397

Review: Genetics and Osteoarthritis: Exposing the Iceberg

Daniel Holderbaum, Tariq M. Haqqi, and Roland W. Moskowitz

406

ACR Presidential Address: Y2K, Strategic Alliances, and You

Ronald L. Kaufman

409

Provision of Primary Care by Office-Based Rheumatologists: Results from the National Ambulatory Medical Care Surveys, 1991-1995

Michael M. Ward

In this population-based study of outpatient visits to office-based rheumatologists, only 9.8% of new consultations and 11.9% of return visits involved patients who did not have a musculoskeletal condition or complaint. Among continuing patients with rheumatoid arthritis, 30% of visits included notation of a nonrheumatic complaint and 31% of visits involved the provision of medication for a nonrheumatic condition, indicating that rheumatologists were acting as principal caregivers for a minority of patients. Most of the work of rheumatologists involves consultative or specialized care in rheumatology, and proposals to broaden the work of rheumatologists such that they would be the principal caregivers for patients with rheumatic diseases would change the nature of current rheumatology practice.

415

The Epidemiology of Rheumatoid Arthritis in Rochester, Minnesota, 1955-1985

Sherine E. Gabriel, Cynthia S. Crowson, and W. Michael O'Fallon

In this study of a population-based cohort from Rochester, Minnesota, the incidence of RA over a period of 30 years was demonstrated to be dynamic, not static. These results support the hypothesis that environmental agents may play a role in the pathogenesis of RA.

421

Microscopic Polyangiitis: Clinical and Laboratory Findings in Eighty-Five Patients

Loic Guillevin, Bernard Durand-Gasselin, Ramiro Cevallos, Martine Gayraud, Francois Lhote, Patrice Callard, Jacques Amouroux, Philippe Casassus, and Bernard Jarrousse

MPA is usually considered to be a renal and/or pulmonary vasculitis. This study demonstrated that MPA is a multisystemic disease in which renal symptoms are frequent, but other, more general symptoms are also present. Outcomes are comparable with those of other systemic vaculitides, but relapses are frequent. In patients without glomerulonephritis or alveolar hemorrhage, the presence of antineutrophil cytoplasmic antibodies and the absence of microaneurysms and/or stenoses should be considered criteria for MPA.

431

Filtration Leukocytapheresis Therapy in Rheumatoid Arthritis: A Randomized, Double-Blind, Placebo-Controlled trial

Toshihiko Hidaka, Kimihiro Suzuki, Yasunori Matsuki, Mitsuyo Takamizawa-Matsumoto, Kouji Kataharada, Toshiaki Ishizuka, Makoto Kawakami, and Haruo Nakamura

A simple and practical on-line continuous filtration leukocytapheresis system has recently been developed. In the present study, a randomized, double-blind, placebo-controlled trial was performed to determine whether filtration leukocytapheresis is clinically beneficial for the treatment of RA. The results indicate that this novel modality is an effective and well-tolerated therapy for drug-resistant RA.

438

Tumor Necrosis Factor a Microsatellite Polymorphism is Associated with Rheumatoid Arthritis Severity Through an Interaction with the HLA-DRB1 Shared Epitope

Hua Mu, John J. Chen, Yebin Jiang, Mary-Claire King, Glenys Thomson, and Lindsey A. Criswell

Several lines of evidence implicate an important role for tumor necrosis factor [ga] in RA. The results of the present study suggest that TNF[ga] microsatellite polymorphism influences RA severity through an interaction with the HLA-DRB1 shared epitope.

443

Serum Lipoprotein(a) and Apolipoprotein(a) Phenotypes in Patients with Rheumatoid Arthritis

Yu Asanuma, Shinichi Kawai, Hideyuki Aoshima, Junichi Kaburaki, and Yutaka Mizushima

In this study, serum Lp(a) concentrations and Apo(a) phenotypes were determined in RA patients and healthy controls. The mean serum Lp(a) level was significantly increased in RA patients, possibly due in part to an increased frequency of the S3 phenotype. Since there is growing evidence that Lp(a) is an independent risk factor for atherosclerotic disease and cardiovascular disease is a major cause of death in patients with RA, it is important to investigate serum Lp(a) levels and phenotypes in these patients.

448

Detection of Human Retrovirus 5 in Patients with Arthritis and Systemic Lupus Erythematosus

David J. Griffiths, Stephen P. Cooke, Christine Herve, Shirley P. Rigby, Eleanor Mallon, Ali Hajeer, Matthew Lock, Vincent Emery, Peter Taylor, Panagiotis Pantelidis, Christopher B. Bunker, Ronald du Bois, Robin A. Weiss, and Patrick J. W. Venables

This report describes the frequent detection of a novel retrovirus in patients with arthritis and SLE. If this virus is shown to have a role in the pathogenesis of these diseases, it will have far-reaching effects on their diagnosis and treatment.

455

A Critical Evaluation of Enzyme Immunoassays for Detection of Antinuclear Autoantibodies of Defined Specificities. I. Precision, Sensitivity, and Specificity

Eng M. Tan, Josef S. Smolen, J. S. McDougal, Brian T. Butcher, Doyt Conn, Roger Dawkins, Marvin J. Fritzler, Thomas Gordon, John A. Hardin, Joachim R. Kalden, Robert G. Lahita, Ravinder N. Maini, Naomi F. Rothfield, Ruud Smeenk, Yoshinari Takasaki, Walther J. van Venrooij, Allan Wiik, Merlin Wilson, and James A. Koziol

In this study, an international committee carried out a comprehensive evaluation of commercial enzyme-based immunoassay kits for the detection of ANA. Nine manufacturers participated in this study and were asked to evaluate coded human sera containing ANA of defined specificities. Some immunoassay kits performed poorly, but others performed well in terms of sensitivity, specificity, and precision. Diagnostic laboratory personnel contemplating the use of these immunoassay kits would be justified in contacting manufacturers for information concerning performance characteristics of their kits and asking whether deficiencies detected in this study have been corrected.

465

Influence of Ethnic Background on Clinical and Serologic Features in Patients with Systemic Sclerosis and Anti-DNA Topoisomerase I Antibody

Masataka Kuwana, Junichi Kaburaki, Frank C. Arnett, Robert F. Howard, Thomas A. Medsger, Jr., and Timothy M. Wright

This study shows that clinical features and autoantibody specificities are different among white, black, Japanese, and Native American SSc patients who have serum anti-DNA topoisomerase I antibody. The results suggest that multiple factors related to ethnic background have important influences on the clinical and serologic features of SSc.

475

Effects of Joint Lavage and Steroid Injection in Patients with Osteoarthritis of the Knee: Results of a Multicenter, Randomized, Controlled trial

Philippe Ravaud, Laurence Moulinier, Bruno Giraudeau, Xavier Ayral, Corinne Guerin, Eric Noel, Philippe Thomas, Bruno Fautrel, Bernard Mazieres, and Maxime Dougados

This report describes the results of a randomized, controlled trial of joint lavage and intraarticular steroid injection, alone and in combination, in symptomatic treatment of patients with knee OA. The effects of these 2 treatments were found to be additive but not synergistic, and the mean duration of pain relief differed between the 2 treatments: 4 weeks for steroid injection and 24 weeks for joint lavage. Further studies should be undertaken to identify subgroups of patients who might best benefit from either or both of these treatments.

483

The Associations of Bone Mineral Density and Bone Turnover Markers with Osteoarthritis of the Hand and Knee in Pre- and Perimenopausal Women

Maryfran Sowers, Laurie Lachance, David Jamadar, Marc C. Hochberg, Bruce Hollis, Mary Crutchfield, and Mary L. Jannausch

In this study, BMD was recorded in pre- and perimenopausal women with recently diagnosed hand and knee OA. BMD was greater in women with knee OA than in those without knee OA, and osteocalcin measurements indicated that bone turnover was reduced in women with either hand OA or knee OA, compared with controls. Clinicians should consider this information when diagnosing and treating both osteoarthritis and osteoporosis. They should not direct their activities at one disease independently of the other disease.

490

Gene transfer of Cytokine Inhibitors into Human Synovial Fibroblasts in the SCID Mouse Model

Ulf Muller-Ladner, Christopher H. Evans, Barry N. Franklin, Charles R. Roberts, Renate E. Gay, Paul D. Robbins, and Steffen Gay

This study evaluated the feasibility of gene transfer of inhibitors of proinflammatory cytokines into RA synovial fibroblasts, and examined the effects on invasiveness of RA synovial fibroblasts and on perichondrocytic cartilage degradation in the SCID mouse model. The experiements revealed that inhibition of only one destructive pathway might not be sufficient to completely inhibit joint destruction in RA, and "double gene transfer" might be required to inhibit both invasion of RA synovial fibroblasts and perichondrocytic cartilage degradation. The combination of interleukin-1 receptor antagonist and interleukin-10 might therefore be a promising approach.

498

Efficacy of Sustained Blood Levels of Interleukin-1 Receptor Antagonist in Animal Models of Arthritis: Comparison of Efficacy in Animal Models with Human Clinical Data

Alison Bendele, tracy McAbee, Gina Sennello, Jan Frazier, Elizabeth Chlipala, and Dorothy McCabe

This report describes studies that were designed to correlate efficacy of IL-1Ra in rat models of arthritis with blood levels of IL-1Ra sustained by continuous infusion. The results were then compared with those seen in rheumatoid arthritis patients, in an attempt to determine the most relevant animal model for predicting IL-1Ra activity. IL-1Ra might provide substantially more clinical benefit to patients if it were delivered in such a way as to maintain constant blood levels, thus providing a more consistent receptor blockade.

507

Synovial Fluid transforming Growth Factor [gb] Inhibits Dendritic Cell-T Lymphocyte Interactions in Patients with Chronic Arthritis

Kelly L. Summers, John L. O'Donnell, Axel Heiser, John Highton, and Derek N. J. Hart

This study supports the emerging concept that, rather than being solely a location of immune activation, the cytokine milieu of the rheumatoid joint is associated with T lymphocyte hyporesponsiveness, which may also affect antigen-presenting cell function. Antigen clearance and ``natural'' down-regulation of the immune response may be hindered, rather than enhanced, by therapies that further suppress the immune response.

519

Tumor Necrosis Factor [ga] Regulation of the Fas-Mediated Apoptosis-Signaling Pathway in Synovial Cells

Tetsuya Kobayashi, Kazuyoshi Okamoto, Tetsuji Kobata, Tomoko Hasunuma, Takayuki Sumida, and Kusuki Nishioka

Fas-mediated apoptosis is specifically observed in synovial cells from patients with rheumatoid arthritis, but not from patients with osteoarthritis or normal controls. However, the triggers for initial induction of Fas-mediated apoptosis and its mechanisms in rheumatoid synoviocytes have not been elucidated. This study shows that susceptibility to Fas-mediated apoptosis is provided by TNF[ga], which is one of the most important factors in abnormal proliferation of rheumatoid synoviocytes. The results further indicate that this process may be associated with the up-regulation and activation of apoptosis-signaling molecules, such as caspase 8 and caspase 3.

527

Immune Responses to Cartilage Link Protein and the G1 Domain of Proteoglycan Aggrecan in Patients with Osteoarthritis

Alexei Guerassimov, Yiping Zhang, Annie Cartman, Lawrence C. Rosenberg, John Esdaile, Mary-Ann Fitzcharles, and A. Robin Poole

This study identifies cartilage link protein and the G1 globular domain of proteoglycan aggrecan as potential antigens involved in the development of OA. The expression of cellular immunity to cartilage proteins is a common observation in inflammatory joint disesases, and thus may be involved in the pathogenesis of OA.

534

Changes in Joint Cartilage Aggrecan After Knee Injury and in Osteoarthritis

L. Stefan Lohmander, Mirela Ionescu, Hitu Jugessur, and A. Robin Poole

OA is a disease characterized by dynamic, measurable changes in turnover of joint cartilage constituents. In joint fluids from patients with knee injury, OA, or pyrophosphate arthritis, marked changes in a putative marker of aggrecan synthesis were shown, consistent with significant alterations not only in the rate of degradation of aggrecan, but also in its synthesis during the different phases of development of OA. A better understanding of the mechanisms and regulation of these processes may help in the development of treatments for this disease.

545

Diacerhein treatment Reduces the Severity of Osteoarthritis in the Canine Cruciate-Deficiency Model of Osteoarthritis

Gerald N. Smith, Jr., Stephen L. Myers, Kenneth D. Brandt, Elizabeth A. Mickler, and Marjorie E. Albrecht

OA was induced in 20 adult mongrel dogs by transection of the anterior cruciate ligament of the left knee. One group of dogs received a capsule of diacerhein twice daily, beginning the day after surgery (total daily dose 40 mg/kg), and the other group received placebo capsules on the same schedule, for 32 weeks. Diacerhein treatment significantly reduced the severity of morphologic changes of OA compared with placebo. These findings support the view that diacerhein may be a disease-modifying drug for OA.

555

transduction Mechanisms of Porcine Chondrocyte Inorganic Pyrophosphate Elaboration

Lawrence M. Ryan, Indira V. Kurup, and Herman S. Cheung

Calcium pyrophosphate dihydrate crystals may cause acute arthritis and may lead to osteoarthritis. These crystals are formed by extracellular inorganic pyrophosphate from chondrocytes. The results of this study identify cAMP and protein kinase C as two transduction pathways of inorganic pyrophosphate. Modulation of these pathways may be an avenue for the development of novel therapies.

561

Vasculitis in the Palmerston North Mouse Model of Lupus: Phenotype and Cytokine Production Profile of Infiltrating Cells

Irina G. Luzina, Robert H. Knitzer, Sergei P. Atamas, William C. Gause, John C. Papadimitriou, Marcelo B. Sztein, Catherine E. Storrer, and Barry S. Handwerger

Understanding of the immunopathologic mechanisms underlying systemic lupus erythematosus has been aided greatly by the availability of several murine models of the disease. Systemic vasculitis is a prominent feature of both human and murine lupus. PN mice spontaneously develop, with age, a female-predominant, lupus-like disease, characterized by a systemic perivasculitis/vasculitis, immune complex-mediated glomerulonephritis, and abnormalities in T cell and B cell function and autoantibody production. This report describes the phenotype of the cells present in the perivascular and vascular infiltrates in the PN model of lupus and the cytokines produced by those cells.

569

Interferon-[gb]1A-Induced Polyarthritis in a Patient with the HLA-DRB1*0404 Allele

Marc C. Levesque, Frances E. Ward, Douglas R. Jeffery, and J. Brice Weinberg

573

Watermelon Stomach

Frederick T. Murphy, Raymond J. Enzenauer, and Christopher P. Cheney

574

Sacroiliitis, Hyperostosis Sternoclavicularis, and Psoriasis Palmoplantaris in Monozygotic Twins

Axel Hoffmann, Robert Dinser, Roland Linder, Karl F. R. Neufang, and Wilhelm Krone

577

Spinal Epidural Hematoma Complicating Active Systemic Lupus Erythematosus

Berna Goker and Joel A. Block

578

Diffuse Infiltrative Lymphocytosis Syndrome in a Patient with Anti-52-kd Ro/SSA and Human Immunodeficiency Virus Type 1

Arne Hansen, Eugen Feist, Falk Hiepe, Gerd Rudiger Burmester, and Jurgen Scholze

580

Efficacy of Thalidomide in the treatment of Refractory Ankylosing Spondylitis

Maxime Breban, Bruno Gombert, Bernard Amor, and Maxime Dougados

581

Lack of Endothelial Cell Apoptosis in the Dermis of Tight Skin 1 and Tight Skin 2 Mice

Roswitha Sgonc, Hermann Dietrich, Claudia Sieberer, Georg Wick, Paul J. Christner, and Sergio A. Jimenez

585

We Need Simple Guidelines for Reporting Rates of Rheumatic Diseases

Daniel J. McCarty, C. Kent Kwoh, Rosalind Ramsey-Goldman, Susan Manzi, and Thomas A. Medsger, Jr.

585

Significantly Increased Frequency of Baseline IgA Anti-Type II Collagen Positivity in the Placebo Group in a Study of Oral Type II Collagen treatment of Rheumatoid Arthritis: Comment on the Article by Barnett et al

Alfonse T. Masi and Jean C. Aldag

587

Reply

Martha L. Barnett and David E. trentham

587

The Influence of Sex on the Frequency of Erosive Disease and Extraarticular Manifestations in Rheumatoid Arthritis: Comment on the Article by Weyand et al

Graciela S. Alarcon

588

Sex-Associated Factors and the Presentation of Rheumatoid Arthritis: Comment on the Article by Weyand et al

A. Saraux, C. Guedes, H. Belghomari, P. Youinou, and P. Le Goff

589

Reply

Cornelia M. Weyand and Jorg J. Goronzy

590

Expression of Matrix Metalloproteinase 1 in Rodents: Comment on the Article by Huebner et al

Moises Selman and Annie Pardo

590

Reply

Janet L. Huebner and Virginia B. Kraus

590

Interleukin-10 Promoter Polymorphism and Lupus Nephritis: Comment on the Article by Mok et al

Esther Crawley, David Isenberg, Patricia Woo, and Richard Kay

591

Reply

Chi Chiu Mok, Chak Sing Lau, and Jerry S. Lanchbury

593

The Role of Carrier Protein in the Sensitivity of Enzyme-Linked Immunosorbent Assay for Antiribosomal P Protein Antibodies: Further Comment on the Article by Yoshio et al

Shunsei Hirohata, Kunio Isshi, and Satoshi Toyoshima

594

Pyrophosphate Arthritis After Intraarticular Injection of Hyaluronan: Comment on the Article by Luzar and Altawil

Jean Francis Maillefert and Christian Tavernier

17A

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