Takashi Namekawa, Ulf G. Wagner, Jorg J. Goronzy, and Cornelia M. Weyand 2108

CT4+ T cells deficient for the CD28 molecule accumulate and clonally expand in patients with rheumatoid arthritis. The functional properties of these unusual lymphocytes were examined by a candidate molecule approach. CD4+ CD28[minus] T cells possess a cytolytic machinery and are able to lyse target cells. By staining for the cytolytic molecule perforin, these cells could be detected in rheumatoid synovial tissue. The data suggest that cytotoxicity by a specialized subset of CD4 T cells represents an important effector mechanism in rheumatoid arthritis.

Nobuhiro Takagi, Masahiko Mihara, Yoichiro Moriya, Norihiro Nishimoto, Kazuyuki Yoshizaki, Tadamitsu Kishimoto, Yasuhisa Takeda, and Yoshiyuki Ohsugi 2117

To clarify the role of IL-6 in the pathogenesis of collagen-induced arthritis, rat anti-mouse IL-6 receptor monoclonal antibody MR16-1 was injected into mice immediately after immunization with type II collagen. This suppressed the development of arthritis in a dose-dependent manner, inhibited IgG anti-type II collagen antibody production, and reduced the responsiveness of lymphocytes to type II collagen. These results suggest that IL-6 plays an essential role in the development of collagen-induced arthritis.

Percio S. Gulko, Yutaka Kawahito, Elaine F. Remmers, Van R. Reese, Jianping Wang, Svetlana V. Dracheva, Lynn Ge, Ryan E. Longman, Jennifer S. Shepard, Grant W. Cannon, Allen D. Sawitzke, Ronald L. Wilder, and Marie M. Griffiths 2122

This report describes a new non-MHC genetic locus that controls the severity of rat collagen-induced arthritis. This finding may provide new opportunities to define critical biochemical pathways involved in controlling rheumatoid arthritis severity, as well as mechanisms that regulate immune tolerance to autoantigens.

Paul J. Christner, Elena G. Hitraya, Josephine Peters, Rodney McGrath, and Sergio A. Jimenez 2132

These studies examined the levels of messenger RNA for 2 collagen types (I and III) and the role of transcriptional regulation of the gene encoding the α1 chain of type I procollagen in the exaggerated production of collagen in dermal fibroblasts obtained from the Tsk2 mouse, a newly described animal model for systemic sclerosis. The results of these studies may provide valuable insights into the mechanisms responsible for the excessive accumulation of collagen in systemic sclerosis and other diseases in which tissue fibrosis occurs.

Vishwas Ganu, Ronald Goldberg, Jane Peppard, John Rediske, Richard Melton, Shou-Ih Hu, Weigwang Wang, Charlotte Duvander, and Dick Heinegard 2143

Fragments of COMP are present at elevated levels in synovial fluid of patients with arthritis. Thus, they have the potential to serve as markers of altered cartilage turnover. In this study, the role of MMPs in COMP fragmentation was investigated. An understanding of the mechanism of COMP fragment formation is of value in the diagnosis and treatment of arthritis.

Robert Terkeltaub, Martin Lotz, Kristen Johnson, Dalun Deng, Sanshiro Hashimoto, Mary B. Goldring, Doug Burton, and Leonard J. Deftos 2152

PTHrP critically regulates long bone growth by affecting growth plate cartilage chondrocyte differentiation and mineralization (deposition of basic calcium phosphate crystals in the ossification process). Chondrocytes in articular cartilage do not normally proceed through to the terminal phases of this differentiation program, and do not deposit basic calcium phosphate crystals, except in degenerative joint disease. This study characterized PTHrP expression by articular chondrocytes and demonstrated the overabundance of PTHrP in cartilage from patients with advanced osteoarthritis. The results suggest a novel mineralization-related function that is selective for one of the three PTHrP isoforms.

Cinzia Melchiorri, Riccardo Meliconi, Luigi Frizziero, Tania Silvestri, Lia Pulsatelli, Ilaria Mazzetti, Rosa Maria Borz|fi, Mariagrazia Uguccioni, and Andrea Facchini 2165

This study provides evidence that interleukin-1β, tumor necrosis factor α, and inducible nitric oxide synthase are highly expressed by chondrocytes from patients with osteoarthritis, but not from patients with rheumatoid arthritis or psoriatic arthritis. Conversely, synovial expression of these inflammation mediators is elevated only in patients with inflammatory arthritides. These results suggest a primary active role of chondrocytes in the pathogenesis of osteoarthritis and further support the use of anticytokine therapy in this disease.

Martin Fleck, Earl R. Kern, Tong Zhou, Bernhard Lang, and John D. Mountz 2175

In this study, MCMV infection triggered the development of salivary gland inflammation as well as anti-Ro and anti-La autoantibodies in B6-lpr/lpr mice. The sialadenitis continued after the infectious MCMV was cleared from the salivary glands. Defective Fas-mediated apoptosis can lead to a postinfection, chronic inflammatory response that may trigger an autoimmune disease resembling Sjogren's syndrome.

Kimberly E. Brown, Kam Leong, Chia-Hui Huang, Rooshin Dalal, Graham D. Green, Howard B. Haimes, Pablo A. Jimenez, and Joan Bathon 2185

Proteins, unlike synthetic drugs, are often subject to rapid proteolytic degradation in vivo, which may significantly limit the effective local concentration and efficacy of a delivered protein when used in the treatment of joint disease. Encapsulation of proteins in microspheres may partially protect them from proteolytic degradation and allow for slow, continuous release of protein to the locally affected site. This report describes a novel microsphere encapsulation system for therapeutic proteins that appears to be biocompatible and nontoxic. Furthermore, the rate of release of encapsulated protein is shown to be responsive to the degree of inflammation in the joint.

Barry Bresnihan, Jose Maria Alvaro-Gracia, Mark Cobby, Michael Doherty, Zlatko Domljan, Paul Emery, George Nuki, Karel Pavelka, Rolf Rau, Blaz Rozman, Iain Watt, Bryan Williams, Roger Aitchison, Dorothy McCabe, and Predrag Musikic 2196

The effects of IL-1 on chronic inflammation and cartilage damage in RA are regulated by IL-1Ra, which inhibits IL-1 by binding to its target cell receptors. In a 24-week, double-blind, randomized, placebo-controlled trial of IL-1Ra, it was observed that a dosage of 150 mg/day resulted in significant clinical benefit, with no serious adverse events. Moreover, the rate of radiologic progression was significantly reduced. IL-1Ra is the first biologic agent to demonstrate a beneficial effect on the rate of joint erosion in RA.

Douglas J. Perkins, E. William St. Clair, Mary A. Misukonis, and J. Brice Weinberg 2205

Treatment of RA patients with a chimeric monoclonal antibody against TNFα (cA2) results in clinical improvement in the majority of patients. This work demonstrates that cA2 treatment is associated with a reduction in the overexpression of mononuclear cell nitric oxide synthase type 2 (NOS2), an enzyme that catalyzes the production of the inflammatory mediator NO. Results presented here indicate that TNFα likely plays an important role in enhancing NOS2 expression in RA, and that the antiinflammatory effects of cA2 treatment may be mediated by a reduction of NO overproduction.

Carelle C. Reparon-Schuijt, Wim J. E. van Esch, Cees van Kooten, Eleonora W. N. Levarht, Ferdinand C. Breedveld, and Cornelis L. Verweij 2211

This study unambiguously demonstrates that terminally differentiated CD20[minus],CD38+ IgM-RF-producing plasma cells are specifically present in the inflamed joints of patients with seropositive RA. The high frequency of IgM-RF-producing plasma cells provides evidence for a dominant RA-specific antigen-driven response in the development of the synovial plasma cell repertoire.

Marc C. Levesque, Craig S. Heinly, Leona P. Whichard, and Dhavalkumar D. Patel 2221

CD6 is a T cell costimulatory molecule that has been implicated in the pathogenesis of RA. This study shows that expression of the CD6 ligand ALCAM on monocytes/macrophages is enhanced by cytokines that induce macrophage differentiation. Binding of macrophage ALCAM to CD6 may induce autoreactive T cell responses that perpetuate RA.

Bruce A. Huyser, Jerry C. Parker, Richard Thoreson, Karen L. Smarr, Jane C. Johnson, and Robert Hoffman 2230

Fatigue is both common and troublesome for individuals with RA. The present study suggests that fatigue is strongly associated with a number of psychosocial variables, apart from disease activity per se. Correspondingly, the treatment of RA-related fatigue may be enhanced by interventions that address relevant cognitive and/or behavioral dimensions.

Pia Tengner, Anne-Kristine Halse, Hans-Jacob Haga, Roland Jonsson, and Marie Wahren-Herlenius 2238

This report describes the presence of Ro/SSA and La/SSB autoantibody-producing cells in the salivary glands of Sjogren's syndrome patients. The detection method used could be developed into a potential confirmatory diagnostic test. Furthermore, the findings potentially indicate that Ro and La autoantibodies are involved in the pathogenic process of this autoimmune exocrinopathy.

Rafael Segal, Eliezer Avrahami, Ela Lebdinski, Beno Habut, Arthur Leibovitz, Israel Gil, Michael Yaron, and Dan Caspi 2249

This first systematic study of hemiparalysis and OA showed that hemiparalysis reduced ipsilateral expression of hand OA in elderly patients. Moreover, in elderly patients without paralysis, OA was increased in the dominant hand. These results confirm the findings of previous case reports and lend support to the role of biomechanical factors in the development of OA.

Gary S. Hoffman, Yoel Drucker, Mary Frances Cotch, Geri A. Locker, Kirk Easley, and Kent Kwoh 2257

Advances in medical care have transformed Wegener's granulomatosis from a disease with a high potential for short-term mortality to a chronic illness with significant morbidity. This is the first study of patients' assessments of the medical, socioeconomic, and quality of life impact of Wegener's granulomatosis and its treatment. The results show that the costs of this illness to individuals, their families, and society are substantial.

Kirsten MacKay, Christopher Mack, Sinead Brophy, and Andrei Calin 2263

A simple, valid, and reproducible outcome measure for AS is described. If used in conjunction with other outcome measures, it will help the rheumatologist predict the potential disease course in an individual patient. It can be used as an outcome measure in clinical trials. If used in longitudinal and cross-sectional epidemiologic studies, it will improve our basic knowledge of the natural history and disease progression in AS.