Jean-Pierre Pelletier, John P. Caron, Christopher Evans, Paul D. Robbins, Helga I. Georgescu, Dragan Jovanovic, Julio C. Fernandes, and Johanne Martel-Pelletier 1012

This study shows for the first time in vivo that increased localsynthesis of IL-1Ra by synovial cells transduced with the IL-1Ra gene can reduce the progression of early experimental OA knee lesions. Because OA is incurable and responds poorly to treatment, novel therapeutic approaches such as gene therapy are needed.

Harrie L. Glansbeek, Henk M. van Beuningen, Elly L. Vitters, Elisabeth A. Morris, Peter M. van der Kraan, and Wim B. van den Berg 1020

This study demonstrates that BMP-2 is a very potent stimulator of articular cartilage proteoglycan synthesis in vivo. However, BMP-2 appeared to be unable to antagonize the deleterious effects of IL-1α on articular cartilage proteoglycan synthesis and content. In addition, BMP-2 induced the formation of new chondroid tissue in the joint.

Akinobu Okimura, Yasunori Okada, Seicho Makihira, Haiou Pan, Li Yu, Kazuo Tanne, Kazushi Imai, Harumoto Yamada, Takeshi Kawamoto, Mitsuhide Noshiro, Weiqun Yan, and Yukio Kato 1029

This study investigated the synthesis of cartilage matrix protein (CMP) in arthritic cartilage. By immunohistochemical analysis, CMP was localized in only a few chondrocytes in normal human joints, whereas numerous chondrocytes were immunostained in rheumatoid arthritis and osteoarthritis joints. Immunoblotting analyses confirmed the increase of CMP in RA and OA cartilage. The increase in CMP content in arthritic articular cartilage may alter cell-matrix interactions, and studies of CMP may provide a better understanding of the role of collagen-binding proteins in the pathology of joint diseases.

Gabriella Cs-Szabo, Lee I. Melching, Peter J. Roughley, and Tibor T. Glant 1037

Despite the massive degradation of cartilage in end-stage OA, resident chondrocytes tend to replace the extracellular matrix by an increased synthesis of matrix components. An unbalanced synthesis and/or accumulation of noncollagenous matrix components may either contribute to the development of OA or inhibit the repair processes. In this study, the expression of all matrix components investigated, especially small proteoglycans, was increased in OA chondrocytes, most likely due to the repair processes. Any therapeutic intervention that could restore the normal metabolic balance of matrix synthesis might preserve normal cartilage function or protect tissue from extensive degradation.

John R. Matyas, Mark E. Adams, Dinqqiu Huang, and Linda J. Sandell 1046

This study shows that, in OA, adult articular cartilage repair appears to be initiated by mature chondrocytes within the cartilage as opposed to dedifferentiation of chondrocytes or recruitment of noncartilaginous cells. It remains unclear why chondrocytes ultimately fail to maintain the cartilage matrix in late-stage OA. However, evidence of an intrinsic healing response suggests that a therapeutic approach aimed at stimulating and maintaining this repair could be developed.

Mukundan G. Attur, Rajesh N. Patel, Steven B. Abramson, and Ashok R. Amin 1050

The results of this study indicate that IL-17 augments nitric oxide production in osteoarthritic cartilage via nuclear factor κβ activation, and independently of IL-1β signaling. Further analysis of the effects of blocking IL-17 activity may lead to new therapeutic options.

Mituko R. Ito, Shizuko Terasaki, Junpei Itoh, Hideki Katoh, Shin Yonehara, and Masato Nose 1054

This study was undertaken to establish an animal model for several forms of rheumatic diseases, including glomerulonephritis, arteritis, and arthritis, which arise from a deficit in the functional Fas ligand. This model is useful for studying the role of the Fas/Fas ligand system in the development of rheumatic diseases, and for increasing the efficacy of using Fas antibodies and the functional Fas ligand or its derivatives in the treatment of rheumatic disease.

Caralee J. Schaefer, Janey D. Whalen, Terry Knapp, and Paul H. Wooley 1064

Recent reports have suggested that there is an increase in autoantibodies in recipients of silicone breast implants. However, the presence of autoantibodies alone is not diagnostic of an autoimmune disease, and should not be interpreted as an indication for explantation. We have developed an animal model to investigate the influence of silicone on autoimmune responses, and our findings confirm that silicone implantation may indeed result in the development of certain autoantibodies. However, this response did not result in the development of disease, nor did it adversely affect the severity of an experimental model of arthritis, which may support a conservative approach to silicone implant recipients who have autoantibodies.

A. Hui, G. V. Kulkarni, W. L. Hunter, C. A. G. McCulloch, and T. F. Cruz 1073

This study demonstrates that paclitaxel is a potent inhibitor of synoviocyte proliferation and induces synoviocyte apoptosis in a concentration- and cell cycle-dependent manner. However, paclitaxel had no effect on confluent synoviocytes or chondrocytes, indicating that the drug is selectively toxic to proliferating synoviocytes. In view of the current interest in paclitaxel as a potential antiarthritic drug, these findings suggest that palitaxel, and perhaps other microtubule-stabilizing agents, may be considered as a new class of compounds for the treatment of arthritis.

Tammy A. Spain, Ren Sun, Margaret Gradzka, Su-Fang Lin, Joseph Craft, and George Miller 1085

This study demonstrates that Sp1, an RNA polymerase II transcription activator, is a previously unrecognized autoantigen. Antibodies to Sp1 were detected in sera containing antinuclear antibodies of unknown specificity, obtained from a group of 8 patients with undifferentiated connective tissue disorders. The results indicate that RNA polymerase II transcription complexes may be autoantigenic, and that Sp1 may be a diagnostic marker for an as-yet-undefined connective tissue disorder.

Hideyuki Okamoto, Masahiro Yamamura, Yoshitaka Morita, Seishi Harada, Hirofumi Makino, and Zensuke Ota 1096

IL-11, LIF, and oncostatin M are known to share several biologic activities with IL-6, such as stimulating the synthesis of acute-phase proteins by cultured hepatocytes. This study demonstrates that these IL-6-type cytokines are expressed at high levels in the joints of patients with RA, but that only IL-6 is significantly elevated in their blood in proportion to the level of serum CRP. Therefore, IL-6 may play a predominant role in inducing acute-phase proteins in this inflammatory arthritis, despite the local production of factors with IL-6-like activities.

Peter B. Martens, Jorg J. Goronzy, Daniel Schaid, and Cornelia M. Weyand 1106

This study explores the role of CD4+CD28[minus] T cells in RA. These unusual T cells show an abnormal growth behavior, with oligoclonal proliferation and autoreactivity. CD4+CD28[minus] T cells are very infrequent in most individuals but detectable in a subset of normal donors and in most RA patients, which raises the possibility that a genetic factor controls the generation of these T cells. In RA patients, CD4+CD28[minus] T cells appear to have a primary role in the development of extraarticular manifestations, rather than in the joint disease. Expansion of the unusual lymphocytes is a feature of patients with nodular disease and rheumatoid vasculitis.

Gijs F. M. Verheijden, Antonius W. M. Rijnders, Ebo Bos, Christina J. J. Coenen-de Roo, Catherina J. van Staveren, Andre M. M. Miltenburg, Jan H. Meijerink, Dirk Elewaut, Filip de Keyser, Eric Veys, and Annemieke M. H. Boots 1115

The initiation of many autoimmune responses depends on activation of antigen-specific T cells, which thus can be selectively targeted for potential therapeutic benefit. The identification of relevant autoantigens is therefore of major importance. So far, the quest for novel autoantigens in RA has met with little success. Identification of a relevant autoantigen would be a major breakthrough in designing antigen-based forms of therapy that combine specificity with lack of the toxicity that is associated with current treatments. The present data suggest that HC gp-39 is a candidate for antigen-specific immunotherapy in RA.

Kazuhisa Nozawa, Nobuhiko Kayagaki, Yoshiaki Tokano, Hideo Yagita, Ko Okumura, and Hiroshi Hasimoto 1126

Previous reports have indicated abnormalities of Fas or sFas in sera from rheumatic disease patients. This report describes the relationship between sFas and sFas-L, mediators of apoptosis, in patients with various rheumatic diseases.

William Stohl, Julie E. Elliott, Lily Li, Eckhard R. Podack, David H. Lynch, and Chaim O. Jacob 1130

Immune dysregulation is a hallmark of SLE. It has previously been documented that generation of nonrestricted cytolytic activity in SLE is impaired. This defect is independent of disease activity and may antedate disease onset. Thus, it may play an important role in the pathogenesis and/or perpetuation of SLE. This report deals with the effector pathway underlying the cytolytic activity.

Ling-Ying Lu, Wei-Zi Ding, Dolores Fici, Richard Deulofeut, He-Hsiung Cheng, Ching-Cheng Cheu, Ping-Kuang Sung, Peter H. Schur, and Patricia A. Fraser 1138

This study used polymerase chain reaction techniques to investigate the association of HLA class II alleles/haplotypes, type I C2 deficiency gene, and the tumor necrosis factor α gene promoter (TNF2) allele in Chinese patients in Taiwan who had SLE, the most common autoimmune disease in that country. No HLA-DRB1 association was found, but frequencies of DQB1*0501 and TNF2 were shown to be increased among SLE patients compared with controls. Thus, DQB1 and tumor necrosis factor α maybe important factors in SLE susceptibility in this population.

Virginia D. Steen and Thomas A. Medsger, Jr. 1146

The palpable tendon friction rub is an easily detected, inexpensively obtained physical examination finding which was shown to be highly associated with diffuse cutaneous scleroderma and decreased survival. When present early in disease, before more proximal skin thickening was evident, it was shown to predict the development of diffuse scleroderma and identify patients at increased risk for serious visceral involvement who are thus candidates for potential disease-modifying therapy.

Yasodha Natkunam, Kojo S. Elenitoba-Johnson, Douglas W. Kingma, and Onsi W. Kamel 1152

Immunomodulatory therapy for patients with rheumatic disease predisposes to the development of lymphoproliferative diseases associated with EBV. This study shows that both EBV strain types A and B are involved in the development of lymphoproliferative disorders in patients with rheumatic diseases. The findings further implicate the wild-type virus, as well as viruses containing a deleted form of the latent membrane protein of EBV, in the genesis of immunosuppression-associated lymphoproliferative diseases.

Noboru Suzuki, Sakae Kaneko, Motohide Ichino, Shoji Mihara, Sueshige Wakisaka, and Tsuyoshi Sakane 1157

This study clarifies the in vivo mechanisms of action of FK-506 that can be applied to the treatment of various autoimmune diseases. In addition, a new consideration for the clinical application of FK-506 is suggested. Levels of FK-506 binding protein in T lymphocytes from patients treated with FK-506 vary considerably, and reduced levels may be associated with diminished clinical efficacy. However, PCR or Western blotting could be used to determine FK-506 binding protein levels, and therefore, to monitor the clinical efficacy of FK-506 treatment.