1309

International Consensus Statement on Preliminary Classification Criteria for Definite Antiphospholipid Syndrome: Report of an International Workshop

Wendell A. Wilson, Azzudin E. Gharavi, Takao Koike, Michael D. Lockshin, D. Ware Branch, Jean-Charles Piette, Robin Brey, Ronald Derksen, E. Nigel Harris, Graham R. V. Hughes, Douglas A. triplett, and Munther A. Khamashta

1312

Review: Stiff-Man Syndrome: From the Bedside to the Bench

Simon M. Helfgott

1321

In Memoriam: Richard H. Freyberg, MD, 1904-1999

Charles L. Christian

1322  

Pharmacokinetics, Safety, and Efficacy of Combination treatment with Methotrexate and Leflunomide in Patients with Active Rheumatoid Arthritis

Michael E. Weinblatt, Joel M. Kremer, Jonathan S. Coblyn, Agnes L. Maier, Simon M. Helfgott, Martin Morrell, Vilma M. Byrne, Mari V. Kaymakcian, and Vibeke Strand  

In a substantial number of patients with active RA, the disease fails to respond adequately to methotrexate, a purine synthesis inhibitor that is widely used in the treatment of RA. This study indicates that the addition of leflunomide, an inhibitor of de novo pyrimidine synthesis, to the methotrexate regimen may result in improvement of disease activity, is relatively safe, and results in no significant pharmacokinetic interactions between methotrexate and leflunomide. Based on this initial clinical experience, the combination of methotrexate and leflunomide warrants further study.

1329  

HLA-DRB1 Alleles Associated with Susceptibility or Resistance to Rheumatoid Arthritis, Articular Deformities, and Disability in Mexican Americans

Inmaculada Del Rincon and Agust|fin Escalante  

This report describes the influence of DRB1 alleles on the susceptibility to and severity of RA among Mexican Americans, an understudied US population. A strong association was found between DRB1 alleles containing the shared epitope sequences and RA susceptibility and severity. In addition, the results showed a protective influence of DRB1*08.

1339  

Estimating the Incidence of Rheumatoid Arthritis: trying to Hit a Moving Target?

Nicola Wiles, Deborah P. M. Symmons, Beverley Harrison, Elizabeth Barrett, Jennifer H. Barrett, David G. I. Scott, and Alan J. Silman  

This report takes a community-based cohort of patients who developed inflammatory polyarthritis in 1990 and applies the 1987 American College of Rheumatology (formerly, the American Rheumatism Association) criteria in a variety of ways to estimate the incidence of RA. The estimates differ substantially depending on the length of time from symptom onset in which notification of patients to the arthritis register was allowed, and whether the criteria were applied cumulatively. Accurate estimation of RA incidence requires the long-term followup of patients who initially have undifferentiated inflammatory polyarthritis.

1347 

Strong Association of Autoantibodies to Human Nuclear Lamin B1 with Lupus Anticoagulant Antibodies in Systemic Lupus Erythematosus

Jean-Luc Senecal, Joyce Rauch, Tamara Grodzicky, Jean-Pierre Raynauld, Imad Uthman, Arnulfo Nava, Martin Guimond, and Yves Raymond  

The results of this study show that high titers of autoantibodies to nuclear lamin B1 are highly specific for a subset of patients with SLE, characterized by the presence of LAC antibodies. The frequency of thrombosis in SLE patients expressing both LAC and anti-lamin B1 autoantibodies was similar to that in patients without LAC. However, patients expressing LAC without anti-lamin B1 had a significantly greater frequency of thrombosis. The presence of LAC without anti-lamin B1 may define a subset of SLE patients at greater risk for thrombosis.

1354  

Sensitivity of the Systemic Lupus Erythematosus Disease Activity Index, British Isles Lupus Assessment Group Index, and Systemic Lupus Activity Measure in the Evaluation of Clinical Change in Childhood-Onset Systemic Lupus Erythematosus

Hermine I. Brunner, Brian M. Feldman, C. Bombardier, and Earl D. Silverman  

This study investigates the validity of disease activity measures in assessing the response to treatment in children with SLE. The SLEDAI, BILAG, and SLAM have all been previously validated for use in adults with SLE. This study provides evidence that all 3 measures are responsive in the assessment of clinical change in childhood-onset SLE as well.

1361  

Effectiveness of Exercise Therapy in Patients with Osteoarthritis of the Hip or Knee: A Systematic Review of Randomized Clinical trials

Margriet E. van Baar, Willem J. J. Assendelft, Joost Dekker, Rob A. B. Oostendorp, and Johannes W. J. Bijlsma  

In the treatment guidelines of the American College of Rheumatology, exercise therapy is recommended for patients with OA of the hip or knee. Since the publication of the guidelines, several new randomized clinical trials have been published. This report presents a systematic review of the available evidence on exercise therapy in OA of the hip and knee, applying presently required review methodology. There is sufficient evidence of beneficial short-term effects of exercise therapy, and it seems to be indicated for patients with mild-to-moderate OA of the hip or knee. Further research is needed to expand on this observation.

1370  

tramadol Allows Reduction of Naproxen Dose Among Patients with Naproxen-Responsive Osteoarthritis Pain: A Randomized, Double-Blind, Placebo-Controlled Study

Thomas J. Schnitzer, Marc Kamin, and William H. Olson  

Many patients with painful OA cannot tolerate higher doses of nonsteroidal antiinflammatory drugs (NSAIDs) or are at risk for serious NSAID-related adverse events. This risk is decreased when lower NSAID doses are used. In this study, tramadol, 200 mg/day, allowed for a significant reduction ([lt]75%) in the daily dosage of naproxen in patients who achieved good pain relief while taking naproxen, 1,000 mg/day.

1378  

Osteoarthritis and Risk of Falls, Rates of Bone Loss, and Osteoporotic Fractures

Nigel K. Arden, Michael C. Nevitt, Nancy E. Lane, L. Robert Gore, Marc C. Hochberg, Jean C. Scott, Alice R. Pressman, and Steven R. Cummings, for the Study of Osteoporotic Fractures Research Group  

Low bone mineral density (BMD) is associated with an increased risk of fracture, and the measurement of BMD is the most commonly used tool to assess fracture risk in clinical practice. Patients with OA have an increased BMD compared with controls and were thought to be at a lower risk of fracture. This study demonstrates that the increased BMD in patients with OA is not fully translated into a reduced risk of fracture, and should therefore be interpreted with caution.

1386  

No Benefit of Long-Term Ciprofloxacin treatment in Patients with Reactive Arthritis and Undifferentiated Oligoarthritis: A Three-Month, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study

Joachim Sieper, Claas Fendler, Sigrid Laitko, Helmut Sorensen, Christel Gripenberg-Lerche, Falk Hiepe, Rieke Alten, Wolfgang Keitel, Annemarie Groh, Jaakko Uksila, Ulrich Eggens, Kaisa Granfors, and Jurgen Braun 

This study investigates the important question of whether antibiotics are effective in a large group of patients with ReA or possible ReA (undifferentiated oligoarthritis). Long-term treatment of ReA with ciprofloxacin is not effective; however, it might be useful in a subgroup of patients who have Chylamydia-induced arthritis.

1397 

The Association Between Tender Points, Psychological Distress, and Adverse Childhood Experiences: A Community-Based Study

John McBeth, Gary J. Macfarlane, Sidney Benjamin, Stella Morris, and Alan J. Silman  

The presence of tender points in a psychologically distressed population sample was found to be strongly associated with fatigue, illness behavior, and reports of adverse experiences that occurred in childhood. This observation may explain susceptibility to fibromyalgia.

1405 

Fat Conversion of Femoral Marrow in Glucocorticoid-treated Patients: A Cross-Sectional and Longitudinal Study with Magnetic Resonance Imaging

B. C. Vande Berg, J. Malghem, F. E. Lecouvet, J.-P. Devogelaer, B. Maldague, and F. A. Houssiau  

This report describes the femoral bone marrow changes that occur in corticosteroid-treated patients evaluated cross-sectionally and longitudinally by magnetic resonance imaging. By demonstrating that bone marrow fat conversion is commensurate with steroid intake, the data presented here provide additional insights into the deleterious effects of steroid on bones and, more specifically, into the pathogenesis of osteonecrosis, a major concern in patients given high-dose steroid therapy.

1412  

Dendritic Cell Presentation of Antigens from Apoptotic Cells in a Proinflammatory Context: Role of Opsonizing Anti-[gb]2-Glycoprotein I Antibodies

Patrizia Rovere, Maria Grazia Sabbadini, Cristina Vallinoto, Umberto Fascio, Maria Rescigno, Mariacristina Crosti, Paola Ricciardi-Castagnoli, Genesio Balestrieri, Angela Tincani, and Angelo A. Manfredi  

This study verified that opsonization of apoptotic cells by anti-[gb]2GPI facilitated presentation of epitopes from internalized apoptotic cells to major histocompatibility complex class II-restricted, but not to class I-restricted, T lymphocytes, and that this event was accompanied by secretion of interleukin-1[gb], tumor necrosis factor [ga], and interleukin-10 in an autocrine/paracrine manner. Opsonization by anti-[gb]2GPI therefore influences the outcome of the disposal of low numbers of apoptotic cells by dendritic cells. Moreover, the results imply that soluble factors bound to apoptotic cells modulate their immunogenicity.

1421  

Monoclonal Anti-Endothelial Cell Antibodies from a Patient with Takayasu Arteritis Activate Endothelial Cells from Large Vessels

Miri Blank, Ilan Krause, Tzipora Goldkorn, Sonja Praprotnik, Avi Livneh, Pnina Langevitz, Ella Kaganovsky, Sara Morgenstern, Shlomo Cohen, Vivian Barak, Amiram Eldor, Babette Weksler, and Yehuda Shoenfeld  

A panel of monoclonal anti-endothelial cell antibodies (mAECA) was generated from peripheral blood lymphocytes of a patient with Takayasu arteritis. Activity against macrovascular and microvascular EC antigens was detected, and it was determined which of the monoclonal antibodies shared the same EC epitope binding as the total IgG-AECA from the patient. The 6 mAECA selected showed high activity against macrovascular EC but not against microvascular EC. The findings suggest that AECA may directly stimulate EC in Takayasu arteritis, and may therefore play a pathogenic role in the development of the vasculopathy in the disease.

1433  

Stable transfection of Human Fetal Chondrocytes with a Type II Procollagen Minigene: Expression of the Mutant Protein and Alterations in the Structure of the Extracellular Matrix In Vitro

R. M. Dharmavaram, G. Liu, R. S. Tuan, D. G. Stokes, and S. A. Jimenez  

A type II procollagen minigene that lacks exons 16-27 was stably transfected into human fetal epiphyseal chondrocytes in vitro. A shortened type II collagen encoded by the transfected minigene was biosynthesized and produced in the cultures of transfected cells. The study shows the feasibility of performing stable transfections of gene constructs into human chondrocytes under conditions that allow the preservation of the chondrocyte-specific phenotype. Stable transfection of human chondrocytes is a crucial step for gene therapy of various heritable and acquired cartilage diseases.

1443  

Reexpression of Type IIA Procollagen by Adult Articular Chondrocytes in Osteoarthritic Cartilage

Thomas Aigner, Yong Zhu, Howard H. Chansky, Frederick A. Matsen, III, William J. Maloney, and Linda J. Sandell  

The results of this study demonstrate that OA chondrocytes reexpress the splice variant of type II collagen (containing the cysteine-rich NH2 propeptide), which is characteristic of chondroprogenitor cells during skeletal development. This splice variant of type II collagen is absent in normal adult articular cartilage.

1451  

Identification of Multiple, Differentially Expressed Messenger RNAs in Dermal Fibroblasts from Patients with Systemic Sclerosis

Carol A. Feghali and Timothy M. Wright  

This report provides important novel information regarding quantitative differences in gene expression in fibroblasts from patients with SSc. This is an illness for which the etiology is still unknown, and the collection of mRNAs identified as being differentially expressed in patients with SSc in this study suggests that potential new disease-related genes may be identified as targets for therapy.

1458  

High Prevalence of T Cell Type I Protein Kinase A Deficiency in Systemic Lupus Erythematosus

Gary M. Kammer  

T lymphocytes from patients with SLE have a profound deficiency of the type I isozyme of protein kinase A (PKA-I). Deficient PKA-I activitiy is associated with aberrant T cell immune functions in SLE. Identification of a high prevalence of this isozyme deficiency in lupus T cells that is not associated with clinical disease activity raises the possibility that underlying molecular defects of signaling pathways may exist and contribute to defective T cell functions. Because low PKA activity has not been observed in healthy control subjects and appears to be specific for SLE, measuring enzyme activity may become a useful clinical test.

1466  

Lymphoma Development in Sjogren's Syndrome: Novel p53 Mutations

Nikolaos I. Tapinos, Mary Polihronis, and Haralampos M. Moutsopoulos  

Lymphoma development in patients with Sjogren's syndrome is the final and most serious stage in the evolution of the disease. Until now the causative mechanism has remained unclear. This report describes 2 novel mutations in the p53 gene that seem to play a role in the induction of lymphoma in patients with Sjogren's syndrome.

1473  

Detection of Borrelia burgdorferi Sensu Stricto by Reverse Line Blot in the Joints of Dutch Patients with Lyme Arthritis

Ineke M. van der Heijden, Bert Wilbrink, Sjoerd G. T. Rijpkema, Leo M. Schouls, Peter H. M. Heymans, Jan D. A. van Embden, Ferdinand C. Breedveld, and Paul P. Tak  

The results of this study indicate that the association between the different species of Borrelia burgdorferi sensu lato and arthritis can be studied using direct analysis of extracted DNA from joint samples. The detection of B burgdorferi sensu stricto described in this study is compatible with the premise that the development of Lyme arthritis is associated with infection with this particular species of B burgdorferi sensu lato. The results also suggest that polymerase chain reaction on DNA extracted directly from joint samples may be an additional tool in the diagnostic process.

1481  

Distinct Vascular Patterns of Early Synovitis in Psoriatic, Reactive, and Rheumatoid Arthritis

R. J. Reece, J. D. Canete, W. J. Parsons, P. Emery, and D. J. Veale  

The prognosis of seronegative spondylarthropathies, including PsA and ReA, may vary from that of RA. Specific microscopic differences in the lining layer and vasculature have been described in PsA and RA. This study revealed differences in the macroscopic pattern of blood vessels and assessed common features of grading synovitis using 3 independent observers. These findings may provide important clues for pathogenesis, diagnosis, and prognosis.

1485  

Synovial Epstein-Barr Virus Infection Increases the Risk of Rheumatoid Arthritis in Individuals with the Shared HLA-DR4 Epitope

Johannes G. Saal, Michael Krimmel, Michael Steidle, Friederike Gerneth, Silvia Wagner, Peter Fritz, Silvia Koch, Josef Zacher, Stefan Sell, Hermann Einsele, and Claudia A. Muller  

Microbial agents such as EBV might function as environmental triggers of RA in the presence of a predisposing immunogenetic background. This study demonstrates EBV DNA/RNA as a sign of frequent synovial EBV persistence in 29 of 84 RA patients, compared with 8 of 81 control subjects with non-RA arthritis. Individuals who have synovial EBV DNA and a shared epitope-positive HLA-DRB1 genotype are shown to have a remarkably higher risk of RA than those who are negative for one or both of these variables. The results suggest that synovial EBV infection might function as an additional risk factor in RA and interact with the RA-linked HLA-DRB1 genotypes in the development or progression of the disease.

1497 

T Cell Responses to a Human Cartilage Autoantigen in the Context of Rheumatoid Arthritis-Associated and Nonassociated HLA-DR4 Alleles

Andrew P. Cope, Salil D. Patel, Frances Hall, Mauro Congia, Henk A. J. M. Hubers, Gijs F. Verheijden, Annemieke M. H. Boots, Rajasree Menon, Massimo trucco, Antonius W. M. Rijnders, and Grete S\onderstrup  

The HLA class II transgenic mouse model described in this report defines a set of immunogenic T cell epitopes of a human synovial antigen, human cartilage glycoprotein-39 (HCgp-39), which selectively stimulate peripheral blood T cells from HLA-DR4 positive human subjects. This study also shows that the immunodominant epitopes of HCgp-39 that are presented by RA-associated and non-RA-associated HLA-DR4 molecules are completely different and induce distinct profiles of cytokines. These findings provide insight into how HLA-DRB1 alleles may contribute to the sustained chronic inflammatory responses observed in rheumatoid joints.

1508  

Production of Interleukin-7 and Interleukin-15 by Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis

Seishi Harada, Masahiro Yamamura, Hideyuki Okamoto, Yoshitaka Morita, Masanori Kawashima, Tetsushi Aita, and Hirofumi Makino  

Activated fibroblast-like synoviocytes are believed to contribute to chronic inflammation and immune reactions as well as joint destruction in RA. This study demonstrated that synovial fibroblast cell lines from RA patients are able to produce IL-7 and IL-15, and that, similar to IL-2, both cytokines can induce the proliferation of T cells isolated from the RA synovium. In the joints of patients with chronic RA, where IL-2 production by T cells is deficient, T cell activation and expansion may be regulated mainly by cytokines with IL-2-like activity, such as IL-15 derived from macrophages and fibroblast-like synoviocytes.

1517  

Characterization of Collagenase 3 (Matrix Metalloproteinase 13) Messenger RNA Expression in the Synovial Membrane and Synovial Fibroblasts of Patients with Rheumatoid Arthritis

Claudia Schulze Westhoff, Dirk Freudiger, Peter Petrow, Christine Seyfert, Josef Zacher, Jorg Kriegsmann, Thomas Pap, Steffen Gay, Peter Stiehl, Erika Gromnica-Ihle, and Dirk Wernicke  

Collagenase 3 is a powerful collagenolytic enzyme that preferentially cleaves type II collagen of hyaline cartilage. In this study, its mRNA expression was localized in fibroblast-like cells of the lining and sublining layers of the synovial membrane and at the synovial membrane-cartilage interface in patients with RA. The expression of collagenase 3 mRNA could be detected in 58% of the patients and showed a positive correlation with systemic markers of inflammation, i.e., erythrocyte sedimentation rate and C-reactive protein. These findings could have implications with respect to the pathogenesis and prognosis of RA.

1528  

Apoptotic Chondrocyte Death in Rheumatoid Arthritis

Hyun Ah Kim and Yeong Wook Song  

Synovial inflammation and joint damage manifested by articular cartilage erosion do not always go parallel in RA. This suggests that there may be an inherent and independent degradation pathway that is operating in diseased cartilage. This study provides evidence that chondrocyte apoptosis occurs in RA cartilage and sets the basis for further research into the cartilage breakdown of RA.

1538  

Inhibitory Effect of Annexin I on Synovial Inflammation in Rat Adjuvant Arthritis

Yuanhang Yang, Paul Hutchinson, and Eric F. Morand  

Annexin I, a glucocorticoid-induced protein, mediates important antiinflammatory effects of glucocorticoids. In this study, the role of annexin I in the regulation of inflammation was examined in rat adjuvant arthritis. Monoclonal antibody antagonism of annexin I depleted intracellular annexin I and led to exacerbation of arthritis, demonstrating the contribution of this molecule to the constitutive counterregulation of the inflammatory response in arthritis. Annexin I antagonism increased synovial production of tumor necrosis factor [ga] and prostaglandin E2. The results suggest modulation of annexin I as a therapeutic target in human RA.

1545  

Octreotide treatment of Chronic Intestinal Pseudoobstruction Secondary to Connective Tissue Diseases

Gabriel Perlemuter, Patrice Cacoub, Stanislas Chaussade, Bertrand Wechsler, Daniel Couturier, and Jean-Charles Piette  

1549  

Early Diagnosis of Takayasu Arteritis Using Gadolinium-Enhanced Magnetic Resonance Imaging

Masahiro Iwamoto, Yuko Ogawa-Shirota, Hidetomo Sato, Taku Yoshio, Hitoaki Okazaki, Akifumi Fujita, Hideharu Sugimoto, and Seiji Minota  

1550  

Femoral Head Osteonecrosis in a Child with Hemophilia

Ray F. Kilcoyne and Rachelle Nuss  

1552  

A Preliminary Definition of the Term ``Cure'' as Applied to Systemic Lupus Erythematosus

H. H. Euler  

1552  

An Update on HLA Association of Mi-2 Autoantibodies: The Association with a tryptophan at Position 9 of the HLA-DR[gb] Chain is Strong but Not Absolute

Rudolf Mierau, Thomas Dick, Ekkehard Genth, Peter Bartz-Bazzanella, Elisabeth Keller, and Ekkehard D. Albert  

1553  

Rheumatic Diseases in Ayurveda: A Historical Perspective

G. Ulrich-Merzenich, K. Kraft, and L. M. Singh  

1556 

Dose-Loading with Hydroxychloroquine in Rheumatoid Arthritis: Comment on the Article by Furst et al

Richard P. Handler  

1556  

Reply

Daniel E. Furst  

1556 

Methodologic Issues for the Assessment of Reproducibility: Comment on the Article by Genant et al

Bruno Giraudeau and Philippe Ravaud  

1557  

Correlation Analysis Versus Bland-Altman Analysis: Comment on the Article by Genant et al

Martin Utley, Steve Gallivan, Josh Dixey, and Adam Young  

1558  

Reply

Harry K. Genant and Ying Lu  

1559  

Lymphoma Infiltrate or Hyperparathyroidism? Comment on the Clinical Image by Drosos and Bai

Ray F. Kilcoyne  

1559  

Reply

Alexandros A. Drosos and Mary K. Bai  

1560  

Systemic Lupus Erythematosus in Patients Native to West and Central Africa: Comment on the Article by Bae et al

Zahir Amoura, Le Thi Huong Du, Patrice Cacoub, Camille Frances, and Jean-Charles Piette  

1561 

Reply

Sang-Cheol Bae, Patricia Fraser, and Matthew H. Liang  

1561 

Can HLA-DR Explain the Varying Frequency of Synovitis in Polymyalgia Rheumatica? Comment on the Article by Salvarani et al

Miguel A. Gonzalez-Gay, Carlos Garc|fia-Porrua, Ali Hajeer, and William E. R. Ollier  

1562  

Reply

Carlo Salvarani, PierLuigi Macchioni, Luigi Boiardi, Fabrizio Cantini, and Ignazio Olivieri  

19A  

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