Jorge Sanchez-Guerrero, Elizabeth W. Karlson, Matthew H. Liang, David J. Hunter, Frank E. Speizer, and Graham A. Colditz 804

This 14-year prospective cohort study determined that the risk of developing SLE in women who had a history of oral contraceptive use was slightly increased compared with that in women who never used oral contraceptives. These results might be considered when choosing a method of contraception for healthy white women, although the increase in absolute risk was so small that other factors should carry greater weight in the decision.

Dafna D. Gladman, Murray B. Urowitz, Charles H. Goldsmith, Paul Fortin, Ellen Ginzler, Caroline Gordon, John G. Hanly, David A. Isenberg, Kenneth Kalunian, Ola Nived, Michelle Petri, Jorge Sanchez-Guerrero, Michael Snaith, and Gunnar Sturfelt 809

The SLICC/ACR Damage Index is a validated index for the assessment of damage occurring in patients with SLE, while the SLEDAI is a valid measure to assess disease activity. The aim of this investigation was to test the reliability of the SLICC/ACR Damage Index in live patients with SLE. The results showed that physicians from different centers were able to assess patients with SLE in a reproducible way, using the SLEDAI to assess disease activity and the SLICC/ACR Damage Index to assess accumulated damage.

Ralf W. Denfeld, Peter Kind, Richard D. Sontheimer, Erwin Schopf, and Jan C. Simon 814

The findings of B7-1, B7-2, and CD28 expression in active lesions of lupus erythematosus suggest that costimulation via the B7-CD28 pathway may be important for the generation and/or propagation of T cell activity in skin lesions of human LE. Thus, this description serves as essential background material for the development of human trials of therapies which target this pathway (e.g., CTLA-4 fusion protein).

David A. Horwitz, Fu Lin Tang, Mary M. Stimmler, Alan Oki, and J. Dixon Gray 822

This report describes impaired T cell responses to a mitogenic combination of anti-CD2 monoclonal antibodies in SLE. To explain this defect, it is shown that the interactions between T cells and accessory cells are impaired in the majority of patients and a costimulatory pathway that may explain this proliferative defect is identified. These findings may account for many of the abnormalities of T cell function in SLE.

Maria Jose Cuadrado, Charo Lopez-Pedrera, Munther A. Khamashta, Maria Teresa Camps, Francisco Tinahones, Antonio Torres, Graham R. V. Hughes, and Francisco Velasco 834

This study reveals that monocyte expression of tissue factor, an inducible cell glycoprotein that is a major initiator of coagulation in vivo, is increased in primary antiphospholipid syndrome patients with thrombosis, compared with primary antiphospholipid syndrome patients without thrombosis, thrombosis patients without antiphospholipid syndrome, and healthy controls. These results may help to elucidate a mechanism by which hypercoagulability occurs in the primary antiphospholipid syndrome and may lead to the development of new therapeutic regimens.

James R. O'Dell, Claire E. Haire, William Palmer, Walter Drymalski, Steven Wees, Kent Blakely, Melvin Churchill, P. James Eckhoff, Arthur Weaver, Deborah Doud, Nils Erikson, Fred Dietz, Rich Olson, Pierre Maloley, Lynell W. Klassen, and Gerald F. Moore 842

Because RA has been increasingly recognized as a disease with significant morbidity and mortality and one in which irreversible joint damage occurs early, there has been recent emphasis on early aggressive treatment, despite limited data. This double-blind, placebo-controlled study was undertaken to assess minocycline treatment in rheumatoid factor-positive RA patients with disease duration of [lt]1 year (average 5 months). The minocycline-treated group improved dramatically (65% with [lt]50% improvement) compared with placebo-treated patients (13% with [lt]50% improvement). If these initial results can be confirmed, it would have a dramatic impact on the way early RA is treated.

Arthur F. Kavanaugh, Hendrik Schulze-Koops, Laurie S. Davis, and Peter E. Lipsky 849

As the immunopathogenesis of RA becomes more clearly defined, clinical rheumatologists have the expectation that progress in this area may yield important new therapeutic agents. Several potential therapeutic targets, including adhesion receptors, have been defined in recent years. Previous work has suggested the potential utility of inhibiting ICAM-1 in RA patients. This study shows that a second course of therapy with a murine MAb was neither as well tolerated nor as effective as the first course. This work illustrates the importance of not only the choice of target, but also the particular agent in devising novel therapies.

Valerie Pinet, Bernard Combe, Odile Avinens, Sophie Caillat-Zucman, Jacques Sany, Jacques Clot, and Jean-Francois Eliaou 854

This is the first description of a genetic association between RA and specific DM alleles (DMA*0103 and DMB*0104). In addition to being of major interest for understanding RA pathogenesis as it relates to a possible dysregulation of HLA class II-restricted antigen presentation, the study defines new genetic markers that directly contribute to genetic susceptibility to RA. Perhaps more interesting is that DMA*0103 was found to be strongly associated with RA in patients who carry the DRB1*01 alleles (DRB1*0101 and DRB1*0102) as well as in those who are negative for the RA-associated alleles (so-called DRX) and are therefore expected to be at low risk of developing a severe form of RA. The presence of the DMA*0103 allele in such patients would increase the risk of developing persistent and/or severe RA.

Ricardo Blanco, Victor M. Martinez-Taboada, Vicente Rodriguez-Valverde, Miguel Garcia-Fuentes, and Miguel A. Gonzalez-Gay 859

HSP is the most common vasculitic syndrome in childhood. It is generally considered a benign and self-limited disorder. A few reports of HSP in adulthood have described a worse outcome. However, those studies have used various inclusion criteria, and most of them used selected populations of patients with kidney dysfunction. In the present study, based on a large series of unselected patients with HSP classified according to strict criteria, adult patients were found to have a more severe clinical syndrome with a higher frequency of renal involvement. However, the outcome was equally benign in the adults as in children.

Ingrid Lundberg, Ann-Kristin Ulfgren, Pernilla Nyberg, Ulf Andersson, and Lars Klareskog 865

In this study of the pattern of cytokine production in muscle tissue of patients with inflammatory myopathies, interleukin-1α (IL-1α), IL-1β, and transforming growth factor β were found to predominate. There was no difference in cytokine staining patterns among the 3 subsets of inflammatory myopathies (dermatomyositis, polymyositis, and inclusion body myositis). A striking finding of IL-1α in the vascular walls was observed, indicating the importance of blood vessels in the pathogenesis of the inflammatory myopathies.

Yrjo T. Konttinen, Louise A. M. Platts, Susanne Tuominen, Kari K. Eklund, Nina Santavirta, Jyrki Tornwall, Timo Sorsa, Mika Hukkanen, and Julia M. Polak 875

If the sicca symptoms in Sjogren's syndrome are caused by functional disturbances rather than destruction of the secretory elements, this has obvious relevance for therapy. Localization of such disturbances in the nitrinergic system could be particularly useful in the near future, because this whole field is currently evolving very rapidly.

Carola J. E. Kaandorp, Pieta Krijnen, Hein J. Bernelot Moens, J. Dik F. Habbema, and Dirkjan van Schaardenburg 884

In a survey on the outcome of bacterial arthritis in 154 consecutive patients, patient outcome was found to be poor in 21%, and joint outcome in 33%, of the patients. Adverse prognostic factors were higher age, preexistent joint disease, and infected joints containing synthetic material.

Andrew C. Bakker, Leo A. B. Joosten, Onno J. Arntz, Monique M. A. Helsen, Alison M. Bendele, Fons A. J. van de Loo, and Wim B. van den Berg 893

In this study, the knees of mice prone to collagen-induced arthritis were injected with human IL-1Ra- producing cells. Arthritis onset was almost completely prevented in the experimental knees compared with control cell-injected knees. Moreover, collagen-induced arthritis was prevented in the ipsilateral paws of the treated knees. These results indicate the feasibility and potential efficacy of gene transfer as a treatment of human arthritis.

Tetsuya Tomita, Hideo Hashimoto, Naruya Tomita, Ryuichi Morishita, Seung Bak Lee, Kenji Hayashida, Norimasa Nakamura, Kazuo Yonenobu, Yasufumi Kaneda, and Takahiro Ochi 901

This report describes the establishment of a system for direct gene transfer into articular cartilage by intraarticular injection of HVJ-liposomes. The transfection frequency and stability of expression recognized in this study show the possibility of a strategy for treatment of joint disorders using a direct gene transfer method.

Phil J. Williams, Richard H. V. Jones, and Thomas W. Rademacher 907

This study uses a murine arthritis model and is the first to show the protective benefit of exogenous DHEA against the development of murine collagen-induced arthritis. The data presented offer support to clinical studies suggesting that low DHEA levels are a risk factor for the development of RA.

Hiroshi Asahara, Koushi Fujisawa, Tetsuji Kobata, Tomoko Hasunuma, Toshiro Maeda, Masato Asanuma, Norio Ogawa, Hajime Inoue, Takayuki Sumida, and Kusuki Nishioka 912

This study provides direct evidence of high activation of AP-1 in RA synovium, which might cause proliferation of the synovium, high expression of tissue-degrading molecules, and abnormal immune network. Studies of transcription regulation may help to clarify the pathogenesis of RA and to provide a new approach to its treatment.

Kazuyoshi Okamoto, Koushi Fujisawa, Tomoko Hasunuma, Tetsuji Kobata, Takayuki Sumida, and Kusuki Nishioka 919

This is the first report that Fas-mediated apoptosis selectively induces activation of the JNK/AP-1 signaling pathway in RA synovial cells. It was previously reported that functional Fas antigen was expressed on RA synovial cells and that anti-Fas antibody induced apoptosis in RA synovial cells but not in osteoarthritic or normal synovial cells in vitro. The current findings strongly suggest that a specific mechanism can regulate RA synovial cell hyperplasia and may provide a new strategy for a successful therapy for RA.

Xue Wei Meng, John M. Feller, John B. Ziegler, Sally M. Pittman, and Christine M. Ireland 927

Although HCQ has been used widely in the treatment of rheumatic disorders and systemic lupus erythematosus, its specific mechanism of action is largely unknown. The present study showed that HCQ was able to induce peripheral blood lymphocytes to undergo apoptosis in a dose- and time-dependent manner, thus suggesting that understanding of this effect may contribute to our knowledge of this drug's mechanism of action in these and other disorders.

Chung-E Tseng, Edward K. L. Chan, Eugenia Miranda, Michael Gross, Francis Di Donato, and Jill P. Buyon 936

Autoantibodies to 52-kd SS-A/Ro are found in high prevalence in patients with Sjogren's syndrome and in mothers whose children have neonatal lupus. Studies to address the near-universal linkage of anti-52-kd SS-A/Ro antibodies with 60-kd SS-A/Ro and 48-kd SS-B/La RNPs in healthy nonautoimmune mice should help explain these mixed antibody patterns and facilitate the development of an animal model of neonatal lupus.

Wolfgang Kuon, Roland Lauster, Ute Bottcher, Armin Koroknay, Matthias Ulbrecht, Matthias Hartmann, Martina Grolms, Sanja Ugrinovic, Jurgen Braun, Elisabeth H. Weiss, and Joachim Sieper 945

This report describes a new animal model which could help identify the bacterial epitopes derived from reactive arthritis-associated bacteria presented by HLA-B27. The model might therefore make a contribution toward clarifying the pathogenesis of the spondylarthropathies.

Peter T. Chapman, Helen Yarwood, Andrew A. Harrison, Claire J. Stocker, Francois Jamar, Robert H. Gundel, A. Michael Peters, and Dorian O. Haskard 955

This study explored the role of IL-1 and TNFα in activating endothelium, a central component of the inflammatory response, in a model of monosodium urate monohydrate crystal-induced inflammation. Using a combined in vitro and in vivo approach, IL-1 and TNFα were shown to be the dominant cytokines involved, and anti-TNFα monoclonal antibody was effective in suppressing both endothelial activation and leukocyte recruitment in vivo. This study also highlights the potential of E-selectin imaging in assessing the endothelial response to therapy.

Ann K. Rosenthal, Beth A. Derfus, and Lisa A. Henry 966

This work contributes to our understanding of the pathophysiology of CPPD deposition disease, an increasingly common form of degenerative arthritis affecting the elderly. Understanding how and why these crystals form in cartilage will lead to the development of logical therapies for this currently untreatable disease. These studies describe a role for a new enzyme in CPPD crystal formation, and thus identify another potential site at which the process of crystal formation might be interrupted.