Paul P. Tak, Tom J. M. Smeets, Mohamed R. Daha, Philip M. Kluin, Katharina A. E. Meijers, Ronald Brand, A. Edo Meinders, and Ferdinand C. Breedveld 217

In light of recent interest in different antirheumatic therapy for various stages of disease, this study attempted to provide more insight into the rheumatoid synovitis process in terms of the duration and activity of disease. It was found that the immunohistologic features of rheumatoid synovium are similar in all phases of the disease, which indicates that it is likely that therapeutic strategies that interfere with immunologic responses will produce similar effects on synovial inflammation in early RA and longstanding RA. The results presented here also support the view that macrophages and monokines play an important role in the development of clinical signs of RA.

Leslie J. Crofford, Bing Tan, Conor J. McCarthy, and Timothy Hla 226

Prostaglandins are important mediators of inflammation and joint destruction in rheumatoid arthritis; their synthesis is mediated by cyclooxygenase (COX; prostaglandin H synthase). The inducible form of this enzyme, COX-2, is stimulated by proinflammatory cytokines such as interleukin-1, and is increased in rheumatoid synovial tissues. This report describes the involvement of the transcription factor NF-κB, which is constitutively active in rheumatoid synovia, in the interleukin-1-stimulated increase of COX-2 expression in rheumatoid synoviocytes. Understanding how COX-2 is regulated may suggest targets for therapeutic intervention in rheumatoid arthritis.

Eddie C. Y. Wang, Tom M. Lawson, Kav Vedhara, Paul A. H. Moss, Paul J. Lehner, and Leszek K. Borysiewicz 237

A role for CD8+, CD57+ T cells in RA has been suggested because peripheral blood CD8+, CD57+ T cells increase in RA, and CD8+, CD57+ T cells associate with synovial dendritic cells from RA patients but not healthy subjects. This report considerably extends the findings of previous studies by using age-matched controls and by investigating the T cell receptor usage of CD8+, CD57+ T cells. The proportion, but not the absolute numbers, of CD8+ T cells expressing CD57 was found to increase significantly in RA patients, underlining the importance of using age-matched controls when studying oligoclonal expansions of T cell subsets. In addition, CD8+, CD57+ T cells had restricted TCR usage in RA, suggesting that RA-specific factors generate this subset. More expansions were detected in RA patient-derived CD8+, CD57[minus] T cells than in those from controls, suggesting that the detection of expanded oligoclonal populations within both CD8+, CD57[minus] and CD57+ T cells may be associated with the development of RA.

Leo A. B. Joosten, Erik Lubberts, Patrick Durez, Monique M. A. Helsen, Marike J. M. Jacobs, Michel Goldman, and Wim B. van den Berg 249

IL-4 and IL-10 are modulatory cytokines that have a suppressive effect on IL-1 and TNFα production. This study shows that IL-4 and IL-10, in particular, are pivotal regulators of arthritis expression in the murine model of collagen-induced arthritis. Moreover, combination therapy with IL-4 and IL-10 markedly suppressed established CIA, with a major protective effect against cartilage destruction.

Takeshi Hayashi, Etsuko Abe, Tomoo Yamate, Yasuto Taguchi, and Hugo E. Jasin 261

Nitric oxide has been shown to mediate both deleterious and protective effects in inflammation. Increased NO production at the cartilage surface-synovial fluid interface may play an important role in the modulation of cartilage damage in inflammatory arthritis.

Richard F. Loeser 270

Regulation of chondrocyte integrins by growth factors may have an important function in processes involved in cartilage repair and remodeling. In this study, 2 cartilage growth factors, IGF-1 and TGFβ, were shown to modulate integrin expression and function, having opposite effects on levels of the α1β1 integrin, with IGF-1 increasing and TGFβ decreasing α1β1. These findings provide further insight into the mechanisms of growth factor action in cartilage.

Silvia Ragno, M. Joseph Colston, Douglas B. Lowrie, Vivienne R. Winrow, David R. Blake, and Ricardo Tascon 277

In recent years, there has been much speculation concerning the role of heat shock proteins in rheumatoid arthritis. The present study shows that the requirement for purified heat shock protein can be circumvented by the use of appropriate DNA constructs. These findings should greatly facilitate studies aimed at understanding the role of these proteins in autoimmune diseases, and could lead to novel methods for disease intervention.

Julio C. Fernandes, John P. Caron, Johanne Martel-Pelletier, Dragan Jovanovic, Francois Mineau, Ginette Tardif, Ivan G. Otterness, and Jean-Pierre Pelletier 284

This study demonstrates that treatment with a therapeutic concentration of tenidap, an antirheumatic and cytokine-modulating drug, is effective in reducing the progression of experimental OA, when therapy is begun after initiation of OA by transection of the anterior cruciate ligament. The drug's action is likely mediated through a reduction in the expression and/or synthesis of metalloproteases and IL-1.

Anna von Mikecz, Konstantin Konstantinov, Dedra S. Buchwald, Larry Gerace, and Eng M. Tan 295

Patients with arthralgias, myalgias, and fatigue with a clinical picture that is insufficient to allow categorization as a conventional rheumatic disease may have chronic fatigue syndrome. This study shows that chronic fatigue syndrome patients have a profile of autoantibodies distinct from those of patients with rheumatic diseases and that the autoantibodies are directed against certain insoluble cellular antigens associated with the nuclear envelope, the nuclear matrix, and the intermediate filament proteins.

Hanns-Martin Lorenz, Mathias Grunke, Thomas Hieronymus, Martin Herrmann, Almuth Kuhnel, Bernhard Manger, and Joachim R. Kalden 306

Based on findings in several mouse models and some ex vivo and in vitro findings in human systemic lupus erythematosus cells, a role for apoptosis in the pathogenesis of SLE was investigated. The results did not indicate that apoptosis plays a role in SLE pathogenesis. Further studies are needed to elucidate the pathogenesis of this disease.

Salvatore De Vita, Mauro Boiocchi, Dario Sorrentino, Antonino Carbone, Claudio Avelline, Riccardo Dolcetti, Alessandra Marzotto, Annunziata Gloghini, Ettore Bartoli, Carlo Alberto Beltrami, and Gianfranco Ferraccioli 318

This study attempted to better characterize the prelymphomatous stages of B cell lymphoproliferation in SS by integrating the findings of clinical, histopathologic, and molecular studies. Different types of B cell clonal expansion were observed (oligoclonal or monoclonal, smaller or larger in size, fluctuating or established, localized or disseminated) and may imply a different risk for lymphoma progression. Thus, an accurate characterization may be crucial in future studies aimed at clairfying the pathobiology of SS-associated lymphoproliferation.

Ursula M. Davies, Jennifer Jones, Jonathan Reeve, Cecilia Camacho-Hubner, Andre Charlett, Barbara M. Ansell, Michael A. Preece, and Patricia M. M. Woo 332

Growth retardation and osteoporosis are serious complications in children with JRA. It was previously reported that treatment of these children with recombinant human growth hormone resulted in significant increases in height velocity. The laboratory findings in this report highlight the defects in the growth hormone axis in these children, thus opening up areas for further research and intervention therapy.

Ulf Wagner, Sylke Kaltenhauser, Heidemarie Sauer, Sybille Arnold, Wolfram Seidel, Holm Hantzschel, Joachim R. Kalden, and Ralf Wassmuth 341

This study addresses current issues concerning the immunogenetics of RA, with particular emphasis on HLA markers in the diagnosis and clinical course of RA. Based on retrospective and prospective analyses, evidence is presented that HLA markers are particularly helpful in predicting disease severity, as judged by clinical and radiologic scores. It is concluded that detailed HLA genotyping can be helpful as a prognostic parameter in patient management.

Faisel Khan, Stuart J. Litchfield, Margaret McLaren, Douglas J. Veale, Roberta C. Littleford, and Jill J. F. Belch 352

Vasospasm occurs in a large proportion of patients with rheumatologic problems. It is found in [approximate]95% of patients with systemic sclerosis and in 10% of patients with RA. Understanding the mechanism of vasospasm is therefore important. This study shows that endothelial cell damage may be a contributory factor to vasospasm in patients with Raynaud's phenomenon. Furthermore, oral supplementation with l-arginine, the precursor of endothelium-derived nitric oxide, a potent vasodilator, does not improve vascular reactivity.

Antonio Banares, Juan A. Jover, Benjam|fin Fernandez-Gutierrez, Jose M. Ben|fitez del Castillo, Javier Garc|fia, Emilio Vargas, and Cesar Hernandez-Garc|fia 358

A classification system for the medical evaluation of patients with uveitis, based on 12 clinical presentation patterns and 18 other morphologic features, is described. With this diagnostic approach, a core of specific disease entities must be ruled out for each presentation pattern, minimizing the number of tests that are needed to reach a final diagnosis. Rheumatologic evaluation might be more cost-effective if the referring ophthalmologist follows the recommended classification system.

A. R. Exley, P. A. Bacon, R. A. Luqmani, G. D. Kitas, C. Gordon, C. O. S. Savage, and D. Adu 371

This article describes the development and initial validation of the Vasculitis Damage Index for the standardized assessment of damage in each of the systemic vasculitides. This index provides a clinical tool to differentiate damage from activity, and to investigate the effect of different therapies on long-term outcome.