bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, double‐blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia
Authors: Goldenberg Don , Mayskiy Michael , Mossey Christopher , Ruthazer Robin , Schmid Christopher
Published: February 2007

Objective. To study the effect of fluoxetine (FL) and amitriptyline (AM), alone and in combination, in patients with fibromyalgia (FM).

Methods. Nineteen patients with FM completed a randomized, double‐blind crossover study, which consisted of 4 6‐week trials of FL (20 mg), AM (25 mg), a combination of FL and AM, or placebo. Patients were evaluated on the first and last day of each trial period. Outcome measures included a tender point score, the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI) scale, and visual analog scales (VAS) for global well‐being (1 completed by the physican and 1 by the patient), pain, sleep trouble, fatigue, and feeling refreshed upon awakening.

Results. Both FL and AM were associated with significantly improved scores on the FIQ and on the VAS for pain, global well‐being, and sleep disturbances. When combined, the 2 treatments worked better than either medication alone. Similar, but nonsignificant, improvement occurred in the BDI scale, the physician global VAS, and the VAS for fatigue and feeling refreshed upon awakening. Trends were less clear for the tender point score.

Conclusion. Both FL and AM are effective treatments for FM, and they work better in combination than either medication alone.
Common occurrence of an antiidiotypic antibody that recognizes T14+ anti‐DNA antibodies in patients with systemic lupus erythematosus
Authors: Lim Pak‐Leong , Ng Lawrence W. K. , Leung Danny T. M. , Wong Kong‐Chiu , Song Si‐Yang , Chui Yiu‐Loon , Leung Joseph C. K. , Lai Kar‐Neng , Lui Siu‐Fai
Published: February 2007

Objective. To investigate whether antibodies to a T14 anti‐DNA antibody can be found in patients with systemic lupus erythematosus (SLE).

Methods. Seventy‐six serum samples (37 from patients with SLE) were randomly selected from among sera submitted for routine antinuclear antibody testing. Short, overlapping peptides based on the partial VH (variable region of the heavy chain) sequence of the T14 antibody were synthesized on multipins and screened for reactivity with SLE sera. In addition, selected peptides from T14 and related proteins were synthesized in bulk and screened for reactivity with both SLE and control sera. A monoclonal antibody was generated to determine the prevalence of the T14 idiotype (T14+ Id) in the different study populations.

Results. Antibodies were detected by a peptide based on the third complementarity‐determining region (CDR3) of the T14 protein in 15 (41%) of 37 patients with SLE or 15 (54%) of 28 who had anti‐DNA antibodies, in 3 (9%) of 34 patients without anti‐DNA antibodies (9 of whom had SLE), and in 6 (10%) of 57 healthy controls. In SLE sera, the antiidiotypic (anti‐Id) responses (IgM and IgG) correlated well with the anti‐DNA responses (IgG), and both responses correlated well with the T14+ Id activity in SLE sera. Control peptides based on the 18/2 (16/6+ Id) and S107 proteins detected low antibody activities in SLE sera, attributable to cross‐reactivity with the T14 peptide. A peptide based on an unrelated human antibody was not reactive with these sera.

Conclusion. Anti‐Id antibodies directed to T14 VHCDR3 were found commonly in the sera of patients with SLE, and they appeared to be induced by the anti‐DNA antibodies present in the sera. Based on these findings, these secondary antibodies may be pathogenic in SLE.
The effect of prophylactic penicillin treatment on the course of arthritis episodes in patients with Behçet's disease. A randomized clinical trial
Authors: Çalgüneri Meral , Kiraz Sedat , Ertenli Ihsan , Benekli Mustafa , Karaarslan Yaşar , Çelik Ismail
Published: February 2007

Objective. Because exposure to streptococcal antigens might be a major disease activity—provoking factor in Behçet's disease, this study was undertaken to evaluate the effectiveness of benzathine penicillin in the prophylaxis of recurrent arthritis episodes during the course of this disease.

Methods. A prospective, randomized study design was used to allocate patients to receive colchicine alone or colchicine plus benzathine penicillin for 24 months.

Results. The duration, severity, and pattern of arthritis episodes were found to be similar in the 2 treatment groups, but the number of arthritis episodes was significantly reduced, and the duration of episode‐free time significantly prolonged, in the penicillin group compared with the colchicine‐alone group.

Conclusion. Penicillin treatment was demonstrated to offer adjunctive benefits in the prevention of arthritis episodes which are not obtainable with colchicine monotherapy. This finding could provide additional evidence for antigen triggering in the pathogenesis of Behçet's disease.
Evidence of qualitatively altered nociception in patients with fibromyalgia
Authors: Bendtsen Lars , Nørregaard Jesper , Jensen Rigmor , Olesen Jes
Published: February 2007

Objective. To investigate the perception of pain in tender muscles of patients with fibromyalgia.

Methods. Twenty‐five women with fibromyalgia and 25 healthy women were examined. Seven different pressure intensities were used to palpate a highly tender muscle and a largely normal muscle. Subjects then recorded their response to induced pain on a visual analog scale. The examiner was blinded to each subject's response.

Results. The stimulus‐response function for pressure versus pain recorded for normal muscle was well described by a power function. For highly tender muscle, the stimulus‐response function was displaced toward lower pressures and, more importantly, it was linear, i.e., qualitatively different from that of normal muscle.

Conclusion. This study demonstrates that nociception is qualitatively altered in patients with fibromyalgia, which is consistent with recent findings in other patients with tender muscles. The data strongly indicate that fibromyalgic pain, at least in part, is due to aberrant central pain mechanisms.
Similarities of specificity and cofactor dependence in serum antiphospholipid antibodies from patients with human parvovirus B19 infection and from those with systemic lupus erythematosus
Authors: Loizou Sozos , Cazabon John K. , Walport Mark J. , Tait Dereck , So Alex K.
Published: February 2007

Objective. To assess the phospholipid specificity and immunoglobulin isotype of antiphospholipid (aPL) antibodies in patients with acute parvovirus B19 infection.

Methods. Specificity of aPL and isotype distribution in the negatively charged phospholipids, cardiolipin and phosphatidyl serine, and in the neutral phospholipid, phosphatidyl ethanolamine, were measured in the sera of patients with acute parvovirus B19 infections (n = 12), in those with other acute viral infections (n = 10), and in those with syphilis (n = 15) by enzyme‐linked immunosorbent assays. The dependence of anticardiolipin (aCL) binding on the presence of β2‐glycoprotein I (β2‐GPI) as a binding cofactor was assessed in these same groups, and was compared with sera from systemic lupus erythematosus (SLE) patients (n = 11) with raised aCL antibody reactivity.

Results. Antibodies against any of the 3 phospholipids were found in all 3 groups of patients with infections (B19 in 11 of 12 patients, other viral infections in 8 of 10 patients, and syphilis in 14 of 15 patients). B19 patients' sera contained predominantly IgG antibodies against the negatively charged phospholipids, cardiolipin and phosphatidyl serine, and differed in their specificity and isotype distribution from those found in the other 2 patient groups. B19‐associated aCL increased their binding to antigen in the presence of β2‐GPI as a binding cofactor, similar to aCL found in SLE patients, but unlike antibodies from patients with other viral infections or from those with syphilis.

Conclusion. The results show the remarkable similarity in specificity of aPL antibodies between B19‐infected patients and SLE patients, and raise the question of whether parvovirus infection may be a trigger for the development of aPL antibodies in autoimmune diseases.
Methotrexate‐associated appearance and rapid progression of rheumatoid nodules in systemic‐onset juvenile rheumatoid arthritis
Authors: Falcini Fernanda , Taccetti Giovanni , Ermini Marialisa , Trapani Sandra , Calzolari Anna , Franchi Alessandro , Cerinic Marco Matucci
Published: February 2007

Rheumatoid nodules are a rare extraarticular manifestation of juvenile rheumatoid arthritis (JRA), usually detected in patients with polyarticular‐onset disease and positive rheumatoid factor (RF). To date, there has not been a published report of rheumatoid nodules in systemic‐onset JRA. Low‐dose methotrexate (MTX) is generally considered to be the most useful second‐line drug in the treatment of polyarticular JRA. In adult RA, MTX has been shown to be associated with appearance and progression of rheumatoid nodules. This report describes a 3‐year‐old girl with RF‐negative, antinuclear antibody‐negative systemic JRA who developed multiple rheumatoid nodules on the scalp and trunk during MTX therapy. The first nodule developed on the scalp 6 months after MTX treatment was initiated. Previous treatment with azathioprine was not associated with nodulosis. This represents an atypical case of MTX‐associated accelerated nodulosis in systemic JRA, and raises the problem of treatment plan modification in the presence of this side effect.
The arthropathy of fibroblastic rheumatism
Authors: Romas Evangelos , Finlay Moira , Woodruff Timothy
Published: February 2007

Fibroblastic rheumatism (FR) is a relatively rare syndrome characterized by the association of multiple cutaneous nodules with polyarthritis. The unique histologic finding in the skin and synovium of patients with FR is a proliferation of myofibroblast‐like cells within a background matrix of collagen. The occurrence of erosive arthritis has not been emphasized in previous descriptions of FR. We describe a patient with FR who presented with symmetric polyarthritis, skin thickening, and dermal nodules. Despite treatment with prednisone and D‐penicillamine, he developed a progressive, destructive polyarthropathy that mimicked multicentric reticulohistiocytosis.
Protection of rats from adjuvant arthritis by immunization with naked dna encoding for mycobacterial heat shock protein 65
Authors: Ragno Silvia , Colston M. Joseph , Lowrie Douglas B. , Winrow Vivienne R. , Blake David R. , Tascon Ricardo
Published: February 2007

Objective. To assess the feasibility of vaccination with naked DNA encoding for mycobacterial heat shock protein 65 (hsp65) in the modulation of experimental arthritis.

Methods. Adjuvant arthritis (AA) was induced in Lewis rats preimmunized, intramuscularly, with a plasmid encoding for hsp65 (pCMV3.65). Clinical scores were recorded for 3–4 weeks, and histologic and radiologic parameters were evaluated. Cellular and antibody reactivity to hsp65 was assessed. The expression of the hsp65 gene was investigated in injected muscles.

Results. The pCMV3.65‐treated rats were significantly protected from disease development in comparison with the control groups. This finding correlated with the results of histologic and radiologic examinations of the involved joints. The message for hsp65 was detected in injected muscles. T cell proliferation and antibodies to this protein were found to be elevated in pCMV3.65‐treated rats when compared with both the arthritic control (AA‐induced) and the naive (did not receive adjuvant) animals.

Conclusion. We have demonstrated for the first time that naked DNA delivery is feasible in controlling experimental autoimmune disease. Although the actual mechanism of protection has not been fully elucidated, this simple and versatile approach could represent a useful tool in dissecting basic autoimmune mechanisms.
Characterization of prelymphomatous stages of B cell lymphoproliferation in Sjögren's syndrome
Authors: de Vita Salvatore , Boiocchi Mauro , Sorrentino Dario , Carbone Antonino , Avellini Claudio , Dolcetti Riccardo , Marzotto Alessandra , Gloghini Annunziata , Bartoli Ettore , Beltrami Carlo Alberto , Ferraccioli Gianfranco
Published: February 2007

Objective. To determine whether the prelymphomatous stages of B cell lymphoproliferation in Sjögren's syndrome (SS) may be better characterized by the integration of clinical, pathologic, and molecular data, the latter focusing on the expansion, persistence, and dissemination of clonal B cells in the course of the disease.

Methods. Multiple tissue lesions (synchronous from different tissues and metachronous from the same tissue) were evaluated in biopsy specimens obtained from 6 consecutive patients with SS who had an associated lymphoproliferative disorder. Fully benign gastric lesions were evaluated in tissue from an additional 11 patients with SS who had no associated lymphoproliferative disorder. Multiple and complementary molecular analyses of B cell clonality were used: Southern blot, polymerase chain reaction, single‐strand conformation polymorphism, DNA sequencing, and hybridization with clonospecific oligoprobes. All the patients were then strictly followed up for the appearance of lymphoma.

Results. Different scenarios of SS‐associated B cell lymphoproliferation were identified: 1) the ongoing expansion of the same dominant clone, localized or disseminated, in tissue from 2 patients, 1 of whom later developed an overt B cell lymphoma; 2) different dominant clones in different synchronous or metachronous tissues from the remaining 4 patients with an associated lymphoproliferative disorder; and 3) small oligoclonal expansions in 7 of the 11 benign gastric lymphoid infiltrates.

Conclusion. Prelymphomatous B cell lymphoproliferation in SS was better characterized following integration of the findings. The different types of B cell clonal expansion (oligoclonal or monoclonal, smaller or larger in size, fluctuating or established, localized or disseminated) may imply a different risk of lymphoma progression. An accurate clinical, histopathologic, and molecular characterization may therefore be crucial in future studies aimed at clarifying the pathobiology of SS‐associated lymphoproliferation.
Meaningful improvement criteria sets in a rheumatoid arthritis clinical trial
Authors: Pillemer Stanley R. , Fowler Sarah E. , Tilley Barbara C. , Alarcón Graciela S. , Heyse Stephen P. , Trentham David E. , Neuner Rosemarie , Clegg Daniel O. , Leisen James C. C. , Cooper Sheldon M. , Duncan Howard , Tuttleman Marilyn
Published: February 2007

Objective. To compare 3 sets of criteria for meaningful improvement in a rheumatoid arthritis (RA) clinical trial, and to evaluate the implications of these criteria sets for RA trial design.

Methods. Data were obtained from the Minocycline in Rheumatoid Arthritis (MIRA) trial (primary outcome measures: 50% improvement in joint tenderness and 50% improvement in joint swelling, based on joint scores). These MIRA data were evaluated against 1) the Paulus criteria (20% improvement in 4 of 6 measures: joint tenderness scores, joint swelling scores, physician's and patient's global assessments, erythrocyte sedimentation rate [ESR], and morning stiffness); and 2) the American College of Rheumatology (ACR) criteria (20% improvement in joint tenderness and joint swelling counts, and in 3 of 5 other measures: physician's and patient's global assessments, ESR, modified Health Assessment Questionnaire, and patient's pain assessment). The ACR criteria were modified using 3 of 4 remaining measures, since baseline pain assessment data were not available.

Results. Percentages of minocycline‐treated patients versus placebo‐treated patients showing meaningful improvement were as follows: by MIRA criteria, for joint tenderness, 56% versus 41% (P = 0.021), and for joint swelling, 54% versus 39% (P = 0.023); by Paulus criteria, 41% versus 28% (P = 0.040); and by ACR criteria, 44% versus 26% (P = 0.004). Both the modified ACR criteria and the Paulus criteria demonstrated a reduced placebo response rate. Compared with the MIRA criteria, the ACR criteria increased, and the Paulus criteria decreased, absolute between‐group differences in improvement; however, both criteria sets increased relative percentages of patients showing improvement in the minocycline group versus the placebo group. Study design considerations indicated that application of the ACR criteria would reduce the required sample size.

Conclusion. Different placebo response rates and treatment group differences were found using the 3 RA improvement criteria sets. These findings support the use of the ACR criteria for defining improvement in RA clinical trials.
Tenosynovial nodulosis in a patient infected with human T cell lymphotropic virus I
Authors: Hasunuma Tomoko , Morimoto Tadanobu , Hoa Tran Thi Minh , Müller‐Ladner Ulf , Aono Hiroyuki , Ogawa Ryokei , Gay Steffen , Nishioka Kusuki
Published: February 2007

We describe a 45‐year‐old man who presented with multiple nodules along the tendons of the scapular region, the elbows, wrists, forearms, thighs, and ankles. The patient was a carrier of human T cell lymphotropic virus I (HTLV‐I), which was probably transmitted from his mother; his mother also had polyarthritis. Histopathologically, the nodules consisted of numerous, small, fibrinoid masses. The synovium adjacent to the tendon sheath was hyperplastic, with fibrinoid necrosis mimicking rheumatoid synovium. However, synovitis was not present inside the adjacent joint. HTLV‐I proviral DNA was detected in the cells of the nodule, in tenosynovial cells, and in peripheral blood lymphocytes, but not in skin fibroblasts. In situ reverse transcription assay showed a high quantity of tax/rex messenger RNA in the proliferating lining cells. Based on these features, we classified this case as an atypical manifestation of HTLV‐I‐associated arthropathy associated with fibrinoid nodules resulting from chronic tenosynovitis.
T cell receptor α‐chain and β‐chain junctional region homology in clonal CD3+, CD8+ T lymphocyte expansions in Felty'S syndrome
Authors: Bowman Simon J. , Hall Margaret A. , Panayi Gabriel S. , Lanchbury Jerry S.
Published: February 2007

Objective. Up to 42% of patients with Felty's syndrome (FS) have peripheral blood expansions of CD3+, CD8+ large granular lymphocytes (LGLs). The aim of this study was to determine whether the T cell receptor (TCR) α‐ and β‐chain sequences of these expansions from different patients have features in common that would support the hypothesis of an antigen‐driven process.

Methods. Extraction of RNA from peripheral blood lymphocytes followed by synthesis of complementary DNA, inverse polymerase chain reaction (PCR) with TCR‐specific primers, bacteriophage transformation, and sequencing of PCR products.

Results. Structural analysis of TCR β‐chain usage in such patients demonstrated a junctional region motif comprising the amino acids ‐LG‐ or ‐RG‐ in 7 of 14 clonal sequences and the motif ‐GXG‐ in 8 of 14. A biased α‐chain junctional region usage of a hydrophobic and/or basic amino acid at position 2 was seen in 5 of 8 expanded sequences. These features differed significantly from control sequences.

Conclusion. Given current models of TCR–peptide–major histocompatibility complex interaction, these observations are consistent with an antigen‐driven, rather than a superantigen‐driven, process in at least a subgroup of patients with FS.
Perinuclear antineutrophil cytoplasmic antibody in rheumatoid arthritis. A marker of severe disease with associated nephropathy
Authors: Mustila Anu , Korpel Markku , Mustonen Jukka , Helin Heikki , Huhtala Heini , Soppi Esa , Pasternack Amos , Miettinen Ari
Published: February 2007

Objective. To evaluate the clinical significance of antineutrophil cytoplasmic antibodies (ANCA) in patients with rheumatoid arthritis (RA), and especially in those with clinically suspected or histologically proven nephropathy.

Methods. A total of 246 RA patients with (n = 149) and without (n = 97) histologically proven (n = 99) or clinically suspected (n = 50) nephropathy were studied for the presence of ANCA by immunofluorescence and enzyme immunoassay.

Results. Perinuclear ANCA (pANCA) were found in 52 (21%) of the 246 patients. Patients with clinically suspected or histologically proven nephropathy were significantly more frequently positive for pANCA (30% versus 7%; P < 0.00005) and had significantly higher mean (±SD) pANCA log titers (103 ± 5.6 versus 27 ± 3.0; P = 0.0011) than patients without clinically evident renal disease. Positivity for pANCA was associated with clinical and laboratory findings indicating severe basic disease and increased inflammatory activity. Irrespective of this association, pANCA acted as a significant and independent predictor of RA‐associated nephropathy.

Conclusion. Perinuclear ANCA in RA indicate severe disease with increased inflammatory activity. There is an especially strong and independent association between pANCA and RA‐associated nephropathy.
Abnormal homocysteine metabolism in rheumatoid arthritis
Authors: Roubenoff Ronenn , Dellaripa Paul , Nadeau Marie R. , Abad Leslie W. , Muldoon Bernadette A. , Selhub Jacob , Rosenberg Irwin H.
Published: February 2007

Objective. To assess total homocysteine (tHcy) metabolism in patients with rheumatoid arthritis (RA).

Methods. Assessments were performed to determine the fasting levels of tHcy and the increase in tHcy in response to methionine (Met) challenge in blood samples from 28 patients with RA and 20 healthy age‐matched control subjects.

Results. Fasting levels of tHcy were 33% higher in the RA patients than in the control subjects (mean ± SD 11.7 ± 1.5 nmoles/ml versus 8.8 ± 1.1 nmoles/ml; P < 0.01). Four hours after Met challenge, the increase in plasma tHcy levels (ΔtHcy) was higher in the RA patients (20.9 ± 10.4 nmoles/ml) than in the control subjects (15.5 ± 1.6 nmoles/ml) (P < 0.02). In a subgroup analysis, the ΔtHcy in patients taking methotrexate (12.9 ± 2.2 nmoles/ml) did not differ from that in the control group, while the ΔtHcy in patients not taking methotrexate (25.3 ± 1.7 nmoles/ml) was significantly higher (P < 0.0001).

Conclusion. Elevated tHcy levels occur commonly in patients with RA, and may explain some of the increased cardiovascular mortality seen in such patients. Studies of the prevalence and mechanism of hyperhomocysteinemia in RA are warranted.
Thrombosis in primary antiphospholipid syndrome. A pivotal role for monocyte tissue factor expression
Authors: Cuadrado Maria José , López‐Pedrera Charo , Khamashta Munther A. , Camps Maria Teresa , Tinahones Francisco , Torres Antonio , Hughes Graham R. V. , Velasco Francisco
Published: February 2007

Objective. The antiphospholipid syndrome (APS) is a disorder of recurrent thrombosis, pregnancy loss, and thrombocytopenia associated with the production of anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC). The mechanisms of thrombus formation remain unknown. Tissue factor (TF), an inducible cell glycoprotein, is a major initiator of coagulation in vivo. The present study was therefore undertaken to investigate TF expression and procoagulant activity on monocytes from patients with primary APS and its correlation with thrombotic events.

Methods. Three groups of patients were studied: group 1 comprised 23 primary APS patients with thrombosis, group 2 consisted of 10 primary APS patients without thrombosis, and group 3 contained 20 patients with thrombosis but without antiphospholipid antibodies. Twenty age‐ and sex‐matched healthy blood donors were used as controls (group 4). Anticardiolipin antibodies were measured by enzyme‐linked immunosorbent assay (ELISA) and LAC by standard methodology. Cell surface expression of TF on monocytes was assessed by flow cytometry. The amount of TF in cell lysates (TFAg) and soluble TFAg plasma levels were analyzed by ELISA, and the TF‐related procoagulant activity (PCA‐TF) on intact cells and cell lysates by a chromogenic assay. Levels of the cytokines that influence TF production, i.e., tumor necrosis factor α (TNFα) and interleukin‐1β (IL‐1β), were determined by ELISA.

Results. Cell surface expression of TF was increased in group 1 (mean ± SEM 50.2 ± 4% positive cells) compared with group 2 (14.6 ± 1.6%), group 3 (16.8 ± 3.7%), and group 4 (14.1 ± 1.6%). TFAg levels were also elevated in group 1 (215.8 ± 11.2 pg/106) compared with group 2 (150.8 ± 15.2), group 3 (101.4 ± 14.8), and group 4 (80.32 ± 5.5). PCA‐TF on intact cells and cell lysates was significantly increased in group 1 (148.8 ± 16.3 units/105 lysate cells, compared with 54.5 ± 11.5, 38.6 ± 9.7, and 22.5 ± 3.1 in groups 2, 3, and 4, respectively). Among group 1 patients, there was a significant increase in the degree of TF expression in those positive for IgG aCL, but not in those positive for IgM aCL or LAC. TNFα and IL‐1β plasma levels did not differ significantly between any of the groups.

Conclusion. These results suggest that monocyte TF expression is directly involved in the pathogenesis of thrombotic complications in patients with the primary APS.
The synovial expression and serum levels of interleukin‐6, interleukin‐11, leukemia inhibitory factor, and oncostatin m in rheumatoid arthritis
Authors: Okamoto Hideyuki , Yamamura Masahiro , Morita Yoshitaka , Harada Seishi , Makino Hirofumi , Ota Zensuke
Published: February 2007

Objective. To determine the expression of interleukin‐6 (IL‐6), IL‐11, leukemia inhibitory factor (LIF), and oncostatin M (OSM) and their major cellular sources in the joints of rheumatoid arthritis (RA) patients, as well as the correlation of circulating levels of these IL‐6‐type cytokines and C‐reactive protein (CRP).

Methods. Messenger RNA (mRNA) and protein levels for IL‐6, IL‐11, LIF, and OSM were determined by using reverse transcription‐polymerase chain reaction and enzyme‐linked immunosorbent assay, respectively.

Results. Cells isolated from the synovium of RA patients expressed mRNA for IL‐6, IL‐11, LIF, and OSM at higher levels than did synovial cells from osteoarthritis (OA) patients, and spontaneously released greater quantities of these proteins in culture. Fibroblast cell lines derived from RA synovium were able to produce IL‐6, IL‐11, and LIF, but not OSM, when stimulated with IL‐1 and tumor necrosis factor α. OSM was found to be produced spontaneously by synovial tissue macrophages. IL‐6, IL‐11, LIF, and OSM were present in synovial fluid from the RA patients; levels of IL‐6, LIF, and OSM were present in significantly greater quantities in RA patients than in OA patients. However, only IL‐6 was significantly elevated in the serum of RA patients and correlated with the serum CRP level, while other IL‐6‐type cytokines were not detected.

Conclusion. IL‐6, IL‐11, LIF, and OSM are all produced in large amounts at the site of disease activity, but IL‐6 derived from synovial fibroblasts may be the major hormone‐like mediator that induces the hepatic synthesis of acute‐phase proteins in RA.
In vivo mechanisms for the inhibition of T lymphocyte activation by long‐term therapy with tacrolimus (FK‐506)
Authors: Suzuki Noboru , Kaneko Sakae , Ichino Motohide , Mihara Shoji , Wakisaka Sueshige , Sakane Tsuyoshi
Published: February 2007

Objective. To examine the in vivo mechanisms of suppression of T lymphocyte function in patients with Behçet's disease (BD) undergoing long‐term treatment with tacrolimus (FK‐506).

Methods. Intracellular proteins were analyzed by immunoprecipitation and Western blotting. Messenger RNA expression was studied by a polymerase chain reaction—based technique.

Results. Interleukin‐2 production was suppressed in patients treated with tacrolimus. This suppression was found to be due to inhibition of interactions between activated calcineurin (Cn) and nuclear factor of activated T cells (NF‐AT), inhibition of cleavage of the autoinhibitory domain of the CnA subunit, and inhibition of heterodimer formation by CnA and CnB sub‐units, resulting in the absence of NF‐AT in nuclei of the T cells. We found that T lymphocytes in some BD patients treated with tacrolimus had reduced amounts of FK‐506 binding protein (FKBP) in their cytoplasm.

Conclusion. Tacrolimus reduces the Cn activity of T cells in vivo by the cumulative effects of several distinct mechanisms. It is plausible that reduced amounts of FKBP may be associated with diminished clinical efficacy in some BD patients receiving prolonged treatment with tacrolimus.
Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes. A mechanism for methotrexate‐induced nodulosis in rheumatoid arthritis
Authors: Merrill Joan T. , Shen Christine , Schreibman David , Coffey Dan , Zakharenko Olga , Fisher Robert , Lahita Robert G. , Salmon Jane , Cronstein Bruce N.
Published: February 2007

Objective. To determine why methotrexate (MTX) exacerbates rheumatoid nodules in some patients, despite the effective suppression of synovial inflammation.

Methods. Phorbol myristate acetate (PMA)‐induced differentiation of monocytes into multinucleated giant cells was used as an in vitro model to study the effects of adenosine on nodulosis.

Results. MTX at 200‐2,000 nM or the adenosine A1 agonist N5‐cyclopentyl adenosine (CPA) (10−12 to 10‐9 M) or the A2 antagonist 3,7‐dimethyl‐1‐propargylxanthine markedly enhanced giant cell formation, whereas the adenosine A1 antagonist 8‐cyclopentyl‐dipropylxanthine completely reversed these effects. PMA, CPA, and MTX induced adenosine release by cultured monocytes at concentrations consistent with those associated with predominantly A1 effects. Furthermore, surface expression of A1 receptors was found to remain unchanged on the differentiating cells throughout the culture period.

Conclusion. Agents that inhibit adenosine A1 receptors might be useful in the treatment of MTX‐induced rheumatoid nodulosis, while still potentiating the A2‐mediated antiinflammatory effects of MTX on synovitis.
Mechanisms of drug‐induced lupus. III. Sex‐specific differences in T cell homing may explain increased disease severity in female mice
Authors: Yung Raymond , Williams Robert , Johnson Kent , Phillips Carrie , Stoolman Lloyd , Chang Sandra , Richardson Bruce
Published: February 2007

Objective. To determine if sex‐specific differences in lymphocyte trafficking could contribute to increased disease severity in female mice.

Methods. A lupus‐like disease was induced by injecting male and female mice with procainamide‐treated T cell clones. Trafficking was examined by labeling the injected cells with 51Cr or 5‐chloromethylfluorescein diacetate.

Results. Females developed more autoimmune liver disease and greater titers of anti‐DNA antibodies than did males, and 2‐7 times more cells accumulated in the female spleens. Splenectomy prevented the development of autoantibodies and renal and liver disease. Oophorectomy decreased the splenic homing, autoantibody titer, and liver disease severity, to levels found in males.

Conclusion. T cells traffic differently to the spleen in male and female mice, and the spleen appears to be essential in the disease process. This suggests that differences in T cell homing could contribute to sex‐specific disease severity in this murine model, and also possibly in human disease.
Human chondrocyte expression of growth‐arrest‐specific gene 6 and the tyrosine kinase receptor axl. Potential role in autocrine signaling in cartilage
Authors: Loeser Richard F. , Varnum Brian C. , Carlson Cathy S. , Goldring Mary B. , Liu Edison T. , Sadiev Sagypash , Kute Tim E. , Wallin Reidar
Published: February 2007

Objective. To determine if human articular chondrocytes express the axl tyrosine kinase receptor and its ligand Gas‐6, a protein product of growth‐arrest‐specific gene 6, and to determine if Gas‐6 and axl function in the regulation of chondrocyte growth and survival.

Methods. The presence of Gas‐6 and axl was examined in situ in human articular cartilage by immunohistochemistry and in vitro in cell culture studies using primary human chondrocytes and immortalized human chondrocytes. The ability of recombinant Gas‐6 to mediate adhesion of chondrocytes and to stimulate chondrocyte axl phosphorylation was determined. Studies of the role of Gas‐6 and axl in cell proliferation and survival were also performed.

Results. Both Gas‐6 and axl were detected in cartilage by immunohistochemical staining. Gas‐6 and axl messenger RNA (mRNA) and protein were also detected in cultures of primary and immortalized human chondrocytes. Compared with cells cultured in medium containing 10% serum, Gas‐6 mRNA levels were increased in immortalized chondrocytes cultured in serum‐free medium, while axl expression decreased. Chondrocytes attached to Gas‐6‐coated plastic, and the attachment was blocked by a soluble Ig fusion protein containing the axl extracellular domain. Recombinant human Gas‐6 and serum‐free conditioned medium from primary and immortalized human chondrocyte cultures stimulated chondrocyte axl tyrosine phosphorylation. A mitogenic effect was noted both when immortalized chondrocytes were stimulated with recombinant Gas‐6 or when they were made to overexpress axl by transfection. Addition of recombinant Gas‐6 to serum‐free medium resulted in increased survival of primary chondrocytes cultured at low density in agarose.

Conclusion. These findings present evidence for an autocrine signaling pathway in cartilage involving Gas‐6 and the axl tyrosine kinase adhesion receptor. Stimulation of axl by Gas‐6 may play an important role in the control of chondrocyte growth and survival.
Resource utilization and cost of care for rheumatoid arthritis and osteoarthritis in a managed care setting. The importance of drug and surgery costs
Authors: Lanes Stephan F. , Lanza Lee L. , Radensky Paul W. , Yood Robert A. , Meenan Robert F. , Walker Alexander M. , Dreyer Nancy A.
Published: February 2007

Objective. To describe the frequency and costs of medical services for patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in a managed care setting.

Methods. Individual utilization records of medical and pharmacy services for OA and RA patients were obtained from a group‐model health maintenance organization (HMO). Estimates were made for costs of drugs and medical services for arthritis from July 1, 1993 to June 30, 1994 using Medicare reimbursement schedules and average wholesale drug prices. Calculated rates for each population were expressed as counts of events or as dollars per person‐year.

Results. The average individual cost rate of arthritis‐related care for 365 RA patients was $2,162 per year, and the total cost of RA care to the HMO was $703,053. Prescription medications accounted for 62% ($436,440) of the total cost of RA care, while ambulatory care accounted for 21% ($150,938), and hospital visits accounted for 16% ($115,674). With regard to 10,101 OA patients, the average individual cost rate was $543 per year, and total cost to the HMO was $4,728,425. Hospital care accounted for 46% ($2,170,890) of the total cost of OA care, medications accounted for 32% ($1,509,637), and ambulatory care accounted for 22% ($1,047,898).

Conclusion. RA care, in the setting of this study, was characterized by intensive treatment, especially frequent use of medications that were delivered to most patients. Although the cost of RA care per patient was high, cost to the managed care provider was relatively low, owing to the rarity of RA. OA care tended to be infrequent, and the largest component of cost was hospital care for a small proportion of patients (5%). Owing to the greater prevalence of OA, care of OA was nearly 7 times more costly to the managed care provider than was care of RA.
Catastrophic antiphospholipid syndrome. Response to repeated plasmapheresis over three years
Authors: Neuwelt C. Michael , Daikh David I. , Linfoot John A. , Pfister David A. , Young Robyn G. , Webb Ronald L. , London Stuart S. , Asherson Ronald A.
Published: February 2007

The catastrophic antiphospholipid syndrome (CAPS) is rare and usually fatal. In this report, we describe an unusual patient who, 31 years after experiencing an atypical preeclampsia‐eclampsia presentation known today as the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), developed CAPS, which seemed to complicate a diagnosis of primary antiphospholipid syndrome. She responded to repeated plasmapheresis over 3 years. Anticoagulants, corticosteroids, intravenous gamma globulin, and intravenous cyclophosphamide had all failed to halt the progression of CAPS, but repeated plasmapheresis not only halted the condition, but it led to the reversal of a leukoencephalopathy. The relationship between HELLP syndrome and CAPS is discussed, and possible patho‐genetic mechanisms that explain the efficacy of repeated plasmapheresis in this setting are suggested. It is postulated that perhaps plasmapheresis, through removal of cytokines or other mediators, disrupts the interaction between phospholipid‐protein complexes and endothelial cells. Repeated plasmapheresis should be considered in the most refractory cases of CAPS when more conventional treatment regimens have failed.
Sensitivity and positive predictive value of medicare part B physician claims for rheumatologic diagnoses and procedures
Authors: Katz Jeffrey N. , Barrett Jane , Liang Matthew H. , Bacon Aane M. , Kaplan Herbert , Kieval Raphael I. , Lindsey Stephen M. , Roberts W. Neal , Sheff Daniel M. , Spencer Robert T. , Weaver Arthur L. , Baron John A.
Published: February 2007

Objective. To examine the sensitivity and positive predictive value of Medicare physician claims for select rheumatic conditions managed in rheumatology specialty practices.

Methods. Eight rheumatologists in 3 states abstracted 378 patient office records to obtain information on diagnosis and office procedures. The Medicare Part B physician claims for these patient visits were obtained from the Health Care Financing Administration. The sensitivity of the claims data for a specific diagnosis was calculated as the proportion of all patients whose office records for a particular visit documented that diagnosis and who also had physician claims for that visit which identified that diagnosis. The positive predictive value was evaluated in a separate sample of 331 patient visits identified in Medicare physician claims. The positive predictive value of the claims data for a specific diagnosis was calculated as the proportion of patients with that diagnosis coded in the claims for a particular visit who also had the diagnosis documented in the medical record for that visit.

Results. Ninety percent of abstracted office medical records were matched successfully with Medicare physician claims. The sensitivity of the Medicare physician claims was 0.90 (95% confidence interval [CI] 0.85–0.95) for rheumatoid arthritis (RA), 0.85 (95% CI 0.73–0.97) for systemic lupus erythematosus (SLE), and 0.85 (95% CI 0.78–1.0) for aspiration or injection procedures. The sensitivity for osteoarthritis (OA) of the hip or knee was ≤0.50 if 5‐digit codes specifying anatomic site were required. The sensitivity for fibromyalgia (FM) was 0.48 (95% Cl 0.28–0.68). The positive predictive values were at least 0.90 for RA, SLE, and aspiration or injection procedures. Positive predictive values for FM and the 5‐digit site‐specific codes for OA of the knee were 0.83 (95% CI 0.66–1.0) and 0.88 (95% CI 0.75–1.0), respectively, while the positive predictive value of the 5‐digit site‐specific codes for OA of the hip was zero (95% CI 0–0.26). The positive predictive value of OA at any site was 0.83 (95% CI 0.76–0.90).

Conclusion. In specialty practice, Medicare physician claims had high sensitivity and positive predictive value for RA, SLE, OA without specification of anatomic site, and injection or aspiration procedures. The claims had lower sensitivity and predictive value for FM and for OA of the hip. The accuracy of Medicare physician claims for other conditions and in the primary care setting requires further investigation.
Heterotopic ossification in the setting of neuromuscular blockade
Authors: Goodman Thomas A. , Merkel Peter A. , Perlmutter Gary , Doyle Mittie Kelleher , Krane Stephen M. , Polisson Richard P.
Published: February 2007

Objective. Heterotopic ossification (HO) is a disorder characterized by the formation of new bone in tissue that does not ossify under normal conditions. We report a series of 6 cases in which HO occurred in the setting of adult respiratory distress syndrome (ARDS). We wished to show that HO can occur after neuromuscular blockade and that these cases might provide additional evidence that HO is influenced by neural mechanisms.

Methods. Cases of HO were selected from the consultation services at the Massachusetts General Hospital and the Brigham and Women's Hospital. Affected patients all had ARDS and had been treated with a neuromuscular blocking agent. Patients with a history of stroke, burn, head trauma, spinal cord injury, or joint replacement were excluded from this study.

Results. Heterotopic bone appeared around large joints in a pattern identical to that seen in patients with paralysis, traumatic brain injury, severe burns, or trauma. New bone formation was self‐limited over a period of 1–2 years. Alkaline phosphatase and technetium bone scan were sensitive ways of detecting early disease and monitoring disease activity. Medical therapies had limited benefit. Surgical excision of mature new bone appeared to be the only definitive therapy.

Conclusion. Neuromuscular blockade in the setting of ARDS appears to be an important risk factor for the development of HO. The similarity of these cases of HO occurring in patients with brain or spinal cord injury raises the possibility that neural mechanisms may be important in the pathogenesis of this disease. Whether the type of neuromuscular blocking agent and the duration of use are important determinants of disease severity remains to be determined.
Deficient Fas ligand expression by synovial lymphocytes from patients with rheumatoid arthritis
Authors: Cantwell Mark J. , Hua Tinh , Zvaifler Nathan J. , Kipps Thomas J.
Published: February 2007

Objective. To examine the expression and function of CD95 (Fas) and its ligand in rheumatoid arthritis (RA).

Methods. We used flow cytometry and reverse transcriptase‐polymerase chain reaction methods to assess lymphocyte expression of CD95 and its ligand. We also examined whether lymphocytes could undergo Fas‐mediated apoptosis with anti‐CD95 monoclonal antibody (MAb) or human Fas ligand‐expressing fibroblasts, and if synovial fluid contained a soluble factor(s) that could inhibit such interactions. Finally, we determined whether anti‐CD3 MAb could induce synovial T cells to express the Fas ligand in vitro.

Results. Nearly all RA synovial fluid or synovial tissue lymphocytes expressed CD95 and could be induced to undergo apoptosis by CD95 crosslinking. We did not detect a soluble inhibitor in RA synovial fluid that could account for the survival of CD95+ synovial cells in vivo. Instead, we detected little or no expression of Fas ligand by RA synovial lymphocytes. However, we could induce such cells to express Fas ligand with anti‐CD3 MAb or phorbol ester and ionomycin in vitro.

Conclusion. There is ineffective clearance of activated cells in the RA joint due to deficient expression of the Fas ligand.
Suppression of collagen‐induced arthritis through adenovirus‐mediated transfer of a modified tumor necrosis factor α receptor gene
Authors: Le Christine H. , Nicolson A. Graham , Morales Alejandro , Sewell K. Lea
Published: February 2007

Objective. To evaluate the efficacy of systemic and intraarticular adenoviral transfer of a modified tumor necrosis factor α receptor (TNFαR) gene and its expression in rat collagen‐induced arthritis (CIA).

Methods. Rats with CIA received injections of replication‐deficient adenovirus containing either a TNFα inhibitor (TNFI) gene or a control β galactosidase (β‐gal) gene. The TNFI gene codes for a fusion protein consisting of the human 55‐kd TNFαR and a mouse IgG heavy chain. Successful gene transfer was determined by serum TNFαR measurements and by histologic examination of injected joints with in situ blue staining.

Results. Serum TNFαR levels were detectable for 8 days following systemic TNFI gene transfer. CIA severity was significantly suppressed by TNFI gene transfer, both prior to and following arthritis onset (P = 0.0001, by repeated‐measures 2‐factor analysis of variance). Direct synovial TNFI gene transfer was successful, but induced an inflammatory response without any net TNFI benefit.

Conclusion. Systemic adenoviral‐mediated transfer of the TNFI gene suppressed CIA during its transitory expression. Intraarticular gene transfer was limited by an adenoviral synovitis that was not overcome by delivery of the TNFI gene. TNFI is an excellent protein candidate for further therapeutic study.
Complexed plasma elastase as an in vivo marker for leukocyte activation in antineutrophil cytoplasmic antibody‐associated vasculitis
Authors: Haubitz M. , Schulzeck P. , Schellong S. , Schulze M. , Koch K. M. , Brunkhorst R.
Published: February 2007

Objective. It has been postulated that antineutrophil cytoplasmic antibody (ANCA)‐induced degranulation of primed granulocytes and monocytes is involved in the pathogenesis of ANCA‐associated vasculitis. Since elastase is the major lysosomal protein released during leukocyte degranulation, we investigated cell activation in vivo in patients with ANCA‐associated vasculitis by determining complexed plasma elastase levels.

Methods. Plasma elastase complexed with α1‐antitrypsin was measured in 20 patients with ANCAassociated vasculitis, using an immunoactivation assay. In parallel, C‐reactive protein (CRP) and ANCA levels were determined and clinical disease activity was assessed.

Results. Complexed elastase levels were significantly elevated in patients with ANCA‐associated vasculitis who had not received immunosuppressive therapy (mean ± SD 71.5 ± 22.6 μg/liter), compared with healthy volunteers (12.2 ± 11.4 μg/liter; P < 0.001). Elastase decreased significantly after 2 weeks (46.5 ± 26.8 μg/liter; P < 0.01) and further after 8–10 weeks of immunosuppressive treatment (28.1 ± 13.4 μg/liter; P < 0.02), in correlation with decreasing vasculitis activity. Concomitantly, ANCA titers and CRP levels decreased.

Conclusion. These data support the theory that, by the release of lysosomal proteinases, leukocyte activation may be involved in the pathogenesis of ANCAassociated vasculitis. In addition, plasma elastase may be used as a marker for disease activity.
Investigation of the association of the CRTM and CRTL1 genes with radiographically evident osteoarthritis in subjects from the rotterdam study
Authors: Meulenbelt I. , Bijkerk C. , De Wildt S. C. M. , Miedema H. S. , Valkenburg H. A. , Breedveld F. C. , Pols H. A. P. , Te Koppele J. M. , Sloos V. F. G. , Hofman A. , Slagboom P. E. , Van Duijn C. M.
Published: February 2007

Objective. To investigate whether radiographically evident osteoarthritis (ROA) in 55–65‐year‐old men and women is associated with specific alleles or genotypes of the cartilage matrix protein (CRTM) and cartilage link protein (CRTLl) genes.

Methods. Cases were selected from a populationbased study on the presence of ROA of the knee or hip. Further radiographic analysis included scoring for spine and hand ROA. Controls, selected from the same population, were free of ROA in all joints.

Results. The CRTM locus was significantly associated with hip ROA in men (odds ratio 0.50, 95% confidence interval 0.26–0.95). A significant association between ROA and the CRTLl gene was not observed.

Conclusion. These results suggest that the CRTM locus may play a role in the sex‐ and joint site‐specific pattern of ROA development.