bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, double‐blind, 24‐week controlled study of low‐dose cyclosporine versus chloroquine for early rheumatoid arthritis
Authors: Landewé ROBERT B. M. , Goeithè Henk S. , Van Rijthoven ANDRE W. A. M. , Breedveld Ferdinand C. , Dijkmans BEN A. C.
Published: February 2007

Objective. To investigate whether low‐dose cyclosporin A (CSA) is safe and effective in comparison with chloroquine (CQ) in patients with early rheumatoid arthritis (RA).

Methods. We performed a randomized, double‐blind study comparing CSA with CQ in patients with early RA (duration <2 years) who had had active disease for at least 3 months. Forty‐four RA patients with a mean disease duration of 6 months were randomly allocated to receive CSA (initial dosage 2.5 mg/kg/day, maintenance dosage 3.6 mg/kg/day) or CQ (initial dosage 300 mg/day, maintenance dosage 100 mg/day) for 24 weeks.

Results. Five patients (2 taking CSA and 3 taking CQ) discontinued the study prematurely. Intention‐to‐treat analysis disclosed a decrease in the swollen joint count by 7 in both groups. The erythrocyte sedimentation rate and C‐reactive protein level did not change significantly. CSA and CQ were tolerated equally well, although mild paraesthesia occurred more frequently in the CSA‐treated group. The serum creatinine level increased by 13 μmoles/liter (95% confidence interval [95% CI] 4, 22) in the CSA group and by 6 μmoles/liter (95% CI 1, 11) in the CQ group (difference not statistically significant).

Conclusion. Both CSA and CQ are effective in alleviating the symptoms of active early RA. There is only slightly impaired renal function after 24 weeks of drug administration of either drug in patients with early RA.
Synovial interleukin‐1 receptor antagonist and interleukin‐1 balance in rheumatoid arthritis
Authors: Firestein Gary S. , Boyle David L. , Yu Carolyn , Paine Mary M. , Whisenand Teri D. , Zvaifler Nathan J. , Arend William P.
Published: February 2007

Objective. To quantify interleukin‐1 receptor antagonist (IL‐1ra) and IL‐1 production and gene expression by rheumatoid arthritis (RA) synovial tissue (ST) cells.

Methods. IL‐1α, IL‐1β, and IL‐1ra protein levels were measured by enzyme‐linked immunosorbent assay in fresh and cultured ST cells, purified synovial macrophages, and fibroblast‐like synoviocytes (FLS). The relative expression of the secreted form of IL‐1ra (sIL‐1ra) and the alternatively spliced intracellular form (icIL‐1ra) was determined by reverse transcription polymerase chain reaction (RT‐PCR) techniques.

Results. IL‐1α, IL‐1β, and IL‐1ra were present in fresh and cultured ST cell samples of synovium from RA and osteoarthritis patients. IL‐1ra:IL‐1 ratios ranged from 1.2 to 3.6, which is below the 10–100‐fold excess of IL‐1ra needed to inhibit IL‐1 bioactivity. Isolated CD14+ synovial macrophages secreted IL‐1ra, but the amount was much less than that of alveolar or in vitro–derived macrophages. Cultured FLS contained intracellular IL‐1ra but secreted little IL‐1ra into the culture supernatants. RT‐PCR showed that icIL‐1ra mRNA was more abundant than sIL‐1ra mRNA in FLS and unfractionated ST cells.

Conclusion. IL‐1ra production by RA ST cells is deficient relative to total production of IL‐1.
Aberrant production of gliostatin/platelet‐derived endothelial cell growth factor in rheumatoid synovium
Authors: Takeuchi Masanori , Otsuka Takanobu , Matsui Nobuo , Asai Kiyofumi , Hirano Takayoshi , Moriyama Akihiko , Isobe Ichiro , Eksioglu Yaman Z. , Matsukawa Kohei , Kato Taiji , Tada Toyohiro
Published: February 2007

Objective. To purify a protein inhibitor from rheumatoid arthritis (RA) synovial fluids which suppresses the apparent incorporation of 3H‐thymidine into fibroblasts and synovial cells, and to define its biochemical features that have clinical relevance to the pathogenesis of RA.

Methods. Several standard chromatographic techniques were employed for the purification of the protein. Immunochemical methods with monoclonal antibody were used to quantify and visualize the protein in sera, synovial fluids, and tissues from RA patients.

Results. The chemical properties of purified inhibitor from RA synovial fluids confirmed its identity as gliostatin/platelet‐derived endothelial cell growth factor (PD‐ECGF), a potent angiogenic factor. The gliostatin/ PD‐ECGF level in synovial fluid and serum was higher in RA patients than in osteoarthritis controls.

Conclusion. These findings strongly suggest that gliostatin/PD‐ECGF might play an important role in the aberrant neovascularization of rheumatoid synovium.
“Homozygosity” for the HLA–DR shared epitope contributes the highest risk for rheumatoid arthritis concordance in identical twins
Authors: Jawaheer D. , Thomson W. , Macgregor A. J. , Carthy D. , Davidson J. , Dyer P. A. , Silman A. J. , Ollier W. E. R.
Published: February 2007

Objective. To assess the contribution of HLA–DRB1 alleles in determining rheumatoid arthritis (RA) concordance in monozygotic twins.

Methods. Ninety‐one monozygotic twins pairs in which at least 1 twin was affected were typed for HLA–DRB1 using both serologic methods and polymerase chain reaction amplification with sequence‐specific oligonucleotide hybridization. The role of DR4 and of the shared epitope in disease concordance was investigated. Relative risks (RR) with 95% confidence intervals were determined.

Results. Increased concordance for RA was observed in both DR4 positive and shared epitope positive pairs (RR 3.4 and 3.7, respectively). A 5‐fold risk for RA concordance was seen in twins who were “homozygous” for the shared epitope, compared with those negative for the shared epitope.

Conclusion. In the absence of the shared epitope, RA concordance in monozygotic twins is rare. In contrast, “homozygosity” for the shared epitope is the most important factor in determining RA concordance.
HLA and T cell receptor β‐chain DNA polymorphisms identify a distinct subset of patients with pauciarticular‐onset juvenile rheumatoid arthritis
Authors: Charmley Patrick , Nepom Barbara S. , Concannon Patrick
Published: February 2007

Objective. To evaluate and extend upon a reported association of a T cell receptor (TCR) V β coding region polymorphism with pauciarticular‐onset juvenile rheumatoid arthritis (JRA).

Methods. TCR V β6.1 genotypes and haplotypes in JRA and control groups were determined by DNA amplification.

Results. Haplotypes of the V β6.1 gene which encode a nonfunctional form of V β6.1 were significantly associated with pauciarticular JRA in patients possessing the HLA–DQA1*0101 allele (P = 0.0073).

Conclusion. A TCR V β gene segment in the vicinity of V β6.1, possibly V β6.1, is apparently involved in the pathogenesis of pauciarticular‐onset JRA in DQA1*0101‐positive individuals.
Identification of neisseria gonorrhoeae in synovial fluid using the polymerase chain reaction
Authors: Liebling Michael R. , Arkfeld Daniel G. , Michelini Giulia A. , Nishio Midori J. , Eng Bett J. , Jin Tian , Louie James S.
Published: February 2007

Objective. To analyze synovial fluid (SF) for the presence of Neisseria gonorrhoeae DNA using the polymerase chain reaction (PCR).

Methods. We used a modified, nested PCR to detect the presence of N gonorrhoeae DNA in 41 samples of SF obtained from 10 patients with clinical gonococcal arthritis whose SF samples were sterile by culture and from 27 controls, including 11 patients with Reiter's syndrome. Results obtained using this method were compared with those obtained using the GEN‐PROBE system, an RNA–DNA hybridization technique.

Results. With nested PCR, N gonorrhoeae DNA was detected in 11 of 14 SF samples obtained from patients with culture‐negative clinical gonococcal arthritis but in none of the 11 SF samples from Reiter's syndrome patients. The specificity of this technique was 96.4%, with a sensitivity of 78.6%. The rate of false‐positive results was 3.6%. The GEN‐PROBE technique was unable to detect N gonorrhoeae ribosomal RNA in any of the samples.

Conclusion. These findings demonstrate the potential utility of the PCR in confirming the clinical diagnosis of gonococcal arthritis as well as providing insight into the pathogenesis of this disorder in patients whose SF are sterile by standard culture techniques. PCR may also prove helpful in differentiating N gonorrhoeae arthritis from acute Reiter's syndrome.
Use of the polymerase chain reaction to study arthritis due to neisseria gonorrhoeae
Authors: Muralidhar Bethi , Rumore Peter M. , Steinman Charles R.
Published: February 2007

Objective. To explore the utility of the polymerase chain reaction (PCR) in the diagnosis, management, and investigation of arthritis due to Neisseria gonorrhoeae.

Methods. The PCR was used to detect DNA from N gonorrhoeae in model systems and in extracts of synovial fluid (SF) from patients with systemic gonococcal infections and objective evidence of arthritis.

Results. One N gonorrhoeae organism or its equivalent was detectable in human SF from inflamed joints. Five of 8 patients with systemic N gonorrhoeae infection and arthritis had N gonorrhoeae DNA demonstrated by PCR in at least 1 pretreatment SF specimen that was N gonorrhoeae culture positive. Thirty‐seven of 38 control specimens were negative, the exception probably being due to cross‐contamination from a positive specimen. All specimens that were positive for N gonorrhoeae by other methods were also positive by PCR. Two others were positive by PCR but negative by other methods. Four pretreatment specimens were negative by all methods, including PCR. This suggests that, for these patients, negative cultures reflected true absence of N gonorrhoeae, and not the presence of unculturable organisms. This group also had a significantly shorter duration of disease than did the patients with N gonorrhoeae DNA found in their SF. All patients had a prompt response to antibiotic treatment. Two of 3 patients whose specimens were previously positive showed marked decreases in SF N gonorrhoeae DNA after treatment.

Conclusion. The PCR using these or similar oligonucleotide primers can be a useful adjunct in the diagnosis of gonococcal arthritis and can be of value in assessing its response to therapy. In some N gonorrhoeae–associated arthritides, there appears to be a lack of both viable and nonviable N gonorrhoeae organisms in the SF. These observations may have implications regarding the pathogenesis of this form of arthritis.
Paradiaphyseal calcific tendinitis with cortical bone erosion
Authors: Fritz Pierre , Bardin Thomas , Laredo Jean‐Denis , Ziza Jean‐Marc , D'Anglejan Georges , Lansaman Juliette , Bucki Barbara , Forest Maurice , Kuntz Daniel
Published: February 2007

Objective. To determine the clinical, radiologic, and histologic features of calcific tendinitis with cortical bone erosion.

Methods. The records of 6 patients with paradiaphyseal calcific tendinitis and adjacent bone cortex erosion were reviewed.

Results. Calcific tendinitis involved the linea aspera in 4 patients, the bicipital groove in 1 patient, and the deltoid insertion in another. Calcium deposits were associated with cortical bone erosions, revealed on plain radiographs in 4 patients and computed tomography scans in 2. Bone scans were performed in 2 patients and showed local hyperfixation of the isotope. In 4 patients, suspicion of a neoplasm led to a biopsy. Calcium deposits appeared to be surrounded by a foreign body reaction with numerous giant cells. Apatite crystals were identified by transmission electron microscopy and elemental analysis in 1 surgical sample.

Conclusion. Paradiaphyseal calcific tendinitis with cortical bone erosion is an uncommon presentation of apatite deposition disease.
Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide
Authors: Åkesson Anita , Scheja Agneta , Lundin Anders , Wollheim Frank A.
Published: February 2007

Objective. Pulmonary fibrosis is a common feature of systemic sclerosis (SSc) and a major cause of morbidity and mortality. Since alveolitis may be an essential step in the development of pulmonary fibrosis, we investigated the use of immunosuppressive drug therapy to improve pulmonary function in patients with SSc.

Methods. Eighteen patients with progressive pulmonary dysfunction, diminished vital capacity (VC), and/or decreased static lung compliance (Cst) were treated with cyclophosphamide and corticosteroids for 1 year. Eight patients had diffuse cutaneous SSc and 10 had limited cutaneous SSc. The median disease duration was 2.5 years (range 0.5–17 years).

Results. VC increased in 14 of 18 patients and the median VC rose from 74% to 80% of predicted. Cst improved in 8 of 12 patients and the median Cst increased from 59% to 66% of predicted. Pulmonary nonfibrotic opacities disappeared in 9 of 12 patients. The erythrocyte sedimentation rate (ESR) and serum concentrations of orosomucoid, C‐reactive protein, and aminopropeptide type III collagen all improved. The patients were divided into 2 groups based on the presence or absence of elevations in acute‐phase protein levels and ESR before therapy. Among the 12 patients with biochemical signs of inflammation, VC increased in 11, and Cst improved or was unchanged in 7 of the 8 who were tested. The median VC in this subgroup increased from 73% to 80% of predicted and the median Cst increased from 57% to 60% of predicted. In the group of 18 patients overall, the skin score decreased, while esophageal and renal function remained stable.

Conclusion. Cyclophosphamide may have a beneficial effect on pulmonary fibrosis in patients with SSc and elevated levels of acute‐phase proteins. Controlled trials of cyclophosphamide in pulmonary SSc should be performed and should focus on such patients.
Magnetic resonance imaging and p‐31 magnetic resonance spectroscopy provide unique quantitative data useful in the longitudinal management of patients with dermatomyositis
Authors: Park Jane H. , Vital Terri L. , Ryder Nova M. , Hernanz‐Schulman Marta , Leon Partain C. , Price Ronald R. , Olsen Nancy J.
Published: February 2007

Objective. To evaluate the utility of magnetic resonance imaging (MRI) and P‐31 magnetic resonance spectroscopy (MRS) in the longitudinal management of patients with dermatomyositis (DM).

Methods. The study group consisted of 11 patients, including 3 children, all of whom had a clinical diagnosis of DM. A control group of 8 subjects was studied simultaneously. MRI included images as well as calculations of T1 and T2 relaxation times. The P‐31 MRS protocol evaluated metabolic status (i.e., inorganic phosphate/phosphocreatine ratios and phosphocreatine and ATP levels) during rest, exercise, and recovery.

Results. T2‐weighted images of the thigh muscles showed inflammation even when serum creatine phosphokinase levels were in the normal range. Metabolic abnormalities, which were accentuated with exercise, were found in 10 patients. In some individuals, bioenergetic defects preceded other changes and persisted after resolution of inflammation. In general, clinical impressions correlated with MRI/MRS data.

Conclusion. MRI and MRS provide unique data which are quantitative and which cannot be obtained from routine laboratory tests. These MR evaluations appear to be of value in assessing the status of DM patients during treatment with steroids and immuno‐suppressive drugs.
Is there an association between injectable collagen and polymyositis/dermatomyositis?
Authors: Rosenberg Michael J. , Reichlin Morris
Published: February 2007

Objective. Recent case reports have raised the possibility that use of injectable bovine collagen may be associated with polymyositis/dermatomyositis (PM/DM). Because the number of collagen users is high, PM/DM would be expected to occur in some for reasons unrelated to the collagen use. A central issue is whether the number of observed cases exceeds the number expected on the basis of background rates alone. The present study was undertaken to investigate this.

Methods. The number of observed cases was determined by review of the medical records of collagen users who had reported illnesses consistent with PM/DM. Because of the uncertainty about diagnosis of PM/DM, population incidence rates, number of patients treated with collagen, and duration of followup after treatment, we examined a range of estimates of each of these factors that would affect the expected number of cases.

Results. From reports among collagen users, 7 probable or definite cases of PM/DM were confirmed. In contrast, 13 cases would be expected based on the best estimates of relevant factors. Under the most conservative estimates for factors that influence the number of expected cases, 12 cases would be expected, while worst‐case assumptions would yield an expected 130 cases.

Conclusion. The consistent finding of fewer‐than‐expected PM/DM cases among collagen users suggests that collagen use is not associated with the development of PM/DM.
Serum antibodies to klebsiella capsular polysaccharides in ankylosing spondylitis
Authors: Sahly Hany , Podschun Rainer , Sass Rainer , Bröker Barbara , Kekow Jörn , Gross Wolfgang Ludwig , Ullmann Uwe
Published: February 2007

Objective. To measure antibodies to Klebsiella capsular polysaccharides in the sera of HLA–B27 positive patients with ankylosing spondylitis (AS), compared with HLA–B27 positive and HLA–B27 negative healthy control subjects.

Methods. Antibodies were detected by means of an enzyme‐linked immunosorbent assay specific for each of the 77 known Klebsiella serotypes.

Results. Significantly elevated frequencies and titers of antibodies to capsular polysaccharides K26, K36, and K50 were detected in sera from AS patients, compared with controls.

Conclusion. These results suggest the predominance of Klebsiella serotypes K26, K36, and K50 in patients with AS.
Application of neural networks to the classification of giant cell arteritis
Authors: Astion Michael L. , Wener Mark H. , Thomas Ronald G. , Hunder Gene G. , Bloch Daniel A.
Published: February 2007

Objective. Neural networks are a group of computer‐based pattern recognition methods that have recently been applied to clinical diagnosis and classification. In this study, we applied one type of neural network, the backpropagation network, to the diagnostic classification of giant cell arteritis (GCA).

Methods. The analysis was performed on the 807 cases in the vasculitis database of the American College of Rheumatology. Classification was based on the 8 clinical criteria previously used for classification of this data set: 1) age ≥50 years, 2) new localized headache, 3) temporal artery tenderness or decrease in temporal artery pulse, 4) polymyalgia rheumatica, 5) abnormal result on artery biopsy, 6) erythrocyte sedimentation rate ≥50 mm/hour, 7) scalp tenderness or nodules, and 8) claudication of the jaw, of the tongue, or on swallowing. To avoid overtraining, network training was terminated when the generalization error reached a minimum. True cross‐validation classification rates were obtained.

Results. Neural networks correctly classified 94.4% of the GCA cases (n = 214) and 91.9% of the other vasculitis cases (n = 593). In comparison, classification trees correctly classified 91.6% of the GCA cases and 93.4% of the other vasculitis cases. Neural nets and classification trees were compared by receiver operating characteristic (ROC) analysis. The ROC curves for the two methods crossed, indicating that the better classification method depended on the choice of decision threshold. At a decision threshold that gave equal costs to percentage increases in false‐positive and false‐negative results, the methods were not significantly different in their performance (P = 0.45).

Conclusion. Neural networks are a potentially useful method for developing diagnostic classification rules from clinical data.
Polyarthritis resembling juvenile rheumatoid arthritis in a girl with chronic granulomatous disease
Authors: Lee B. W. , Yap H. K.
Published: February 2007

Chronic granulomatous disease (CGD) is an uncommon disorder affecting neutrophil function, and is characterized by recurrent and severe pyogenic infections. Associated autoimmune disorders, in particular lupus‐like disorders, are found in carriers of X‐linked CGD and in patients with both the X‐linked and the autosomal recessive (AR) forms of the disease. We describe a girl with the AR form of CGD and with rheumatoid factor–positive polyarthritis resembling juvenile rheumatoid arthritis. This association has been reported previously only in a single case report of a patient with probable CGD. The present report further substantiates the association between autoimmune phenomena and CGD.
Increased incidence of a resonance in the phosphodiester region of 31p nuclear magnetic resonance spectra in the skeletal muscle of fibromyalgia patients
Authors: Jubrias Sharon A. , Bennett Robert M. , Klug Gary A.
Published: February 2007

Objective. To determine if patients with fibromy algia syndrome (FMS) are more susceptible to activityinduced muscle damage than are healthy subjects.
Methods. Eleven FMS patients and 10 healthy subjects performed concentric and eccentric exercise with their dominant and nondominant forearms, respectively. 31P magnetic resonance spectroscopy (to assess inorganic phosphate [Pi] and phosphocreatine [PCr]) and dolorimetry (to assess pain) were performed before and 20 minutes after exercise and at 4 subsequent 24‐hour intervals.
Results. Neither group exhibited increased Pi/ PCr ratios or reduced dolorimetry scores following the exercise protocols. FMS patients did display a phosphodiester resonance at a higher rate than healthy subjects (37% versus 12%), but this was not related to the exercise.
Conclusion. Unchanged Pi/PCr ratios and dolorimetry scores following acute exercise provide evidence against the hypothesis that FMS patients are more susceptible to activity‐induced muscle damage than are healthy subjects, although Pi/PCr and pain may not adequately document such damage. The frequent occurrence of phosphodiester in the spectra of FMS patients may indicate a sarcolemmal abnormality in these subjects.
Breast‐feeding and the onset of rheumatoid arthritis
Authors: Brennan Paul , Silman Alan
Published: February 2007

Objective. In a recent study we demonstrated that the postpartum period, particularly after the first pregnancy, is a time of increased risk for the development of rheumatoid arthritis (RA). The present study was undertaken to investigate whether this risk might be explained by breast‐feeding.
Methods. Through a nationwide media campaign, we identified 187 women who had developed RA within 12 months of a pregnancy, and we compared their breast‐feeding histories with those of 149 similarly aged women chosen from the patient registers of a nationwide group of general practitioners.
Results. In all, 88 of the women with RA developed the disease after their first pregnancy. Eighty‐one percent of these 88 women had breast‐fed. This was higher than the breast‐feeding prevalence of 50% in the 129 controls whose first pregnancy had resulted in a live birth (adjusted odds ratio [OR] 5.4, 95% confidence interval 2.5–11.4). There was a smaller increased risk of breast‐feeding after a second pregnancy in the RA cases (OR 2.0) and no increase after a third pregnancy (OR 0.6). The increase in risk was greatest in those cases whose disease was erosive and who were rheumatoid factor positive.
Conclusion. In a small group of susceptible women, exposure to breast‐feeding after the first pregnancy is associated with a significant increase in risk for RA development. We postulate that this may reflect hormonal influences, specifically the high level of the proinflammatory hormone prolactin.
The lag time between onset of symptoms and diagnosis of rheumatoid arthritis
Authors: Chan KIN‐Wei A. , Felson David T. , Yood Robert A. , Walker Alexander M.
Published: February 2007

Objective. Rheumatoid arthritis (RA) may be biologically reversible if treated in the first several months, yet it is unknown whether patients are diagnosed that early. We investigated the lag time between symptom onset and diagnosis of RA in a population with excellent access to rheumatology care.
Methods. Using review of medical records, we evaluated all patients newly diagnosed as having RA from 1987 through 1990, at a health maintenance organization in central Massachusetts. Total lag time from symptom onset to first definite diagnosis was divided into medical encounter lag time (from symptom onset to first medical encounter) and diagnosis lag time (from first medical encounter to diagnosis).
Results. The median total lag time was 36 weeks (range 4 weeks to > 10 years). The median medical encounter lag time was 4 weeks (not all patients included in the analysis). The median diagnosis lag time was 18 weeks. Diagnosis lag time was shorter for patients with progressive disease and positive rheumatoid factor on the initial test. Of 25 patients with symmetric arthritis and positive rheumatoid factor, only 5 (20%) were diagnosed within 2 months, and 10 (40%) were diagnosed more than 6 months after symptom onset.
Conclusion. RA diagnosis is usually delayed for several months after symptoms begin, in large part because of delay in diagnosis by the physician. Thus, the goal of initiating treatment extremely early may be unrealistic for most patients.
The sensitivity and specificity of computerized databases for the diagnosis of rheumatoid arthritis
Authors: Gabriel Sherine E.
Published: February 2007

Objective. To examine the accuracy of a computerized medical database for the diagnosis of rheumatoid arthritis (RA).
Methods. The complete medical records of all prevalent cases of RA (according to the 1987 American College of Rheumatology diagnostic criteria) on January 1, 1987 were reviewed to determine the sensitivity, specificity, and predictive value of database diagnoses compared with those obtained by medical record review. Agreement between database and medical record diagnoses was calculated using the kappa statistic.
Results. Computerized database diagnoses of RA had a sensitivity of 89%, a specificity of 74%, a positive predictive value of 57%, and a negative predictive value of 94% compared with diagnoses based on clinical information abstracted from the complete medical record. Agreement between database and medical record diagnoses was poor (K = 0.54).
Conclusion. The sole reliance on such databases for the diagnosis of RA can result in substantial misdiagnosis.
Chloroquine reduces the bioavailability of methotrexate in patients with rheumatoid arthritis
Authors: Seideman Peter , Albertioni Freidoun , Beck Olof , Eksborg Staffan , Peterson Curt
Published: February 2007

Objective. To evaluate the effects of a single dose of chloroquine (CQ) on the pharmacokinetics of methotrexate (MTX) in patients with rheumatoid arthritis.
Methods. Eleven patients (ages 41–75 years) who were taking oral doses of MTX (15 mg/week) were studied after a dose of MTX alone and after a dose of MTX plus CQ (250 mg). Plasma and urine samples were collected for 24 hours after dose intake, and the concentrations of MTX and its major metabolite 7‐hydroxymethotrexate were determined by high‐performance liquid chromatography.
Results. Administration of CQ together with MTX caused a reduction in the area under the plasma MTX concentration versus time curve (AUC). The median value of individual AUC ratios (MTX/MTX + CQ) was 1.6 (95% confidence interval 1.2–3.6).
Conclusion. The most likely mechanism for the interaction is that CQ reduces the bioavailability of MTX. This gives a possible explanation for a suggested reduction in MTX‐associated liver toxicity by coadministration of CQ. The significance of the interaction for the therapeutic effect remains to be elucidated.
Treatment of refractory rheumatoid arthritis with a chimeric ANTI‐CD4 monoclonal antibody
Authors: Moreland Larry W. , Pratt Parks W. , Bucy Ralph P. , Jackson Bettie S. , Feldman Janie W. , Koopman William J.
Published: February 2007

Objective. To evaluate CD4+ T cell counts of rheumatoid arthritis (RA) patients at 18 and 30 months after treatment with a chimeric anti‐CD4 monoclonal antibody (MAb), cM‐T412, in a phase I trial.
Methods. Of the 25 RA patients who received the MAb, 23 were available for followup at 18 and 30 months. Levels of circulating CD4+ T cells were measured by flow cytometry.
Results. Circulating CD4+ T cell levels in these 23 RA patients remained below normal at 18 and 30 months posttreatment. More profound CD4+ T cell depletion was noted in the higher‐dose groups (300 and 700 mg).
Conclusion. Prolonged suppression of circulating CD4+ T cells was noted both in single‐infusion and multiple‐infusion groups 18 and 30 months after cM‐T412 treatment. The depression was more pronounced in patients who received multiple infusions of cM‐T412. The prolonged decrease in CD4+ T cell numbers suggests that the capacity to reconstitute CD4+ T cells in this patient population (treated with methotrexate) is limited. One patient, who was also receiving methotrexate and prednisone, died 18 months after receiving 100 mg of cM‐T412. No other significant adverse effects, in particular, no opportunistic infections, were reported in these 23 RA patients at 18 and 30 months of followup.
Regression of collagen‐induced arthritis with taxol, a microtubule stabilizer
Authors: Brahn Ernest , Tang Chris , Banquerigo Mona Lisa
Published: February 2007

Objective. To investigate the capacity of taxol, a microtubule stabilizer, to inhibit collagen‐induced arthritis (CIA), a model of rheumatoid arthritis.
Methods. Louvain rats were immunized with type II collagen (day 0) to induce arthritis. Taxol was administered beginning on day 2 (prevention protocol) or at arthritis onset on day 9 (in either a high‐dose or low‐dose suppression protocol). Rats were assessed clinically and radiographically for arthritis severity. Cellular and humoral immune responses to type II collagen were also evaluated.
Results. Institution of taxol prior to arthritis onset completely precluded the development of CIA (P < 0.0001 versus controls). It also suppressed established clinical disease (high‐dose protocol P < 0.0000001; low‐dose protocol P < 0.0001) and radiographic erosions (high‐dose protocol P < 0.00001; low‐dose protocol P < 0.001) compared with controls. Levels of IgG antibodies, but not delayed‐type hypersensitivity, to type II collagen were reduced after taxol administration.
Conclusion. Taxol completely prevented the induction of CIA and caused significant regression of existing arthritis.
Expression of ICAM‐R (ICAM‐3), a novel counter‐receptor for LFA‐1, in rheumatoid and nonrheumatoid synovium
Authors: El‐Gabalawy Hani , Gallatin Michael , Vazeux Rosemay , Peterman Gary , Wilkins John
Published: February 2007

Objective. To study the distribution of intercellular adhesion molecule receptor (ICAM‐R, or ICAM‐3), a novel ligand for the leukointegrin lymphocyte function‐associated antigen 1 (LFA‐1), in normal and rheumatoid synovial membranes and to compare this with the distribution of ICAM‐1, ICAM‐2, vascular cell adhesion molecule 1 (VCAM‐1), and endothelial leukocyte adhesion molecule 1 (ELAM‐1).
Methods. We performed immunohistochemical analyses of frozen sections of normal and rheumatoid synovial tissue using monoclonal antibodies to the molecules examined.
Results. ICAM‐1 staining was detectable on the vascular endothelium and the synovial lining cells of both normal and rheumatoid synovial membranes. A variable proportion of lymphocytes infiltrating rheumatoid tissues expressed ICAM‐1. ICAM‐2 staining was demonstrable in the vascular endothelium of both normal and inflamed tissues, the latter demonstrating a significantly higher proportion of positive vessels. ELAM‐1 staining was not detectable in normal synovial membranes but was seen on the endothelium of a limited number of rheumatoid synovial vessels, usually close to the synovial lining cell layer. VCAM‐1 staining was intense in both normal and rheumatoid synovial lining cells, but vascular staining was weak in both. In contrast, ICAM‐R staining was not detected in association with any synovial blood vessels, but was widely expressed by lymphocytes and macrophages. Cells of the lining layer did not stain for ICAM‐R.
Conclusion. Although ICAM‐R is a ligand for LFA‐1 and shares considerable sequence homology with ICAM‐1 and ICAM‐2, it does not appear to be expressed by the endothelium of normal or inflamed synovial vessels. Intense expression of ICAM‐R by rheumatoid synovial lymphocytes and macrophages suggests that it may play a role in processes requiring cell‐cell contact, such as antigen presentation and homotypic aggregation.
Preferential utilization of a novel vλ3 gene in monoclonal rheumatoid factors derived from the synovial cells of rheumatoid arthritis patients
Authors: Ermel Richard W. , Kenny Thomas P. , Wong Alice , Solomon Alan , Chen Pojen P. , Robbins Dick L.
Published: February 2007

Objective. To further our understanding about the molecular genetics of rheumatoid factor (RF) in rheumatoid arthritis (RA).
Methods. The heavy and light chain variable region (V) genes of 5 new human monoclonal IgM RFs were cloned and sequenced using the polymerase chain reaction and the dideoxynucleotide termination method.
Results. The results reveal the recurrent usage in two RA patients of a novel Vλ3 germline gene, designated Humlv3c93. Specifically, in 2 of 3 RFs (C93 and D53) from one patient, the light chains in the Vλ gene‐encoded region were identical to each other and to the light chain of an RF (H4) from another patient. Serologically, the light chains of these 3 RFs were classified as members of the Vλ3b sub‐subgroup. Each of the RFs was encoded by a different VH gene. Both C93 and D53 bound specifically with human and rabbit IgG, whereas H4 was monospecific for rabbit IgG.
Conclusion. Since the 1v3c93 gene is not homologous to any reported Vλ sequence from natural auto‐antibodies, it is possible that 1v3c93 may represent a disease‐specific RF‐related Vλ gene. Moreover, the amino acid sequence CSGGSCY in the third complementarity‐determining regions of 2 of the RF heavy chains is encoded by the DLR2 gene segment and has been found previously in 2 other RA‐derived RFs, and thus may play a significant role in antigen binding.
Association of patterns of labial salivary gland inflammation with keratoconjunctivitis SICCA
Authors: Daniels Troy E. , Whitcher John P.
Published: February 2007

Objective. To determine the association between patterns of inflammation in labial salivary glands (LSG) and the ocular component of Sjögren's syndrome (SS).
Methods. We classified LSG biopsy specimens from 618 patients with suspected SS as showing focal lymphocytic sialadenitis (FLS), other chronic sialadenitis (CS), or other diagnoses. We then determined the association of the other component of primary SS, keratoconjunctivitis sicca (KCS), with FLS, CS, parotid flow rate, and xerostomia.
Results. FLS, rather than CS, was associated with a diagnosis of KCS (X = 191, P < 0.0001). The severity of KCS correlated directly with the severity of FLS (r = 0.52, P < 0.0001), but not of CS, and correlated inversely with parotid flow rate in those patients who had FLS (r = ‐0.29), but not in those who had CS (r = −0.03). Xerostomia was marginally associated with KCS (X2 = 5, P = 0.02).
Conclusion. The stronger KCS association found in patients whose LSG biopsies show FLS makes FLS the best criterion presently available for diagnosing the salivary component of SS. CS is a common feature of labial salivary glands but is neither associated with SS nor an end stage of primary SS. Histopathologic examination of salivary tissue is currently essential for diagnosing primary SS as well as secondary SS in which KCS is lacking, especially cases to be included in studies of SS.
Treatment of lyme arthritis
Authors: Steere Allen C. , Levin Robert E. , Molloy Philip J. , Kalish Robert A. , Abraham Iii James H. , , Liu Nancy Y. , Schmid Christopher H.
Published: February 2007

Objective. To test treatment regimens for Lyme arthritis.
Methods. Patients were randomly assigned to treatment with doxycycline or amoxicillin plus probenecid for 30 days. Patients who had persistent arthritis for at least 3 months after treatment with oral antibiotics or parenteral penicillin were given intravenous ceftriaxone for 2 weeks.
Results. Eighteen of the 20 patients treated with doxycycline and 16 of the 18 patients who completed the amoxicillin regimen had resolution of the arthritis within 1–3 months after study entry. However, neuroborreliosis later developed in 5 patients, 4 of whom had received the amoxicillin regimen. Of 16 patients (2 from the oral antibiotic study and 14 additional patients) who had persistent arthritis despite previous oral antibiotics or parenteral penicillin, none had resolution of the arthritis within 3 months after ceftriaxone therapy. The HLA‐DR4 specificity and OspA reactivity were associated with a lack of response.
Conclusion. Lyme arthritis can usually be treated successfully with oral antibiotics, but patients may still develop neuroborreliosis. Patients with certain genetic and immune markers may have persistent arthritis despite treatment with oral or intravenous antibiotics.
Serum levels of soluble interleukin‐2 receptor
Authors: Uziel Yosef , Krafchik Bernice R. , Feldman Brian , Silverman Earl D. , Rubin Laurence A. , Laxer Ronald M.
Published: February 2007

Objective. To determine whether circulating serum levels of soluble interleukin‐2 receptor (sIL‐2R) are elevated in patients with localized scleroderma, and if levels of sIL‐2R can differentiate between active and inactive disease.
Methods. Seventeen patients with localized scleroderma were categorized by overall physician assessment into active, inactive, and indeterminate groups, according to disease activity. Serum sIL‐2R levels were analyzed and correlated with disease activity.
Results. The mean sIL‐2R level was significantly higher (P = 0.005) in those with active disease (1,675 ± 823 units/ml) than in those with inactive disease (722 ± 218 units/ml).
Conclusion. Serum sIL‐2R levels are elevated in patients with localized scleroderma. When present, elevated sIL‐2R levels appear to be able to differentiate active from inactive disease. This fact also suggests cell‐mediated immune activation in this condition. Further serial studies are required to assess the value and sensitivity of sIL‐2R levels in measuring changes in disease activity.
Racial differences in the distribution of systemic sclerosis–related serum antinuclear antibodies
Authors: Kuwana Masataka , Okano Yutaka , Kaburaki Junichi , Tojo Takeshi , Medsger Thomas A.
Published: February 2007

Objective. To determine racial differences in the frequencies of systemic sclerosis (SSc)–related serum antinuclear antibodies (ANA).
Methods. We tested serum samples from 275 Japanese, 416 North American Caucasian, and 24 North American black SSc patients for 8 SSc‐related serum ANA, using indirect immunofluorescence, double immunodiffusion, and radioimmunoprecipitation assays.
Results. In comparing the 3 racial groups, we found that anti–U1 RNP, anti–RNA polymerase I, II, and III, and anti–U3 RNP antibodies were the most frequently detected antibodies in Japanese, Caucasian, and black patients, respectively. Anti–PM‐Scl antibody was found exclusively in Caucasians.
Conclusion. The production of SSc‐related serum ANA is related to immunogenetic background.
Influence of disease manifestation and antineutrophil cytoplasmic antibody titer on the response to pulse cyclophosphamide therapy in patients with wegener's granulomatosis
Authors: Reinhold‐Keller Eva , Kekow Jörn , Schnabel Armin , Schmitt Wilhelm H. , Heller Martin , Beigel Arwed , Duncker Gernot , Gross Wolfgang L.
Published: February 2007

Objective. To assess the effectiveness of pulse cyclophosphamide (CYC) in the treatment of Wegener's granulomatosis (WG) and to identify the patients who are responsive to the treatment.
Methods. The prospective study included 43 patients with biopsy‐proven WG. Clinical, radiographic, laboratory, and immunologic data were evaluated for predicitive values regarding the outcome of pulse CYC therapy.
Results. Only 42% of the patients showed complete or partial remission that lasted at least 6 months after cessation of pulse CYC therapy. These responders had a higher frequency of disease activity limited to the upper and lower respiratory tract (39%, versus 8% in the nonresponder group; P < 0.05) and had lower titers of classic antineutrophil cytoplasmic antibody (cANCA) prior to treatment (<1:64 42%, versus 6% in the nonresponder group; P < 0.05). In the 58% of patients who did not respond to pulse CYC treatment, there was both systemic disease involving more than 4 organ systems (mainly, the heart, nervous system, eye, and skin) and constitutional symptoms. Serious side effects induced by pulse CYC occurred in only 1 patient.
Conclusion. Based on these findings, pulse CYC therapy appears to be effective in WG patients with moderate disease activity and low titers of cANCA, but of little benefit in patients with severe WG. Pulse CYC should therefore not be used as first‐line therapy in patients with severe and rapidly progressing forms of WG associated with high titers of cANCA.
Comparative inhibitory effects of bucillamine and d‐penicillamine on the function of human b cells and t cells
Authors: Hirohata Shunsei , Lipsky Peter E.
Published: February 2007

Objective. Clinical trials have suggested that the efficacy of bucillamine (BUC) in rheumatoid arthritis (RA) may be superior to that of D‐penicillamine (DP), although the basis of the differences remains unclear. Previous studies have revealed that BUC has unique immunomodulatory effects that depend upon its capacity to form an intramolecular disulfide (BUG‐ID). We therefore examined the effects of BUC‐ID on the in vitro function of human B cells and T cells compared with those of DP, at their pharmacologically attainable concentrations.
Methods. IgM production was induced in highly purified B cells from healthy donors by stimulation with Staphylococcus aureus Cowan 1 (SAC) plus interleukin‐2 (IL‐2) or with immobilized anti‐CD3–activated CD4+ T cells. Interferon‐γ (IFNγ) production was induced in CD4+ T cells by stimulation with immobilized anti‐CD3.
Results. BUC‐ID suppressed IgM production iduced by SAC + IL‐2 as well as that induced by immobilized anti‐CD3–activated CD4+ T cells, whereas DP suppressed the latter more markedly than the former. DP (3 μg/ml) significantly suppressed IFNγ production by immobilized anti‐CD3–stimulated CD4+ T cells, but not IgM production induced by SAC + IL‐2 stimulation. By contrast, BUC‐ID (0.3 μg/ml) significantly suppressed IgM production induced by SAC + IL‐2, but not T cell IFNγ production. Of note, BUC‐ID did not suppress IL‐6 production by SAC‐activated B cells.
Conclusion. These results indicate that the target cells of BUC and DP in vivo might be different, with the former inhibiting the function of B cells and the latter that of T cells. The data suggest the possibility that BUC may have a different effect in RA patients compared with the effect of DP, and may be effective in patients who do not respond to DP.
Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1
Authors: Kavanaugh Arthur F. , Davis Laurie S. , Nichols Lisa A. , Norris Stephen H. , Rothlein Robert , Scharschmidt Linda A. , Lipsky Peter E.
Published: February 2007

Objective. To assess the safety and efficacy of a monoclonal antibody (MAb) to intercellular adhesion molecule 1 (ICAM‐1; CD54) in rheumatoid arthritis (RA).

Methods. A phase I/II, open‐label, dose‐escalation study of 32 patients.

Results. During treatment, a peripheral CD3+/CD4+ lymphocytosis was noted, and several patients demonstrated transient cutaneous anergy, which suggests that therapy modified T cell recirculation. Thirteen of the 23 patients who received 5 days of treatment demonstrated clinical improvement through day 29, and 9 of 23 through day 60. Adverse effects were minor and transient.

Conclusion. Anti—ICAM‐1 MAb therapy was well tolerated, resulted in a transient alteration in T lymphocyte recirculation, and effected clinical improvement in some RA patients.
The economic impact of treatment of severe lupus nephritis with prednisone and intravenous cyclophosphamide
Authors: Mcinnes Pamela M. , Schuttinga James , Sanslone William R. , Stark Susan P. , Klippel John H.
Published: February 2007

Objective. It has been reported that outcomes are improved in patients with severe lupus nephritis treated with combined prednisone and intravenous cyclophosphamide, compared with those treated with prednisone alone. These findings motivated this analysis of the economic impact of the combined therapy.

Methods. The annual expected incidence of severe lupus nephritis in the year 1988 in the US was estimated to be 1, 130. A hypothetical patient cohort of this size was used as the model for the present analysis; the costs of treatment with prednisone alone and with combined prednisone and intravenous cyclophosphamide were calculated and compared. The analysis took into account the expected rate of renal failure with each therapeutic approach, as well as age, sex, and the economic value of working years gained.

Results. Although the treatment costs are higher for the combination therapy, the analysis revealed overall savings due to a reduced need for kidney dialysis or transplantation, and the economic value of working capacity gained. Savings attributable to patient care costs were $50.8 million; those attributable to working capacity gained were $42.3 million.

Conclusion. This analysis indicates that over a 10‐year period, as much as $93.1 million per annual cohort is saved by the use of combination therapy for the treatment of severe lupus nephritis.
Giant cell arteritis in Iceland.
Authors: Baldursson Ólafur , Steinsson Kristján , Björnsson Jóhannes , Lie J. T.
Published: February 2007

Objective. To investigate the incidence and clinical and histopathologic features of giant cell (temporal) arteritis (GCA) in the Caucasian population of Iceland.

Methods. AH patients diagnosed between 1984 and 1990 were included. Case ascertainment for the study was done in 2 ways: 1) a computerized search from all hospitals and primary care clinics for the diagnosis of GCA, and 2) a review of all temporal artery biopsies performed during the 7‐year period.

Results. One hundred thirty‐three patients with GCA were identified. All fulfilled the 1990 American College of Rheumatology criteria for the classification of GCA. The incidence rate for the population 50 years and older was 27/100,000 (36/100,000 and 18/100,000 for women and men, respectively). Clinical findings included the following: mean age at diagnosis 72.5 years for women and 70.3 years for men, new headache 63.2%, abnormal temporal artery on palpation 43.6%, mean erythrocyte sedimentation rate 88 mm/hour, symptoms of polymyalgia rheumatica 48.1%, and visual disturbances 14.3%. A total of 744 patients underwent temporal artery biopsy during the 7‐year period; 16.8% had a positive biopsy result. All 133 patients with the diagnosis of GCA underwent a temporal artery biopsy; 94% had a positive result. Histopathologic findings from the positive biopsies included a fragmented internal elastic lamina in 99.2%, giant cells in 65.6%, and fibrinoid necrosis in 12%.

Conclusion. Compared with previous epidemiologic surveys, this study shows a high incidence of biopsy‐proven GCA in Iceland.