Andreas Maetzel, Marcos Bosi Ferraz, and Claire Bombardier 16

In previous economic evaluations of misoprostol, based on information from endoscopy trials, modeling of important clinical downstream events (i.e., serious GI bleeding) and of major health care resource utilization was necessary to calculate cost-effectiveness. This led to conflicting results and an overestimation of the cost-effectiveness of misoprostol. The results of the present study illustrate the dangers inherent in "modeling" important events. Informed clinical and reimbursement decisions can only come from trials examining the ultimate events of clinical interest and from protocols that emulate routine clinical care. This new evaluation of misoprostol, based on such a trial, shows that to prescribe misoprostol for all patients with RA, the cost per averted GI bleed is $94,766 (Canadian). However, targeting subgroups of patients at higher risk is more cost-effective.

Maria C. Cid, Carme Font, Joaquim Oristrell, Alejandro de la Sierra, Blanca Coll-Vinent, Alfons Lopez-Soto, Jaume Vilaseca, Alvaro Urbano-Marquez, and Josep M. Grau 26

This study of 200 patients with biospy-proven GCA demonstrates that cranial ischemic events tend to cluster in particular patients, ischemic complications cannot be attributed solely to delayed diagnosis and treatment, and cranial ischemic complications tend to occur in patients with a poor inflammatory response (defined on clinical and biochemical grounds); conversely, a strong inflammatory reaction is associated with a very low risk of developing irreversible cranial ischemic complications. These results provide a rationale for testing less aggressive treatment regimens in GCA patients who are at low risk of developing irreversible cranial ischemic complications.

Camille J. Anderson, Barbara R. Neas, Zijian Pan, Elizabeth Taylor-Albert, Morris Reichlin, and Haraldine A. Stafford 33

Autoantibodies to the ribosomal P proteins (anti-P) may be pathogenic in childhood-onset and adult-onset SLE. This study investigated the presence of these antibodies in healthy children. An understanding of the regulation of these autoantibodies in the nondiseased state may foster new insights into the pathogenesis of and therapy for SLE.

Elizabeth Kozora, Sterling G. West, Brian L. Kotzin, Laura Julian, Scott Porter, and Erin Bigler 41

This study evaluates the usefulness of magnetic resonance imaging to assess cerebral abnormalities in relation to cognitive functioning in patients with SLE. The results are relevant for clinicians who utilize such neuroradiology techniques in the evaluation and treatment of patients with mild cognitive problems associated with SLE.

Arnaud Constantin, Patrick Loubet-Lescoulie, Nathalie Lambert, Bader Yassine-Diab, Michel Abbal, Bernard Mazieres, Claude de Preval, and Alain Cantagrel 48

Recently, significant accomplishments have been made in specifying the mode of action of methotrexate in the treatment of RA. This study, using competitive RT-PCR, demonstrated an in vitro modulation of the cytokine network by MTX during the course of RA: a decrease in IL-2 and IFNγ gene expression and an increase in IL-4 and IL-10 gene expression. This in vitro modulation of Th1-Th2 cytokines could explain the antiinflammatory and immunoregulatory action of MTX in vivo in the treatment of RA.

Jurgen Braun, Mathias Bollow, Gerold Remlinger, Ulrich Eggens, Martin Rudwaleit, Armin Distler, and Joachim Sieper 58

This is the first study to determine the prevalence of spondylarthropathies among Caucasians. The study findings suggest that spondylarthropathies are frequent inflammatory rheumatic diseases and that HLA-B27 is of value for diagnosis in early disease, when inflammatory back pain is the only clinical symptom.

Naoyuki Tsuchiya, Michiko Shiota, Satoshi Moriyama, Atsuko Ogawa, Miki Komatsu-Wakui, Hiroshi Mitsui, Daniel E. Geraghty, and Katsushi Tokunaga 68

This study describes the results of allele typing of MICA, a recently described polymorphic gene located in the proximity of HLA-B. Comparison of MICA alleles of HLA-B27 positive Japanese patients with spondylarthropathies and those of healthy individuals revealed strong linkage disequilibrium between HLA-B*2704 and MICA010, as well as HLA-B*2705 and MICA007. These results indicate that although HLA-B*2704 and B*2705 are highly homologous, each subtype is carried by an entirely different MHC haplotype. Such information may be useful in elucidating the role of HLA-B27 in the development of the diseases.

Dewayne Falkner, John Wilson, Thomas A. Medsger, Jr., and Penelope A. Morel 74

Autoantibodies to Th/To RNP are found in [approximate]5% of systemic sclerosis patients. These patients were found to have clinical features in common with ACA-positive SSc patients. Analysis of HLA alleles associated with anti-Th/To-positive SSc patients revealed a significant increase in HLA-DR11 (DRB1*1104) frequency and a significant decrease in HLA-DR7 frequency.

Emmanuel Maheu, Bernard Mazieres, Jean-Pierre Valat, Gerard Loyau, Xavier Le Loet, Pierre Bourgeois, Jean-Marie Grouin, and Sylvie Rozenberg 81

This work presents the results of a double-blind, randomized, placebo-controlled clinical trial of avocado/soybean unsaponifiables (ASU) in knee and hip OA. ASU was found to improve symptoms, with a delayed onset of action (1-2 months) and a prolonged and persistent action. ASU may be used by rheumatologists in clinical practice as a symptomatic drug in the treatment of OA patients.

Tomoko Toyosaki, Yuji Tsuruta, Takeshi Yoshioka, Hiroshi Takemoto, Ryuji Suzuki, Tetsuya Tomita, and Takahiro Ochi 92

The study demonstrates the presence of an RA-specific autoantigen recognized by CD4+ T cell clones which were established from patients with RA and which expressed TCR BV6 or BV12. The antigens had a molecular weight of 50/25 kd and were present exclusively in RA synovial cells, (not in non-RA synovial cells). The expression of unique antigens by synovial cells may trigger the autoreactivity of T cells in RA joints.

Koushi Fujisawa, Kazuyoshi Okamoto, Hiroshi Asahara, Tomoko Hasunuma, Tetsuji Kobata, Tomohiro Kato, Takayuki Sumida, and Kusuki Nishioka 101

This study demonstrates that T cells infiltrating into arthritic joints recognize HTLV-I env-pX gene products in HTLV-I env-pX transgenic mice, suggesting that the HTLV-I env-pX region acts as a transcriptional activator as well as an autoantigen. Moreover, the findings suggest that HTLV-I env-pX gene products may act as autoantigen in patients with HTLV-I-associated arthropathy.

J. S. Mudgett, N. I. Hutchinson, N. A. Chartrain, A. J. Forsyth, J. McDonnell, I. I. Singer, E. K. Bayne, J. Flanagan, D. Kawka, C. F. Shen, K. Stevens, H. Chen, M. Trumbauer, and D. M. Visco 110

This study involving an experimental model of CIA in stromelysin-1-deficient mice demonstrates that stromelysin inhibitors may not elicit the chondroprotective effect needed to reduce cartilage destruction in diseases such as OA and RA. This finding is in stark contrast to the proposed role of stromelysin inhibition, which has been based on correlational rather than direct evidence of matrix metalloproteinase expression and proteolytic activities.

Isabel Siegle, Thomas Klein, Janne T. Backman, Johannes G. Saal, Rolf M. Nusing, and Peter Fritz 122

The 2 identified COX isoforms and their roles, i.e., the proinflammatory role of the COX-2 isoform and the tissue-protective role of COX-1, are widely accepted. In this study, the expression of COX-2, but not the expression of COX-1, was clearly and differentially elevated in the synovial tissue of patients with various inflammatory joint diseases compared with that from patients with osteoarthritis. The observed disease-related variability in the expression of COX-2 may be connected to the clinical efficacy of the selective COX-2 inhibitors used to treat these different diseases; the results suggest high efficacy, especially in patients with ankylosing spondylitis.

Xuelian Tao, Hendrik Schulze-Koops, Li Ma, Jian Cai, Yanping Mao, and Peter E. Lipsky 130

Based on the observed efficacy of the Chinese herbal remedy TWHF, in patients with a variety of inflammatory and autoimmune diseases, the present study was undertaken to determine the mechanism of this therapeutic effect. The results indicate that extracts of TWHF, as well as the triptolide component, directly suppress PGE2 synthesis by inhibiting up-regulation of the cyclooxygenase isoform, COX-2. Patients treated with the TWHF extracts may show clinical benefit from these direct antiinflammatory effects.

Xiao Su, Tong Zhou, Pingar Yang, Carl K. Edwards, III, and John D. Mountz 139

This report describes a novel soluble TNFα binding protein capable of inhibiting arthritis, pneumonitis, and skin disease in autoimmune motheaten mice. These mice exhibit a defect in SHP-1 that results in defective Fas signaling and up-regulation of TNF/TNF receptor pathway. The results indicate that neutralization of TNFα may be effective in the treatment of inflammatory diseases associated with apoptosis defects.

Christopher P. Robinson, Shigeo Yamachika, Denise I. Bounous, Jason Brayer, Roland Jonsson, Rikard Holmdahl, Ammon B. Peck, and Michael G. Humphreys-Beher 150

Advances in understanding of Sjogren's syndrome have been hampered by our inability to develop animal models representative of the disease presentation and organ manifestations. This study analyzed a previously developed genetic derivative of the NOD mouse in which the I-Ag7 locus of the MHC has been replaced with the H2b allele (thus preventing the development of autoimmune diabetes but leaving intact the autoimmune sialadenitis and dacryoadenitis) for the continued presence of hallmark physiologic and biochemical markers of the NOD mouse model of secondary SS. The results establish the NOD.B10.H22 mouse as the first naturally occurring animal model for the study of primary SS, which will allow for the testing of new treatment strategies for control of the autoimmune exocrinopathy.

Louise A. McKenna, Hongxiang Liu, Paul A. Sansom, and Michael F. Dean 157

This work provides insight into the effects of a novel matrix molecule on the synthesis of articular cartilage matrix. This peptide may be involved in the early stages of repair of damaged tissue. Further investigation of its role may lead to the development of therapeutic peptides that could be used clinically to increase synthesis of new cartilage components and thus delay the rate of destruction and aid repair of damaged tissue.

Robert B. Zurier, Ronald G. Rossetti, Joan H. Lane, John M. Goldberg, Sheila A. Hunter, and Sumner H. Burstein 163

In this study, DM4-11C, a nonpsychoactive synthetic derivative of tetrahydrocannabinol, was shown to suppress acute inflammation in the subcutaneous air pouch model in mice, and chronic inflammation in adjuvant-induced arthritis in rats. DMH-11C should thus be further investigated as an antiinflammatory agent in rheumatoid arthritis.