Ravinder N. Maini, Ferdinand C. Breedveld, Joachim R. Kalden, Josef S. Smolen, Diana Davis, John D. Macfarlane, Christian Antoni, Burkhard Leeb, Michael J. Elliott, James N. Woody, Thomas F. Schaible, and Marc Feldmann 1552

A single infusion of the monoclonal chimeric anti-TNFα antibody cA2 was previously shown to exert a marked antiinflammatory effect in RA patients, but relapse was common. The object of this multicenter, placebo-controlled, phase II trial in 101 patients, who had active disease despite weekly low-dose MTX therapy, was to establish whether repeated therapy with cA2 alone or in combination with MTX 7.5 mg/week would prove to be effective and safe. The best results in this 26-week trial were observed when cA2 at 1, 3, and 10 mg/kg was administered with MTX, thus defining a regimen for the further development of cA2 therapy for RA.

David T. Felson, Jennifer J. Anderson, Mary L. M. Lange, George Wells, and Michael P. LaValley 1564

This study was conducted to investigate whether a higher minimal threshold of improvement, i.e., 50% or 70% rather than 20%, should be used to classify patients as improved in RA clinical trials. It was found that use of these higher thresholds would compromise statistical power. It is recommended that 20% improvement still be used as the definition of improvement in clinical trials, with data on the number of patients achieving 50% improvement reported as a secondary efficacy measure.

Frederick Wolfe and John T. Sharp 1571

In comparison with previous studies that have shown a nonlinear pattern for the radiographic progression of RA, in which there is a substantially increased rate of progression in the first few years of RA, this prospective longitudinal study indicates that radiographic progession appears constant over the course of the disease. The strongest correlate of progression was the time-integrated erythrocyte sedimentation rate (ρ= 0.53). This association became stronger with time, and for patients followed up for 10-20 years, the correlation coeffficient was 0.67, indicating that acute-phase reactants are, by far, the strongest determinants of progression.

Harry K. Genant, Yebin Jiang, Charles Peterfy, Ying Lu, Janos Redei, and Peter J. Countryman 1583

This study shows that in patients with RA, semiquantitative scoring of joint erosion and joint space narrowing, as well as combined scoring of these variables, directly from laser-digitized radiographic images at pixel sizes of 100 [gm]m and 50 [gm]m, either at a single time point or serially, is highly reproducible and provides results very close to those obtained using the original conventional radiographs. This approach may be useful in studying the progression of RA, monitoring the response to drug therapy, and investigating the natural history of RA in epidemiologic studies.

Lee S. Simon, Frank L. Lanza, Peter E. Lipsky, Richard C. Hubbard, Sheela Talwalker, Benjamin D. Schwartz, Peter C. Isakson, and G. Steven Geis 1591

Because nonsteroidal antiinflammatory drugs inhibit COX-1 and COX-2 nonselectively, their efficacy in treating rheumatic diseases is tempered by the accompanying risk of serious gastrointestinal and other side effects. This report describes the first of a new class of agents that promise analgesic and antiinflammatory effficacy through selective COX-2 inhibition without the deleterious effects of COX-1 inhibition.

Steven R. Ytterberg, Maren L. Mahowald, and Sharon R. Woods 1603

This study provides the first data on efficacy, toxicity, tolerance, and addiction behaviors with prolonged codeine and oxycodone therapy in a large cohort of patients with well-defined rheumatologic diagnoses. The results provide a key component of ``hard'' data to challenge the textbook dogma that opioids are inappropriate ``for the treatment of pain of nonmalignant origin.'' Publication of this study will provide support and protection for physicians treating patients with chronic musculoskeletal diseases, who may be reluctant to prescribe opioids because of possible sanctions from state medical boards and federal regulatory agencies. More importantly, it will benefit patients by permitting them to receive these effective and safe medications.

Virginia D. Steen and Thomas A. Medsger, Jr. 1613

This retrospective case-control study determined a link between high-dose corticosteroids and the development of scleroderma renal crisis (SRC) in patients with systemic sclerosis. Other types of treatment, such as NSAIDs, calcium channel blockers, and ACE inhibitors, were not associated with an increased risk of SRC. Antecedent D-pencillamine therapy appeared to be protective against the development of SRC. Thus, physicians should be aware of these differences in treatment effects when balancing the use of steroid therapy against the risk of SRC.

Marta B. Moroldo, Patricia Donnelly, Jocelyn Saunders, David N. Glass, and Edward H. Giannini 1620

This study provides evidence, based on results of the transmission disequilibrium test, of linkage between disease and HLA class I and II alleles that have been found to be associated with pauciarticular-onset JRA in population-association studies. These data can be used to counsel families on the genetic basis of the child's disease.

Yasuo Ohosone, Mutsuko Ishida, Yoshiko Takahashi, Mami Matsumura, Michito Hirakata, Yoshie Kawahara, Takeji Nishikawa, and Tsuneyo Mimori 1625

In this study, sera from a large number of patients with rheumatic diseases were screened for the presence of autoantibodies directed against tRNA and tRNA-associated antigens, and the clinical spectrum and significance of these antibodies were investigated. The results suggest that these autoantibodies may be useful as clinical markers and potential predictors of patient outcome.

Sanshiro Hashimoto, Robert L. Ochs, Setsuro Komiya, and Martin Lotz 1632

Cell death in mature articular cartilage may impair tissue integrity by the depletion of cells that are responsible for remodeling of the extracellular matrix and by the formation of cell remnants that may lead to degradation and calcification of the extracellular matrix. This study demonstrates increased chondrocyte apoptosis in human OA cartilage and a linkage between apoptosis and proteoglycan depletion.

Michael Brewster, E. Jonathan Lewis, Kevin L. Wilson, Anna K. Greenham, and Kevin M. K. Bottomley 1639

The report describes the effects of Ro 32-3555, a novel, orally bioavailable matrix metalloproteinase inhibitor which is a potent selective inhibitor of collagenases. Oral administration of this compound to STR/ORT mice, which spontaneously develop osteoarthritis, resulted in significant inhibition of osteoarthritic changes as measured radiologically and histologically. As with the human condition, there are few drugs that inhibit STR/ORT mouse osteoarthritis. These results demonstrate that inhibition of collagenases prevents development of osteoarthritic changes and may have potential as a therapeutic approach in human osteoarthritis.

Merce Amat, Cesar D|fiaz, and Lu|fis Vila 1645

The inflammatory response is regulated by a complex network of cells and mediators. It is essential to have a full understanding of this process for adequate therapeutic intervention. This work adds to our knowledge about the mechanism of the cooperative action of chondrocytes and neutrophils in the generation of proinflammatory mediators.

Chandra Mohan, Laurence Morel, Ping Yang, and Edward K. Wakeland 1652

Expanded B1 cell populations have been described in rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. This study advances a potentially important mechanism by which B1 cells might contribute to autoimmunity in these diseases. The findings demonstrate that the component phenotypes of lupus can now be dissected and each disease susceptibility locus linked to a subset of these phenotypes. This could have important implications in relation to prognosis and therapy.

W. K. Ip, S. Y. Chan, C. S. Lau, and Y. L. Lau 1663

SLE is one of the more serious and common rheumatologic conditions seen and managed by clinical rheumatologists. It is important to be aware of the various risk factors predisposing patients to the development of SLE, such as C2- and C4-null alleles. This study describes another risk factor, the low-producing promoter polymorphism of the mannose-binding lectin (MBL) gene, resulting in low serum MBL levels.

Yoshitaka Morita, Masahiro Yamamura, Masanori Kawashima, Seishi Harada, Kazuhide Tsuji, Kazuko Shibuya, Keisuke Maruyama, and Hirofumi Makino 1669

This study demonstrates the cytokine profile of CD4+ T cells infiltrating RA synovium by using a recently developed technique, flow cytometric single-cell analysis of intracellular cytokines. This indicates that CD4+ T cells with the ability to secrete IFNγ and/or IL-10 predominate in the synovium compared with the peripheral compartment. These findings help further our understanding of the role of T cells in the pathogenesis of RA.

I. Gonzalez-Alvaro, C. Munoz, R. Garc|fia-Vicuna, P. Sabando, C. Cabanas, F. Sanchez-Madrid, and F. D|fiaz-Gonzalez 1677

This study describes a prostaglandin-independent mechanism of action of NSAIDs in lymphocytes. Some NSAIDs diminish the dynamic binding of lymphocytes to endothelial cells through interference with the VLA-4 conformational change that increases the affinity for its endothelial counterreceptor VCAM-1. This effect can account, in part, for the antiinflammatory properties of these drugs through the interference with leukocyte accumulation in inflammatory foci.

Haiko Sprott, Laurence A. Bradley, Shin J. Oh, Winfried Wintersberger, Graciela S. Alarcon, Holly G. Mussell, Anna Tseng, Renate E. Gay, and Steffen Gay 1689

Neuropeptides are known to contribute to pain perception via signaling from the muscle tissue back to the central nervous system in patients with fibromyalgia (FM). The present study failed to demonstrate production of neuropeptides in the peripheral muscle tissue of FM subjects, with the exception of 1 whose muscle tissue expressed galanin receptor (GAR) mRNA. Given that this finding was isolated, it cannot be concluded that activation of the GAR system is involved in the modulation of pain in FM. Nevertheless, treatment with GAR inhibitors might be an option for this particular subject.