833

Review: The Key Role of Nucleosomes in Lupus

Zahir Amoura, Jean-Charles Piette, Jean-Francois Bach, and Sophie Koutouzov

844

Review: Arterial Wall Injury in Giant Cell Arteritis

Cornelia M. Weyand and Jorg J. Goronzy

854

Serum Vitamin D Levels and Incident Changes of Radiographic Hip Osteoarthritis: A Longitudinal Study

Nancy E. Lane, L. Robert Gore, Steven R. Cummings, Marc C. Hochberg, Jean C. Scott, Elizabeth N. Williams, and Michael C. Nevitt, for the Study of Osteoporotic Fractures Research Group

This study assessed women's risk for incidence changes of radiographic hip OA as a function of their serum levels of 25- and 1,25-vitamin D. It was determined that women in the middle and lowest tertiles for serum levels of 25-vitamin D has 3 times the risk for incident findings of joint space narrowing compared with women in the highest tertile. These findings support the need for a randomized controlled trial of vitamin D supplementation to slow the development of new hip OA.

861

Laxity in Healthy and Osteoarthritic Knees

Leena Sharma, Congrong Lou, David T. Felson, Dorothy D. Dunlop, Gretchen Kirwan-Mellis, Karen W. Hayes, David Weinrach, and Thomas S. Buchanan

Laxity adversely affects knee mechanics. In this study, varus-valgus laxity was greater in uninvolved or mildly involved knees of patients with OA compared with older control knees, suggesting that the varus-valgus laxity found in patients with knee OA is not exclusively a consequence of OA pathology that develops at later stages. In patients with knee OA, joint space narrowing and bony attrition were associated with greater varus-valgus laxity. These results raise the possibility that varus-valgus laxity may be a risk factor for the development of knee OA and may cyclically contribute to disease progresion. If these results are supported by longitudinal studies, intervention directed toward correcting laxity may have a disease-modifying effect in patients with knee OA.

871

Elevated Levels and Functional Capacity of Soluble CD40 Ligand in Systemic Lupus Erythematosus Sera

Radha Krishna Vakkalanka, Caroline Woo, Kyriakos A. Kirou, Mary Koshy, Douglas Berger, and Mary K. Crow

The mechanisms that account for autoantibody formation and tissue damage in SLE have not been fully elucidated. This report describes the presence of a soluble form of the T helper cell-devived molecule, CD40 ligand, in the circulation of most patients with SLE, and the capacity of this soluble mediator from SLE sera to trigger B cell activation. The data presented provide a mechanism for generalized B cell activation, including secretion of self-reactive antibodies, in SLE, and support the potential utility of therapeutically targeting CD40 ligand in systemic autoimmune disorders.

882

Frequency of Fractures in Women with Systemic Lupus Erythematosus: Comparison with United States Population Data

Rosalind Ramsey-Goldman, Julie E. Dunn, Cheng-Fang Huang, Dorothy Dunlop, Joan E. Rairie, Shirley Fitzgerald, and Susan Manzi

The increasing life expectancy of lupus patients has focused attention on the morbidity associated with the disease and/or its treatment. Several small case series and 2 cohort studies emphasize the occurrence of low bone mass in women with lupus. This is the first study to quantify the high risk of fracture as a major threat to the health of women with lupus. Potential risk factors are identified and prevention strategies for minimizing the occurrence of fractures are discussed.

891

Hospital Experience and Mortality in Patients with Systemic Lupus Erythematosus

Michael M. Ward

Health outcomes are often better for patients who are hospitalized at hospitals in which there is more experience treating similar patients. In this population-based study of mortality among patients with SLE, the risk of in-hospital mortality was 66% lower for those patients admitted on an emergency basis to hospitals in which there was a large amount of experience with SLE patients compared with hospitals in which there was less experience. The risk of in-hospital mortality among patients admitted on an emergency basis due to SLE was 95% lower for patients admitted to hospitals in which there was a large amount of experience.

899

Long-Term Outcome in Mixed Connective Tissue Disease: Longitudinal Clinical and Serologic Findings

Mark A. Burdt, Robert W. Hoffman, Susan L. Deutscher, Grace S. Wang, Jane C. Johnson, and Gordon C. Sharp

This report describes clinical and serologic findings in a longitudinally studied cohort of 47 patients with MCtd. The results suggest that anti-U1-70 kd and anti-U1 RNA antibodies are more specific for MCtd than are antibodies to nuclear RNP. Core clinical features that usually appear over the course of MCtd were identified, with significant pulmonary and esophageal dysfunction often present prior to the appearance of symptoms referable to those dysfunctions. Anti-U1-70 kd and anti-U1 RNA typically declined and disappeared during prolonged remission, and pulmonary hypertension and IgG anticardiolipin autoantibodies were indicators of a more severe prognosis and were usually associated with proliferative vascular lesions.

910

A Retrospective Cohort Study of Cigarette Smoking and Risk of Rheumatoid Arthritis in Female Health Professionals

Elizabeth W. Karlson, I.-Min Lee, Nancy R. Cook, JoAnn E. Manson, Julie E. Buring, and Charles H. Hennekens

This study examines the association of cigarette smoking and risk of RA among 377,481 female health professionals in the Women's Health Cohort Study, and demonstrates that duration ([lt]20 years), but not intensity, of cigarette smoking is associated with a modest increased risk of RA in women. These data further highlight the hazards of cigarette smoking, which is associated with numerous other chronic diseases.

918

Magnetic Resonance Imaging-Determined Synovial Membrane Volume as a Marker of Disease Activity and a Predictor of Progressive Joint Destruction in the Wrists of Patients with Rheumatoid Arthritis

Mikkel \Ostergaard, Michael Hansen, Michael Stoltenberg, Peter Gideon, Mette Klarlund, Karl Erik Jensen, and Ib Lorenzen

In this randomized, controlled, 1-year clinical trial which included 26 RA patients, combined disease-modifying antirheumatic drug (DMARD) and oral prednisolone therapy caused a faster reduction in MRI-determined wrist joint synovial membrane volumes than DMARD therapy alone, but no significant difference in the rate of erosive progression was observed. A highly significant relation between synovial membrane volumes (area under the curve as well as baseline) and the rate of erosive progression was found. This indicates that quantitative MRI assessment of synovitis may prove valuable as a marker of joint disease activity and a predictor of progressive joint destruction in RA.

930

Activation of Microvascular Pericytes in Autoimmune Raynaud's Phenomenon and Systemic Sclerosis

Vineeth S. Rajkumar, Christian Sundberg, David J. Abraham, Kristofer Rubin, and Carol M. Black

This study demonstrates that within the dermal microvasculature of patients with systemic sclerosis and autoimmune Raynaud's phenomenon, activated pericytes express the platelet-derived growth factor [gb] receptors. Microvascular pericytes may therefore play a significant role in the development of systemic sclerosis.

942

Different Humoral Immune Response to Chlamydia trachomatis Major Outer Membrane Protein Variable Domains I and IV in Chlamydia-Infected Patients with or without Reactive Arthritis

Sylvette Bas, Catherine Scieux, and Thomas L. Vischer

In this study, the pattern of IgG reactivities against the serovar-determining epitopes of C trachomatis was examined in 2 groups of patients with Chlamydia infection, those who did and those who did not have reactive arthritis. Patients with reactive arthritis had a pattern of reactivities compatible with infection by several serotypes of bacteria. Repeated exposure to C trachomatis might therefore be involved in the development of the disease.

948

p53 Overexpression in Synovial Tissue from Patients with Early and Longstanding Rheumatoid Arthritis Compared with Patients with Reactive Arthritis and Osteoarthritis

Paul P. Tak, Tom J. M. Smeets, David L. Boyle, Maarten C. Kraan, Yan Shi, Shunrong Zhuang, Nathan J. Zvaifler, Ferdinand C. Breedveld, and Gary S. Firestein

The p53 tumor suppressor gene is an important factor in the regulation of apoptosis. This report describes overexpression of p53 in synovium from patients with the earliest stages of RA and in clinically uninvolved joints, compared with patients with ReA and OA. The findings may, in part, be related to the presence of transformed cells in the synovium that contribute to the autonomous progression of pannus and joint destruction in RA.

954

C-myc Antisense Oligodeoxynucleotides can Induce Apoptosis and Down-Regulate Fas Expression in Rheumatoid Synoviocytes

Akira Hashiramoto, Hajime Sano, Taira Maekawa, Yutaka Kawahito, Shinya Kimura, Yoshiaki Kusaka, Ronald L. Wilder, Haruki Kato, Motoharu Kondo, and Hiroo Nakajima

This study is the first to demonstrate that direct treatment with c-myc antisense oligodeoxynucleotides (AS ODN) induces apoptosis in cultured synoviocytes from patients with rheumatoid arthritis. In addition, the relationship between c-Myc and Fas was investigated, and c-myc AS ODN was found to down-regulate both messenger RNA expression and the killing activity of Fas. It is proposed that c-myc AS ODN might be a useful therapeutic tool in rheumatoid arthritis, and the results of this study may contribute to the analysis of complex systems of synoviocyte apoptosis.

963

Human Interleukin-17: A T Cell-Derived Proinflammatory Cytokine Produced by the Rheumatoid Synovium

Martine Chabaud, Jean Marc Durand, Nicolas Buchs, Francois Fossiez, Guillaume Page, Lucien Frappart, and Pierre Miossec

In this study, the presence and function of a new T cell-derived cytokine, IL-17, in RA was investigated. Results show the production of functional IL-17 by synovium from patients with RA, but not from those with osteoarthritis. IL-17 was found to contribute to the inflammatory pattern seen in RA.

971

p205 is a Major Target of Autoreactive T Cells in Rheumatoid Arthritis

Stefan Blass, Frank Schumann, Norbert A. K. Hain, Joachim-Michael Engel, Bruno Stuhlmuller, and Gerd Rudiger Burmester

In this study, p205 was identified as a T cell target in RA. This autoantigen thus may be used to improve the diagnosis of the disease. Furthermore, p205 showed an 11-amino acid identity to a rheumatoid factor-binding domain on IgG heavy chains. Therefore, further study of p205 may also help to elucidate the mechanisms of rheumatoid factor production in the course of RA.

981

Predominance of Mononuclear Cells Expressing the Chemokine Receptor CCR5 in Synovial Effusions of Patients with Different Forms of Arthritis

Matthias Mack, Hilke Bruhl, Rudi Gruber, Christian Jaeger, Josef Cihak, Viktoria Eiter, Jir|fi Plachy, Manfred Stangassinger, Katrin Uhlig, Manfred Schattenkirchner, and Detlef Schlondorff

CCR5 is expressed on the vast majority of T cells, monocytes, and natural killer cells isolated from the synovial fluid of patients with arthritis, while in the peripheral blood of the same patients, only a small percentage of these cells express CCR5. The predominance of CCR5-positive cells in the affected joints suggests an important role of CCR5 in the process of joint inflammation and points toward CCR5 as a promising target for therapeutic intervention.

989

Association of Rheumatoid Arthritis with a Functional Chemokine Receptor, CCR5

Juan J. Gomez-Reino, Jose L. Pablos, Patricia E. Carreira, Begona Santiago, Lourdes Serrano, Jose L. Vicario, Alejandro Balsa, Manuel Figueroa, and Mar|fia D. de Juan

Chemokines and their receptors play a major role in the recruitment of cells to the inflammatory site. The homozygous deletion of the chemokine receptor CCR5, [gD]32CCR5, generates a nonfunctional receptor. In this study, none of the rheumatoid arthritis patients carried homozygous [gD]32CCR5. This was significantly different from the frequency of [gD]32CCR5 in systemic lupus erythematosus patients and healthy control subjects. These findings point to the CCR5 receptor as potential target of therapy in rheumatoid arthritis.

993

The Early Molecular Natural History of Experimental Osteoarthritis. I. Progressive Discoordinate Expression of Aggrecan and Type II Procollagen Messenger RNA in the Articular Cartilage of Adult Animals

John R. Matyas, Peter F. Ehlers, Dingqiu Huang, and Mark E. Adams

Altered metabolism of the structural macromolecules aggrecan and type II collagen in articular cartilage could eventually lead to abnormal joint function and OA. The results of this study show that, during the natural history of experimental OA, there is a progressive metabolic imbalance of these molecules in articular chondrocytes. Assessing this metabolic imbalance might be useful for staging clinical OA; controlling this imbalance is a potential therapy for OA.

1003

Age-Related Decrease in Proteoglycan Synthesis of Human Articular Chondrocytes: The Role of Nonenzymatic Glycation

Jeroen DeGroot, Nicole Verzijl, Ruud A. Bank, Floris P. J. G. Lafeber, Johannes W. J. Bijlsma, and Johan M. TeKoppele

The etiology of osteoarthritis is largely unknown. This study shows that an age-related increase in glycation of the extracellular matrix leads to diminished capacity of the chondrocytes to maintain matrix integrity, possibly contributing to the development of osteoarthritis.

1010

The MICA-A9 triplet Repeat Polymorphism in the transmembrane Region Confers Additional Susceptibility to the Development of Psoriatic Arthritis and is Independent of the Association of Cw*0602 in Psoriasis

Segundo Gonzalez, J. Martinez-Borra, J. C. Torre-Alonso, S. Gonzalez-Roces, J. Sanchez Del R|fio, A. Rodriguez Perez, Chaim Brautbar, and C. Lopez-Larrea

Reported are new findings related to MICA-A9 (class I major histocompatibility complex chain-related gene A) polymorphism in the transmembrane region corresponding to the MICA-002 allele in patients with psoriatic arthritis, independent of the HLA-Cw*0602 marker that has been described in patients with psoriasis. This defines MICA as a possible candidate gene for psoriatic arthritis.

1017

Immunization of Mice with Human 60-kd Ro Peptides Results in Epitope Spreading if the Peptides are Highly Homologous Between Human and Mouse

R. Hal Scofield, Kenneth M. Kaufman, Usman Baber, Judith A. James, John B. Harley, and Biji T. Kurien

This report describes the immunization of mice with peptides from 60-kd Ro, with spreading of the immune response beyond the immunogen after use of some, but not all, peptides. The model described is the only animal model of systemic lupus erythematosus (SLE) autoimmunity with high levels of anti-Ro antibodies, one of the most important autoantigens present in the sera of patients with the disease. The model may recapitulate development of autoimmunity in human disease, and thus be relevant to the immune events that lead to SLE and Sjogren's syndrome.

1025

Blood-Induced Joint Damage: A Human In Vitro Study

Goris Roosendaal, Marieke E. Vianen, Joannes J. M. Marx, H. Marijke van den Berg, Floris P. J. G. Lafeber, and Johannes W. J. Bijlsma

This study demonstrates that a single episode or a limited number of intraarticular bleeding episodes, although not directly related to degenerative joint destruction, can cause irreversible changes in human articular cartilage that may eventually lead to joint destruction. For this reason, treatment of intraarticular hemorrhage should be reconsidered, not only in the case of recurrent intraarticular bleeding as in hemophilia but also in the case of sports injuries or trauma, in order to prevent degenerative joint damage that may become manifest years after the bleeding event.

1033

Blood-Induced Joint Damage: A Canine In Vivo Study

Goris Roosendaal, Johan M. TeKoppele, Marieke E. Vianen, H. Marijke van den Berg, Floris P. J. G. Lafeber, and Johannes W. J. Bijlsma

This study, using canine articular cartilage, shows that a single episode or a limited number of intraarticular bleeding episodes, although not directly related to degenerative joint destruction, can cause lasting changes in articular cartilage that may eventually lead to joint destruction. For this reason, treatment of intraarticular hemorrhage should be reconsidered, not only in the case of recurrent intraarticular bleeding as in hemophilia but also in the case of sports injuries or trauma, to prevent degenerative joint damage that may become manifest years after the bleeding event.

1040

Cross-Restriction of a T Cell Clone to HLA-DR Alleles Associated with Rheumatoid Arthritis: Clues to Arthritogenic Peptide Motifs

Simon Hawke, Hidenori Matsuo, Michael Nicolle, Paul Wordsworth, Louise Corlett, Edward Spack, Shrikant Deshpande, Paul C. Driscoll, and Nicholas Willcox

The very clear differences in predisposition to severe RA exhibited by several HLA-DR alleles and DR4 subtypes may reflect differing abilities to present antigenic peptides to pathogenic T cells. This study identified an unusual T cell that recognizes modified peptides when presented by 6 of the 7 major RA-associated DR alleles. This finding suggests that there could even be a single arthritogenic peptide in RA; a consensus motif is included to aid in its identification.

1051

Interferon-[ga] May Exacerbate Cryoglobulinemia-Related Ischemic Manifestations: An Adverse Effect Potentially Related to its Anti-Angiogenic Activity

Maria C. Cid, Jose Hernandez-Rodr|figuez, Jordi Robert, Ana del R|fio, Jordi Casademont, Blanca Coll-Vinent, Josep M. Grau, Hynda K. Kleinman, Alvaro Urbano-Marquez, and Francesc Cardellach

1056

Systemic Lupus Erythematosus-Associated Catastrophic Antiphospholipid Syndrome Occurring After Typhoid Fever: A Possible Role of Salmonella Lipopolysaccharide in the Occurrence of Diffuse Vasculopathy-Coagulopathy

Gilles Hayem, Najiby Kassis, Pascale Nicaise, Philippe Bouvet, Antoine Andremont, Colette Labarre, Marcel-Francis Kahn, and Olivier Meyer

1061

Geographic Tongue

Frederick T. Murphy and Raymond J. Enzenauer

1062

Environmental Factors May Modulate Antiphospholipid Antibody Production in Family Members of Patients with Systemic Lupus Erythematosus

Alain Saraux, Jean Jouquan, Paul Le Goff, Pierre Youinou, Yair Levy, Jean-Charles Piette, Loic Guillevin, Gilbert Semana, Denise Salmon, Jean-Paul Viard, Jean-Francois Bach, and Yehuda Shoenfeld

1064

Failure to Detect Human Papillomavirus in Primary Sjogren's Syndrome

S. Steinfeld, J. C. Noel, and T. Appelboom

1065

Lattice Pattern of Osseous Destruction in Sarcoidosis

Linda E. Grismer, Mark D. Harris, and William B. Morrison

1066

Does treatment with Glucocorticoids or with Disease-Modifying Antirheumatic Drugs Reduce the Rate of Radiographic Progression in Rheumatoid Arthritis? Comment on the Article by Abu-Shakra et al

John R. Kirwan

1066

Reply

Mahmoud Abu-Shakra, Michael Friger, Daniel Flusser, Shaul Sukenik, and Dan Buskila

1067

Proinflammatory Cytokine Production and Cell Adhesion Molecule Expression Compared in Rheumatoid Nodules and Synovial Membranes: Comment on the Article by Wikaningrum et al

Dirk Elewaut, Filip De Keyser, Gust Verbruggen, and Eric M. Veys

1068

Reply

Peter Roberts-Thomson, Michael Ahern, and Malcolm D. Smith

1068

Interpreting the Results of a Segregation Analysis of Generalized Radiographic Osteoarthritis: Comment on the Article by Felson et al

Tim D. Spector, Harold Snieder, Richard Keen, Cathryn Lewis, and Alex MacGregor

1069

Reply

David T. Felson and Richard Myers

17A

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