFβ) modulates the effects and the receptor expression of interleukin‐1 (IL‐1) in rabbit articular chondrocytes (RAC).

Methods. Collagen, glycosaminoglycan, and collagenase production, together with 125I‐labeled IL‐1 binding, were analyzed in RAC cultures.

Results. TGFβ reduced both IL‐1 effects on matrix metabolism and IL‐1 receptor expression.

Conclusion. TGF/3 acts as an antagonist of the effects of IL‐1 through down‐regulation of its receptor expression.
Degradation of human articular cartilage by neutrophils in synovial fluid
Authors: Winn Chatham W. , Swaim Richard , Frohsin Henry , Heck Louis W. , Miller Edward J. , Blackburn Warren D.
Published: February 2007

Objective. To determine whether surface‐adherent immunoglobulins are capable of mediating synovial fluid (SF) neutrophil degradation of proteoglycan and collagen in intact, normal human articular cartilage, and to define the respective roles of neutrophil serine proteases and metalloproteases in degrading these cartilage constituents.

Methods. Pellet explants of normal human articular cartilage pretreated with bovine serum albumin (BSA) or IgG were incubated with polymorphonuclear cells suspended in SF (PMN‐SF), or with supernatants derived from neutrophils stimulated with surface‐associated IgG. Proteoglycan degradation was measured by assaying release of 35S‐proteoglycan fragments from cartilage explants prelabeled with 35S‐sulfate. Collagen degradation was measured by assaying hydroxyproline content in the PMN‐SF preparations or neutrophil supernatants following their incubation with unlabeled explants.

Results. Significant release of both 35S fragments and hydroxyproline was noted following incubation of PMN‐SF with IgG‐treated pellets, compared with pellets treated with BSA. IgG preparations derived from pooled normal serum or rheumatoid arthritis SF were equally efficacious in mediating PMN degradation of cartilage collagens. Explant release of 35S fragments during incubation with PMN supernatant was completely inhibited when serine proteases were inactivated by diisopropyl fluorophosphate (DFP); however, release of 35S fragments was enhanced when metalloprotease activity was present in the supernatant. Release of hydroxyproline during incubation of explants with PMN supernatant was comparable in the presence of DFP or EDTA, but was markedly enhanced when both serine and metalloprotease activity were present in the supernatant.

Conclusion. Neutrophils in SF are capable of degrading both proteoglycans and collagens in intact human articular cartilage. Degradation of these cartilage constituents is facilitated by immunoglobulins adherent to the cartilage surface and by the synergistic action of PMN serine and metalloproteases released during activation of neutrophils with surface‐associated immunoglobulin.
Cyclosporine in systemic sclerosis. results of a forty‐eight–week open safety study in ten patients
Authors: Clements Philip J. , Lachenbruch Peter A. , Sterz Mildred , Danovitch Gabriel , Hawkins Randall , Ippoliti Andrew , Paulus Harold E.
Published: February 2007

Objective. To evaluate safety and efficacy of cyclosporin A (CSA) treatment in systemic sclerosis (SSc).

Methods. Ten patients with ⩽60 months of SSc were entered into a 48‐week open study of CSA. Patients with hypertension or azotemia were excluded. Concurrent use of nonsteroidal antiinflammatory agents or diuretics was not permitted. The extent of cutaneous and visceral involvement at 48 weeks and at study entry were compared.

Results. Adverse reactions (especially nephrotoxicity) were frequent, usually transient, often dose‐limiting, and usually associated with CSA doses ⩾3–4 mg/kg/day. Skin thickening decreased significantly (P <0.001), while pulmonary and cardiac involvement remained unchanged.

Conclusion. CSA should undergo blinded controlled study in patients with SSc.
Contrasting molecular patterns of mhc class ii alleles associated with the anti‐sm and anti‐rnp precipitin autoantibodies in systemic lupus erythematosus
Authors: Olsen Mary L. , Arnett Frank C. , Reveille John D.
Published: February 2007

Objective. To find evidence of a potential genetic predisposition to the anti‐Sm or anti‐RNP precipitin autoantibody responses.

Methods. HLA–DR and DQ alleles determined by restriction fragment length polymorphism and/or oligo‐typing in 49 subjects with either anti‐Sm alone or anti‐RNP alone were compared with those in 139 race‐matched normal control subjects and 59 race‐matched lupus patients without anti‐Sm and anti‐RNP auto‐antibodies.

Results. Black patients with anti‐Sm precipitin had increased frequencies of HLA‐DR2 and the DQw6‐associated DQA1*0102 (P = 0.007, odds ratio [OR] = 6.7) and DQB1*0602 (P = 0.001, OR = 9.1) chain alleles compared with normal black control subjects. Black patients with anti‐RNP precipitin showed significant increases in the DQw5‐associated DQA1*0101 (P = 0.03, OR = 5.5) and DQB1*0501 (P = 0.002, OR = 23.3) chain alleles compared with lupus patients without anti‐Sm or RNP. White patients with anti‐RNP precipitin showed an increased frequency of the DQw8‐associated allele DQB1*0302 (P = 0.02, OR = 3.7) compared with normal controls, as well as an increased frequency of the DQw5‐associated alleles DQA1*0101 and DQB1*0501 (P = 0.05, OR = 4.2) compared with lupus patients without anti‐Sm or RNP. There were no specific HLA–DR2 or DR4 subtype associations found with either anti‐Sm or RNP precipitin autoantibodies.

Conclusion. There are distinct patterns of major histocompatibility complex class II allele associations with the anti‐Sm versus the anti‐RNP precipitin autoantibody responses, and HLA–DQ associations may be more primary than HLA–DR associations.
Crystal‐induced neutrophil activation. II. evidence for the activation of a phosphatidylcholine‐specific phospholipase D
Authors: Naccache Paul H. , Bourgoin Sylvain , Plante Edith , Roberge Charles J. , De Medicis R. , Lussier André , Poubelle Patrice E.
Published: February 2007

Objective. To investigate the involvement of phospholipase D in the signaling pathways activated by 2 pathologically relevant inflammatory microcrystals, monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD).

Methods. Human peripheral blood neutrophils were used throughout. Phospholipase D activity was monitored by measuring 3 separate indices: 1) the mass of phosphatidic acid, 2) the levels of alkyl‐phosphatidic acid, and 3) the levels of formation, in the presence of ethanol, of phosphatidylethanol. The latter 2 parameters were measured in cells labeled with 1‐0‐3H–alkyl‐2‐acetyl‐sn‐glycero‐3‐phosphocholine. The cells were stimulated with microcrystals of triclinic morphology.

Results. Both MSU and CPPD crystals induced a time‐ and concentration‐dependent accumulation of phosphatidic acid mass and elevation in levels of alkyl‐phosphatidic acid and phosphatidylethanol in prelabeled cells. The activation of phospholipase D by the microcrystals was partially sensitive to colchicine and largely resistant to pertussis toxin. Inhibition of phosphatidic acid formation by wortmannin or ethanol reduced the microcrystal‐stimulated production of superoxide anions.

Conclusion. These results indicate that microcrystals stimulate phospholipase D in human neutrophils and that at least some of the functional consequences of neutrophil‐microcrystal interactions may be dependent on this biochemical pathway.
Suppression of adjuvant‐induced arthritis in da rats by incomplete freund's adjuvant
Authors: Cannon Grant W. , Griffiths Marie M. , Woods Marion L.
Published: February 2007

Objective. To define the effects of incomplete Freund's adjuvant (ICFA) on subsequent arthritis induced by complete Freund's adjuvant (CFA) and type II collagen (CII) in DA and Lewis rats.

Methods. ICFA was injected into DA and Lewis rats before CFA or CII injection.

Results. DA rats previously injected with ICFA had significantly less severe arthritis induced by CFA compared with those not receiving ICFA pretreatment (P <0.01). ICFA had no significant impact on CFA‐induced arthritis in Lewis rats or on CII‐induced arthritis in DA rats.

Conclusion. The injection of ICFA alone specifically suppresses subsequent CFA‐induced arthritis in DA rats, but not in Lewis rats.
A randomized, controlled trial of arthroscopic surgery versus closed‐needle joint lavage for patients with osteoarthritis of the knee
Authors: Chang Rowland W. , Falconer Judith , David Stulberg S. , Arnold William J. , Manheim Larry M. , Dyer Alan R.
Published: February 2007

Objective. To compare arthroscopic surgery and closed‐needle joint lavage for patients with non—end‐stage osteoarthritis (OA) of the knee under controlled, experimental conditions.

Methods. Thirty‐two subjects who met specific clinical, radiologic, medical, and rehabilitation criteria were randomized to receive arthroscopic surgery (n = 18) or joint lavage (n = 14). Outcome measures evaluated at baseline and at 3 and 12 months of followup included 3 standard clinical parameters, self‐reported pain and functional status (by the Arthritis Impact Measurement Scales), 50‐foot walk time, 2 global scales, and direct and indirect medical costs.

Results. At 3 months of followup, there were no significant between‐group differences in pain, self‐reported and observed functional status, and patient and “blinded” physician global assessments. The arthroscopic procedure cost $3,840 more than did closedneedle joint lavage. After 1 year, there were no between‐group differences in medication costs, utilization of medical services, or indirect costs related to employment or use of household help. After 1 year, 44% of subjects who underwent arthroscopy reported improvement and 58% of subjects who underwent joint lavage improved. Patients with tears of the anterior two‐thirds of the medial meniscus or any lateral meniscus tear had a higher probability of improvement (by “blinded” physician assessment) after arthroscopic surgery (0.63) than did patients with other intraarticular pathology (0.20).

Conclusion. The search for and removal of soft tissue abnormalities via arthroscopic surgery does not appear justified for all patients with non—end‐stage OA of the knee who fail to respond to conservative therapy, but it may be beneficial for certain subgroups.
The relative toxicity of disease‐modifying antirheumatic drugs
Authors: Fries James F. , Williams Catherine A. , Ramey Dena , Bloch Daniel A.
Published: February 2007

Objective. To compare the toxicities of commonly employed disease‐modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA).

Methods. Toxicity Index scores, computed from symptoms, laboratory abnormalities, and hospitalizations attributable to DMARD therapy, were assessed in 2,747 patients with RA receiving 3,053 courses of 6 DMARDs and 1,309 courses of prednisone over 7,278 patient‐years. Results were adjusted for severity of illness and other covariates.

Results. Least toxic was hydroxychloroquine (mean ± SEM score 1.38 ± 0.15), followed by intramuscular gold (2.27 ± 0.17) and the closely grouped D‐penicillamine (3.38 ± 0.36), methotrexate (3.82 ± 0.35), and azathioprine (3.92 ± 0.39). Auranofin (5.25 ± 0.32) was most toxic, but this toxicity resulted from a high frequency of minor complications. Hospitalizations because of auranofin or hydroxychloroquine therapy were not noted. Prednisone (3.83 ± 0.39) was of comparable toxicity, although it is likely that not all events of prednisone toxicity were captured. For reference, the toxicity of methotrexate and azathioprine was similar to that of the most toxic nonsteroidal antiinflammatory drugs (NSAIDs) (indomethacin 3.99, tolmetin sodium 3.96, and meclofenamate 3.86). Hydroxychloroquine showed less toxicity than the most commonly used prescription NSAIDs.

Conclusion. There are substantial differences in toxicity among DMARDs and less important differences in toxicity between specific DMARDs and specific NSAIDs.
Use of a chimeric monoclonal anti‐CD4 antibody in patients with refractory rheumatoid arthritis
Authors: Moreland Larry W. , Bucy Ralph P. , Tilden Arabella , Pratt Parks W. , Lobuglio Albert F. , Khazaeli M. , Everson Michael P. , Daddona Peter , Ghrayeb John , Kilgarriff Charles , Sanders Martin E. , Koopman William J.
Published: February 2007

Objectives. To evaluate the safety, immunogenicity, and biologic effects of chimeric monoclonal anti‐CD4 (cM‐T412) in patients with refractory rheumatoid arthritis (RA), and to obtain preliminary data on the clinical response to this treatment.

Methods. Twenty‐five patients with active refractory RA were treated with incremental doses (10 to 700 mg) of cM‐T412 in an open‐label, escalating‐dose phase I trial.

Results. Infusion with cM‐T412 was followed by an immediate, rapid decline in CD4+ T cells. The level of circulating CD4+ T cells remained depressed in most patients even at 6 months posttreatment. Following antibody infusion, proliferative responses of peripheral blood lymphocytes to mitogens and antigens were determined; mitogen and antigen responses were decreased compared with pretreatment responses. Mitogen responses tended to return to baseline values more rapidly than did responses to antigen. Adverse events included fever (19 patients), which was associated with myalgias, malaise, and asymptomatic hypotension; these symptoms were self‐limited and appeared to correlate with transient elevations in interleukin‐6. No significant human antibody response to the cM‐T412 variable region was detected; only 2 patients developed transiently low levels of antibodies reactive with cM‐T412. Significant clinical improvement, defined as ≥50% decrease in tender joint counts compared with baseline, was noted in 43% of patients at 5 weeks and 33% at 6 months following cM‐T412 infusion.

Conclusions. Treatment of refractory RA with cM‐T412 appears to be safe and is associated with sustained decreases in circulating CD4+ T cell counts and depressed in vitro T cell responses. No significant human antichimeric antibody response was detected. Nonblinded assessment of clinical end points suggests that treatment with cM‐T412 may have beneficial effects in these patients with refractory RA. A double‐blind clinical trial is warranted to determine its clinical efficacy in treating RA.
Chlorambucil
Authors: Sinoway Patricia A. , Callen Jeffrey P.
Published: February 2007

Objective. To investigate the effectiveness of oral chlorambucil treatment in patients with dermatomyositis (DM) that is recalcitrant to treatment with prednisone and/or immunosuppressive agents.

Methods. Five patients with recalcitrant DM were treated with oral chlorambucil, 4 mg/day, after discontinuation of the other immunosuppressive agent (azathioprine or methotrexate). Three patients were treated with a combination of prednisone and chlorambucil, and 2 with chlorambucil alone.

Results. Beneficial effects were noted within 4–6 weeks in all 5 patients, and corticosteroids were eventually discontinued in 4. Currently, only 1 patient is still receiving therapy; the other 4 have stopped chlorambucil after 13–30 months of treatment, and their disease remains in remission. Minimal chlorambucil toxicity was noted, consisting of leukopenia in 2 patients.

Conclusion. Our findings suggest that chlorambucil is an effective, corticosteroid‐sparing agent for the control of DM.
Determinants of serious liver disease among patients receiving low‐dose methotrexate for rheumatoid arthritis
Authors: Walker Alexander M. , Funch Donnie , Dreyer Nancy A. , Tolman Keith G. , Kremer Joel M. , Alarcón Graciela S. , Lee Randall G. , Weinblatt Michael E.
Published: February 2007

Objective. To assess the risk of serious liver disease in patients with rheumatoid arthritis (RA) taking methotrexate (MTX).

Methods. We surveyed members of the American College of Rheumatology to determine previous use of MTX in the treatment of rheumatoid arthritis and to identify cases of cirrhosis and liver failure. Cases were confirmed by review of pathology specimens, findings from diagnostic testing, and clinical presentations. A case—control study was then conducted to ascertain prognostic factors. Case and control medical records were reviewed for information on MTX therapy as well as other possible determinants of serious liver disease.

Results. Twenty‐four cases of cirrhosis and liver failure were identified, giving a 5‐year cumulative incidence of ˜ 1/1,000 treated patients. Six of the 24 patients had died: 4 died of the initial liver disease, 1 of hepatic complications of another illness, and 1 of unrelated causes. Two patients continue to have active liver disease. Late age at first use of MTX and duration of therapy with MTX were independent predictors of serious liver disease.

Conclusion. Serious liver disease is an uncommon, age‐ and dose‐related complication of low‐dose MTX therapy for RA.
Preliminary criteria for the classification of Sjögren's syndrome. Results of a prospective concerted action supported by the European community
Authors: Vitali Claudio , Bombardieri Stefano , Moutsopoulos Haralampos M. , Balestrieri Genesio , Bencivelli Walter , Bernstein Robert M. , Bjerrum Kirsten B. , Braga Susanna , Coll Joaquin , Vita Salvatore De , Drosos Alexandros A. , Ehrenfeld Michael , Hatron Pierre Y. , Hay Elaine M. , Isenberg David A. , Janin Anne , Kalden Joachim R. , Kater Louis , Konttinen Yrjö T. , Maddison Peter J. , Maini Ravinder N. , Manthorpe Rolf , Meyer Olivier , Ostuni Pierantonio , Pennec Yvon , Prause Jan U. , Richards Andrea , Sauvezie Bernard , Schiødt Morten , Sciuto Maria , Scully Crispian , Shoenfeld Yehuda , Skopouli Fotini N. , Smolen Josef S. , Snaith Michael L. , Tishler Moshe , Todesco Silvano , Valesini Guido , Venables Patrick J. W. , Wattiaux Marie J. , Youinou Pierre
Published: February 2007

Objective. Different sets of diagnostic criteria have been proposed for Sjögren's syndrome (SS), but none have been validated with a large series of patients or in a multicenter study. We conducted the present study involving 26 centers from 12 countries (11 in Europe, plus Israel), with the goals of reaching a consensus on the diagnostic procedures for SS and defining classification criteria to be used in epidemiologic surveys and adopted by the scientific community.

Methods. The study protocol was subdivided into two parts. For part I, questionnaires regarding both ocular and oral involvement were developed; they included 13 questions and 7 questions, respectively. For part II a limited set of diagnostic tests was selected, and the exact procedure to be followed in performing these tests was defined. Part I of the study ipcluded 240 patients with primary SS and 240 age‐ and sex‐matched controls. Two hundred forty‐six patients with primary SS, 201 with secondary SS, 113 with connective tissue diseases but without associated SS, and 133 control patients were studied in part II.

Results. The study resulted in (a) the validation of a simple 6‐item questionnaire for determination of dry eyes and dry mouth, which showed good discriminant power between patients and controls, to be used in the initial screening for sicca syndrome; and (b) the definition of a new set of criteria for the classification of SS. The sensitivity and specificity of the criteria in correctly identifying patients with either the primary or the secondary variant of SS were also determined.

Conclusion. Using the findings of this prospective multicenter European study, general agreement can be reached on the diagnostic procedures to be used for patients with SS. Final validation of the preliminary classification criteria for SS is underway.
Clinical, serologic, and immunogenetic studies in childhood‐onset systemic lupus erythematosus
Authors: Barron Karyl S. , Silverman Earl D. , Gonzales Juanita , Reveille John D.
Published: February 2007

Objective. To determine the frequency of systemic lupus erythematosus (SLE)—associated clinical manifestations, autoantibodies, and HLA class II alleles in a large cohort of patients with childhood‐onset SLE.

Methods. Eighty children with SLE onset before age 18 (27 before age 11) were studied for the frequency of renal, neuropsychiatric, and hematologic complications as well as for anti—native DNA, Ro, La, Sm, and U1 RNP autoantibodies. HLA—DR, DQ, and DP alleles were determined by oligotyping. The results were compared with findings in 213 adults with SLE onset at or after age 18 years.

Results. Renal involvement was more frequent in those with childhood‐onset SLE, especially those with onset before age 11 (82%, compared with 53% in adults). Anti—U1 RNP was more common in American blacks with SLE onset before age 18. HLA—DRB1*0301, DQA1*0501, DQB1*0201 was more common in Caucasians and DRB1*1503, DRB5*0101, DQA1*0102, DQB1*0602 in American blacks, regardless of age at SLE onset. Anti‐Sm autoantibodies were most highly associated with HLA—DQA1*0102 and DQB1*0602.

Conclusion. While childhood‐onset SLE shares many immunogenetic and serologic similarities to adultonset disease, important clinical differences nevertheless exist in children with this disease.
A peptide derived from an autoantibody can stimulate t cells in the (nzb × nzw)f1 mouse model of systemic lupus erythematosus
Authors: Ebling Fanny M. , Tsao Betty P. , Singh Ram R. , Sercarz Eli , Hahn Bevra H.
Published: February 2007

Objective. To assess the ability of peptides derived from anti‐DNA to stimulate syngeneic T lymphocytes and influence lupus in (NZB × NZW)F1 (NZB/W) mice.

Methods. We synthesized (by Geysen pin method) overlapping 12‐mer peptides recapitulating the amino acid sequence of the VH region of a nephritogenic monoclonal IgG2a anti‐DNA antibody (A6.1) from an NZB/W mouse. Splenic T cells were cultured with the peptides; multiple experiments assayed 12‐mer and 16‐mer peptides which contained a triple‐base motif (KFKGK). We immunized 20‐week‐old NZB/W mice with the 12‐mer and evaluated them for evidence of nephritis and for quantities of antibodies in plasma and glomeruli.

Results. Three clusters of peptides caused proliferation of spleen cells from young, nonimmunized mice. Both the 12‐mer FYNQKEKGKATL and the 16‐mer GDTFYNQKEKGKATLT peptides stimulated purified T cells. The KXKXK motif occurs in 15% of murine IgVH (NBRF protein database), compared with 100% (6 of 6) of NZB/W anti‐DNA monoclonal antibody. Immunization with the 12‐mer peptide increased plasma levels of IgG, anti‐DNA, and immune complexes, and levels of anti‐DNA in glomeruli; nephritis was accelerated.

Conclusion. NZB/W anti‐DNA contain peptide sequences in their VH regions that stimulate self—T cells. At least one motif is frequent in NZB/W anti‐DNA. If some activated T cells provide help, this mechanism may contribute to sustained up‐regulation of autoantibodies in murine lupus.
Molecular analysis of rheumatoid factors derived from rheumatoid synovium suggests an antigen‐driven response in inflamed joints
Authors: Ermel Richard W. , Kenny Thomas P. , Chen Pojen P. , Robbins Dick L.
Published: February 2007

Objective. Understanding the molecular genetic basis for rheumatoid factor (RF) production is necessary to a better understanding of the etiology and pathogenesis of rheumatoid arthritis (RA). We sought to define the genetic basis of RF in RA.

Methods. The heavy and light chain variable region genes encoding 4 human monoclonal RF were cloned and sequenced using the polymerase chain reaction and the dideoxynucleotide chain‐termination method.

Results. The heavy and light chains of the C6 RF and the light chain of the G9 RF were encoded by 3 new RF‐related Ig V‐region genes. The heavy and light chains of D5 and G4 RFs were identical; most of their mutations caused amino acid substitutions.

Conclusions. The RF‐related Ig V‐region gene repertoire is large and is still expanding. The data from D5 and G4 strongly suggest that these 2 RFs arise in an antigen‐driven response in rheumatoid synovium. The presumed germline V genes for C6 may represent disease‐specific RF‐related V genes.
Early‐onset osteoarthritis linked to the type ii procollagen gene. detailed clinical phenotype and further analyses of the gene
Authors: Vikkula Miikka , Palotie Aarno , Ritvaniemi Pertti , Ott JÜRg , Ala‐Kokko Leena , Sievers Ulla , Aho Kimmo , Peltonen Leena
Published: February 2007

Objective. To specify in detail the clinical phenotype in 2 Finnish families demonstrating linkage between the type II procollagen gene (COL2A1) and osteoarthritis (OA). We also reevaluated the linkage and screened the exon sequences of the COL2A1 gene for mutations.

Methods. We used single‐stranded conformation polymorphism and denaturing gradient‐gel electrophoresis techniques for the analyses.

Results. The patients' phenotype represented typical, but early‐onset, OA. There was no clinical or radiographic evidence of chondrodysplasia. No mutation in the protein‐coding regions of the COL2A1 gene could be identified. However, the linkage analysis with a new multiallelic marker resulted in a statistically more significant logarithm of odds (LOD) score than has been reported.

Conclusion. Familial OA with classic clinical and radiographic findings is tightly linked to the COL2A1 gene. Systematic screening of the 54 exons did not, however, reveal any mutations; this suggests that the mutation may lie in the promoter region or within the introns of this 35‐kb gene.
Localized scleroderma progressing to systemic disease. case report and review of the literature
Authors: Birdi Nina , Laxer Ronald M. , Thorner Paul , Fritzler Marvin J. , Silverman Earl D.
Published: February 2007

We describe a 15‐year‐old girl with biopsy‐proven morphea who developed progression to systemic disease 2 years after initial presentation. In contrast to other reported patients with localized scleroderma, some of whom have had mild, nonprogressive systemic involvement, this patient developed severe, debilitating disease, with skin tightness, sclerodactyly, esophageal involvement, restrictive pulmonary disease, and myopathy. From the time of her initial evaluation, the patient was positive for antinuclear antibodies (ANA), which were shown to be primarily directed against the Ku antigens. This observation suggests that ANA may be a prognostic indicator for progression to systemic disease.
Primary systemic amyloidosis masquerading as giant cell arteritis. case report and review of the literature
Authors: Rao Jaya K. , Allen Nancy B.
Published: February 2007

Amyloidosis is a rare disease in which a fibrillar protein is deposited in multiple human tissues. Of the 4 subtypes, the most common type involving rheumatic disease features is hemodialysis‐associated amyloidosis. Herein we describe an elderly man who presented with symptoms of giant cell arteritis or systemic vasculitis and was found to have amyloidosis as demonstrated on muscle, nerve, and temporal artery biopsy.
Evidence suggesting that health education for self‐management in patients with chronic arthritis has sustained health benefits while reducing health care costs
Authors: Lorig Kate R. , Mazonson Peter D. , Holman Halsted R.
Published: February 2007

Objective. To determine the effects of the Arthritis Self‐Management Program 4 years after participation in it.

Methods. Valid self‐administered instruments were used to measure health status, psychological states, and health service utilization.

Results. Pain had declined a mean of 20% and visits to physicians 40%, while physical disability had increased 9%. Comparison groups did not show similar changes. Estimated 4‐year savings were $648 per rheumatoid arthritis patient and $189 per osteoarthritis patient.

Conclusion. Health education in chronic arthritis may add significant and sustained benefits to conventional therapy while reducing costs.
The cost‐effectiveness of misoprostol for nonsteroidal antiinflammatory drug–associated adverse gastrointestinal events
Authors: Gabriel Sherine E. , Liisa Jaakkimainen R. , Bombardier Claire
Published: February 2007

Objective. To compare, in a Canadian health care setting, the costs and consequences of 3 strategies of misoprostol prophylaxis for osteoarthritis patients: prophylaxis for all patients taking nonsteroidal antiinflammatory drugs (NSAIDs), for no patients taking NSAIDs, and for only elderly patients (age ≥60) taking NSAIDs.

Methods. We designed a decision‐analysis model which incorporated costs (estimated with ulcer patient profiles and medical records), review, and probabilities (estimated from a companion metaanalysis, selected literature review, and Ontario Ministry of Health Statistics). Effectiveness was defined as the number of episodes of gastric ulceration requiring hospitalization or outpatient management that were averted by each strategy.

Results. On average, prophylaxis cost an additional $650 for every additional gastrointestinal event prevented. Prophylaxis for elderly NSAID users was cost saving if the ulcer complication rate in this group exceeds 1.2%, or if either the charges for outpatient ulcer treatment exceed $2,000, or the 3‐month price of misoprostol is ≤90.

Conclusion. Our results demonstrate that, in this setting, misoprostol prophylaxis may be highly cost effective.
Hla class ii alleles and heterogeneity of juvenile rheumatoid arthritis. drb1*0101 may define a novel subset of the disease
Authors: Ploski Rafal , Vinje Odd , S. Rønningen Kjersti , Spurkland Anne , Sørskaar Dag , Vartdal Frode , Førre øystein
Published: February 2007

Objective. To examine the distribution of HLA class II alleles in clinically distinct juvenile rheumatoid arthritis (JRA) subsets.

Methods. We typed 298 patients and 181 controls for HLA–DRB1, DQA1, DQB1, and DPB1 alleles using polymerase chain reaction and oligonucleotide probe techniques.

Results. Each JRA subset was characterized by a distinct distribution of HLA class II alleles. For the persistently pauciarticular and rheumatoid factornegative polyarticular JRA subsets, certain combinations of DRB1 and DPB1 alleles were characteristic. In patients without antinuclear antibodies and chronic iridocyclitis, there was an increase of DRB1*0101/02 and DQA1*0101.

Conclusion. Findings of HLA typing support clinical subdivisions of the disease and suggest the existence of a novel DRB1*0101/02 and DQA1*0101 associated disease subset.
Soluble tumor necrosis factor receptors in human inflammatory synovial fluids
Authors: Roux‐Lombard Pascale , Punzi Leonardo , Hasler Fritz , Bas Sylvette , Todesco Silvano , Gallati Harald , Guerne Pierre‐André , Dayer Jean‐Michel
Published: February 2007

Objective. To test synovial fluid (SF) for the presence of soluble fragments originating from distinct tumor necrosis factor receptors (TNF‐sR55 and TNF‐sR75) which bind to TNF and inhibit its biologic activity.

Methods. TNF‐sR55 and TNF‐sR75 were measured in 62 SF samples by specific immunoassays using monoclonal antibodies.

Results. Both TNF‐sR were present in all of the SF tested. Their concentrations were higher in SF from patients with seropositive rheumatoid arthritis than in patients with other inflammatory arthritides. The relative amount of TNF‐sR75, as compared with TNF‐sR55, was higher in seropositive RA SF than in other SF.

Conclusion. The balance between TNF and its specific inhibitors may be critical to the biologic outcome mediated by this cytokine.
Levels of circulating tumor necrosis factor α and interleukin‐6 in patients with rheumatoid arthritis. relationship to serum levels of hyaluronan and antigenic keratan sulfate
Authors: Manicourt Daniel‐Henri , Triki Rafak , Fukuda Kanji , Devogelaer Jean‐Pierre , Deuxchaisnes Charles Nagant De , Thonar Eugene J.‐M. A.
Published: February 2007

Objective. To measure serum levels of tumor necrosis factor α (TNF α) and interleukin‐6 (IL‐6) in patients with rheumatoid arthritis (RA) and age‐matched control subjects and to study how these correlate with serum levels of hyaluronan (HA) and antigenic keratan sulfate (KS) and other biochemical as well as clinical indicators of disease activity.

Methods. Immunoassays were used to measure levels of TNFα, IL‐6, HA, and antigenic KS in the serum of 35 patients with RA and a group of age‐ and sex‐matched control subjects. Clinical disease activity in the RA group was assessed using the Lansbury index. Drug intake was recorded and the erythrocyte sedimentation rate, and levels of fibrinogen, creatinine, bilirubin, alkaline phosphatase, lactate dehydrogenase, and aminotransferase were measured.

Results. Serum levels of TNFα, IL‐6, and HA were significantly higher in the RA population than in the control group. In patients with RA, serum levels of HA correlated positively with serum levels of TNFα and with clinical joint scores, but only weakly with other laboratory parameters of inflammation. Serum levels of antigenic KS correlated negatively with levels of circulating TNFα, but much more weakly with other clinical and biochemical parameters of disease activity.

Conclusion. These in vivo data support in vitro studies which have shown that TNFα is a potent stimulator of HA synthesis by synovial lining cells. The results strengthen the contention that serum HA may be a unique marker of synovial involvement and inflammation, rather than of only inflammation, in RA.
Enhanced chondrocyte destruction by lymphokine‐activated killer cells. possible role in rheumatoid arthritis
Authors: Yamaga Karen M. , Bolen Harriet , Kimura Lucille , Lance Eugene M.
Published: February 2007

Objective. The lysis of chondrocytes, the parenchymal cells of cartilage, by lymphocytes may provide a potent mechanism by which the immune system participates in sustaining joint damage in rheumatoid arthritis (RA). We studied the capability of lymphocytes from healthy individuals and patients with arthritis to lyse chondrocytes.

Methods. Peripheral blood mononuclear cells (PBMC) were tested for their ability to lyse chondrocytes in a 51Cr‐release assay. Enhancement of the chondrolytic activity was determined by preincubating the cells with T cell growth factor (TCGF) or recombinant interleukin‐2 (rIL‐2) before cytotoxic testing.

Results. PBMC from healthy individuals possessed a low ability to lyse chondrocytes, whereas cells from the synovial fluid of patients with RA displayed higher chondrolytic activity. In RA, modulating factors must come into play because not all synovial fluid sample cells showed high chondrolytic activity and cells from synovial tissue had little or no lytic action on chondrocytes. Chondrolytic activities of cells from all sources, including PBMC from healthy subjects and patients with arthritis and cells isolated from synovial fluid or from the synovial tissue of RA patients, were greatly increased by incubating the cells with TCGF or rIL‐2. In contrast, treatment of chondrocytes with interferon‐γ, which enhances major histocompatibility complex gene expression, decreased the susceptibility of chondrocytes to lysis.

Conclusion. These observations suggest a mechanism for joint damage in which the destruction of chondrocytes by lymphocytes is controlled by cytokines released during the inflammatory process in arthritic diseases.
Detection of increased levels of circulating intercellular adhesion molecule 1 in some patients with rheumatoid arthritis but not in patients with systemic lupus erythematosus. lack of correlation with levels of circulating vascular cell adhesion molecule 1
Authors: Mason Justin C. , Kapahi Pankaj , Haskard Dorian O.
Published: February 2007

Objective. To compare the levels of circulating intercellular adhesion molecule 1 (cICAM‐1) and vascular cell adhesion molecule 1 (cVCAM‐1) in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

Methods. Levels of cICAM‐1 and cVCAM‐1 were measured in both plasma and synovial fluid using monoclonal antibody sandwich enzyme‐linked immunoassays.

Results. Levels of both cICAM‐1 and cVCAM‐1 were significantly increased (P < 0.001) in RA patients compared with normal controls. In contrast, only cVCAM‐1, and not cICAM‐1, was increased in patients with SLE. Levels of cICAM‐1 and cVCAM‐1 were significantly elevated in synovial fluid compared with plasma in paired samples from patients with RA. There was no correlation between levels of cICAM‐1 and levels of cVCAM‐1, in either plasma or synovial fluid. Whereas levels of cVCAM‐1 correlated significantly with the erythrocyte sedimentation rate (ESR) and C‐reactive protein level in RA patients and with the ESR in SLE patients, no significant correlations were found between cICAM‐1 and either of these indices of disease activity.

Conclusion. These observations indicate that levels of cICAM‐1 and cVCAM‐1 reflect separate pathophysiologic processes. Both may be useful markers for the diagnosis and management of patients with rheumatic diseases.
Different manifestations of the antiphospholipid antibody syndrome in a family with systemic lupus erythematosus
Authors: May Kimberly P. , West Sterling G. , Moulds Joann , Kotzin Brian L.
Published: February 2007

Objective. Familial associations of the antiphospholipid antibody syndrome (APS) offer the opportunity to study genetic mechanisms of autoantibody production and disease, but are unusual. We identified a family, including identical twins and their mother, in which all members had systemic lupus erythematosus (SLE) and presented with different manifestations of the APS.

Methods. Review of case histories and clinical laboratory results, antiphospholipid antibody (aPL) studies, complement C4 protein and gene analysis, and HLA typing of family members were performed.

Results. Each of the 3 family members presented with a different clinical association of the APS. These various clinical presentations were closely temporally related. No particular aPL activity could be separated out that would account for the different manifestations, although the twin with thrombocytopenia and livedo reticularis had a strikingly high IgM anticardiolipin antibody level. C4A or C4B deficiencies could not be implicated in the autoimmune process. However, the mother and the twins shared the HLA haplotype that included the class II antigens DR4, DRw53, and DQw7, which has previously been associated with aPL production.

Conclusion. This family study emphasizes the different clinical associations of aPL production in SLE. In addition to genetic influences that appear to include HLA class II antigens, the clinical presentations also suggest an environmental trigger.
The quantitation of a native chondroitin sulfate epitope in synovial fluid lavages and articular cartilage from canine experimental osteoarthritis and disuse atrophy
Authors: Ratcliffe Anthony , Shurety Wenda , Caterson Bruce
Published: February 2007

Objective. Previous studies have shown the presence of a native chondroitin sulfate epitope in articular cartilage proteoglycans from canine knee joints with experimental early osteoarthritis (OA), but not in normal cartilage. The objective of this study was to quantitate the native epitope recognized by monoclonal antibody 3‐B‐3 in synovial fluids and articular cartilage of diseased joints.

Methods. An immunoassay with monoclonal antibody 3‐B‐3, which recognizes a native chondroitin‐6‐sulfate structure, was developed and used to analyze synovial fluid lavage material and extracts of articular cartilage from canine knee joints with early experimental OA or with mild disuse atrophy, and from control animals.

Results. The concentration of epitope in the OA fluids was elevated 33–35‐fold, and in the OA articular cartilage extracts it was elevated > 200‐fold, compared with samples from the control group. No significant difference was detected in the levels of 3‐B‐3 epitope in the synovial fluid lavage material or cartilage extracts from the joints of the disuse group versus the control group.

Conclusion. The native 3‐B‐3 epitope in articular cartilage and synovial fluids may be a specific marker of ongoing anabolic events in early degenerative joint disease.
Marital status and the progression of functional disability in patients with rheumatoid arthritis
Authors: Ward Michael M. , Paul Leigh J.
Published: February 2007

Objective. To determine if marital status is associated with differences in rates of progression of functional disability in patients with rheumatoid arthritis (RA).

Methods. A community cohort of 282 persons with RA was followed prospectively for up to 9.5 years. The progression of functional disability over time was determined using the Health Assessment Questionnaire Disability Index, which was completed by study participants every 6 months.

Results. At study entry, the Disability Index was 1.1 ± 0.8 (mean ± 1 SD) (possible range 0–3) among the 188 married participants and 1.3 ± 0.9 among the 94 unmarried participants. Over time, the rate of progression of functional disability was generally higher among unmarried participants. However, the extent of this difference varied somewhat over the disease course, with rates of progression higher among unmarried than among married participants during years 5–7 and years 17–29 of RA. Overall estimated rates of progression, adjusted for the effects of other sociodemographic factors, were 0.03 Disability Index units per year in unmarried participants and 0.01 Disability Index units per year in married participants (P < 0.0001).

Conclusion. Marriage, possibly reflecting the influence of social support, is associated with a lower rate of progression of functional disability in persons with RA.
Regulation of the expression of intercellular adhesion molecule 1 in cultured human endothelial cells derived from rheumatoid synovium
Authors: Gerritsen Mary E. , Kelley Keith A. , Ligon Gwenda , Perry Carol A. , Shen Chien‐Ping , Szczepanski Andrew , Carley William W.
Published: February 2007

Objective. To examine the regulation of intercellular adhesion molecule 1 (ICAM‐1) in human synovial microvascular endothelial cells (HSE) and human umbilical vein endothelial cells (HUVE) upon exposure to a variety of agents.

Methods. Cultured endothelial cells were treated with various cytokines alone and in combination. The expression of ICAM‐1 was evaluated at several levels, including an investigation of messenger RNA (mRNA) and surface protein expression.

Results. Treatment of HSE with interleukin‐1α (IL‐1α) or tumor necrosis factor α (TNFα) resulted in minimal increases in ICAM‐1 expression, in contrast to findings with HUVE. Incubation of HUVE or HSE with IL‐1 or TNF in combination with interferon‐γ (IFNγ) greatly potentiated the increase in ICAM‐1 surface expression. The synergistic effect of IFNγ and TNF was confirmed by several methods, including a cell‐based enzyme‐linked immunosorbent assay, fluorescence‐activated cell sorting, immunofluorescence staining, and determination of mRNA levels. IFNγ also augmented the actions of several other agonists on HSE, i.e., IL‐4, lipopolysaccharide, and TNFβ/lymphotoxin. Immunoprecipitation of TNFα + IFNγ–stimulated, 125I‐labeled HSE cells with anti–ICAM‐1 revealed a single 90‐kd band, similar in size to ICAM‐1 from HUVE treated in an identical manner. Unexpectedly, IFNγ alone was a potent stimulus for HSE ICAM‐1 mRNA synthesis, but was relatively ineffective in HUVE.

Conclusion. These studies indicate that IFNγ plays a critical synergistic role in the regulation of ICAM‐1 expression in human synovial endothelial cells.