1785

Guidelines for Referral and Management of Systemic Lupus Erythematosus in Adults

American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines

1797

Current Comment: Listening to the Patient: A Practical Guide to Self-Report Questionnaires in Clinical Care

Frederick Wolfe and Theodore Pincus

1809

Editorial: Lyme Arthritis: Lessons Learned and to be Learned

Leonard H. Sigal

1813

Association of Antibiotic Treatment-Resistant Lyme Arthritis with T Cell Responses to Dominant Epitopes of Outer Surface Protein A of Borrelia burgdorferi

Jie Chen, Jodie A. Field, Lisa Glickstein, Philip J. Molloy, Brigitte T. Huber, and Allen C. Steere

Lyme arthritis may persist for months to years after treatment. In this study of 16 patients with treatment-responsive and 16 with treatment-resistant Lyme arthritis, the maximum severity of joint swelling and the duration of arthritis after antibiotic treatment were associated with T cell responses to specific epitopes of outer surface protein A of Borrelia burgdorferi. This response may be critical in the pathogenesis of treatment-resistant Lyme arthritis.

1823

Fc[gg] Receptor Polymorphisms in Wegener's Granulomatosis: Risk Factors for Disease Relapse

Hilde M. Dijstelbloem, Ronald H. M. Scheepers, Wia W. Oost, Coen A. Stegeman, W. Ludo van der Pol, Wim J. Sluiter, Cees G. M. Kallenberg, Jan G. J. van de Winkel, and Jan Willem Cohen Tervaert

This study analyzed functional Fc[gg] receptor polymorphisms for a possible relation with disease expression and occurrence of relapses in WG. The study is the first to establish that heritable risk factors for WG are coupled to exogenous factors relevant to WG relapses, such as chronic nasal carriage of the Staphylococcus aureus bacterium. These findings may be of considerable value to the prognosis of disease and prevention of disease relapses in patients with WG.

1828

Overrepresentation of the Fc[gg] Receptor Type IIA R131/R131 Genotype in Caucasoid Systemic Lupus Erythematosus Patients with Autoantibodies to C1q and Glomerulonephritis

Peter Norsworthy, Efstathios Theodoridis, Marina Botto, Panagiotis Athanassiou, Huw Beynon, Caroline Gordon, David Isenberg, Mark J. Walport, and Kevin A. Davies

It is clear that genetic factors are important in determining susceptibility to SLE. The role of genetically determined variations in the function of Fc receptors remains controversial. This study demonstrates that a well-described Fc receptor variant, which has previously been proposed as a risk factor for lupus, has specific clinical associations--notably with glomerulonephritis and autoantibodies to the complement component C1q.

1833

The Spectrum of Apoptotic Defects and Clinical Manifestations, Including Systemic Lupus Erythematosus, in Humans with CD95 (Fas/APO-1) Mutations

Akshay K. Vaishnaw, Elias Toubi, Satomi Ohsako, Jorn Drappa, Saundra Buys, Jaime Estrada, Anneliese Sitarz, Larry Zemel, Jia-Li Chu, and Keith B. Elkon

This is a study of the clinical spectrum of disease in humans with mutations in the CD95 (Fas/APO-1) receptor. The clinical and serologic features from 1 informative family with a heterozygous CD95 mutation are described. It was found that the combination of a CD95 mutation with loss of regulation of B lymphocytes predisposes to systemic lupus erythematosus.

1843

Age-Specific Effects of Juvenile Rheumatoid Arthritis-Associated HLA Alleles

Kevin J. Murray, Marta B. Moroldo, Patricia Donnelly, Sampath Prahalad, Murray H. Passo, Edward H. Giannini, and David N. Glass

This report involving 680 patients with JRA and 254 ethnically matched controls identifies at what age HLA alleles associated with disease susceptibility and protection exert their influence. Some alleles were found to increase susceptibility to disease early in life, but not to contribute risk past a certain age. Others seem to protect very young children from certain forms of the disease, only to become risk factors later in childhood. The study also establishes more clearly the boundaries of onset age for the pauciarticular and polyarticular subtypes of JRA.

1854

Long-Term Course and Outcome of Functional Capacity in Rheumatoid Arthritis: The Effect of Disease Activity and Radiologic Damage Over Time

K. W. Drossaers-Bakker, M. de Buck, D. van Zeben, A. H. Zwinderman, F. C. Breedveld, and J. M. W. Hazes

This study shows that during the first 12 years of RA, disease activity is the most important determinant in the loss of functional capacity in RA patients. This has implications for treatment. Since maintaining optimal function is a main goal in the treatment of RA, achieving maximal control of disease activity is important in both the early and late stages of the disease.

1861

Serum Levels of Hyaluronan, Antigenic Keratan Sulfate, Matrix Metalloproteinase 3, and Tissue Inhibitor of Metalloproteinases 1 Change Predictably in Rheumatoid Arthritis Patients Who Have Begun Activity After a Night of Bed Rest

Daniel-Henri Manicourt, Pascal Poilvache, Adrien Nzeusseu, Anne van Egeren, Jean-Pierre Devogelaer, Mary Ellen Lenz, and Eugene J.-M. A. Thonar

This study provides strong evidence that, after a night of rest, moderate physical activity results in marked changes in serum levels of several markers of joint metabolism. The findings suggest that measurement of these changes in these levels may prove more useful than measuring marker levels at a single time point. They also indicate that in study protocols, more careful attention should be paid to the amount and types of activities patients undergo prior to blood drawing. Without this requirement, comparison of serum marker levels within patient populations may be inappropriate.

1870

Function and Health-Related Quality of Life: Results from a Randomized Controlled Trial of Leflunomide versus Methotrexate or Placebo in Patients with Active Rheumatoid Arthritis

Vibeke Strand, Peter Tugwell, Claire Bombardier, Andreas Maetzel, Bruce Crawford, Catherine Dorrier, Ann Thompson, and George Wells, on behalf of the Leflunomide Rheumatoid Arthritis Investigators Group

Significantly greater improvements in function, performance of activities important to patients, and health-related quality of life were observed in the leflunomide and methotrexate treatment groups when compared with placebo in this 12-month randomized controlled trial. These improvements correlated with the American College of Rheumatology response status and reflected clinically important changes that are meaningful to patients with RA.

1879

Global Statistical Tests for Comparing Multiple Outcomes in Rheumatoid Arthritis Trials

Barbara C. Tilley, Stanley R. Pillemer, Stephen P. Heyse, Shuhui Li, Daniel O. Clegg, Graciela S. Alarcon, and the MIRA Trial Group

The global statistical approach (GST) is used when multiple outcomes per patient are required to assess treatment effectiveness in clinical trials. This study compares the information provided by the GST with that provided by the American College of Rheumatology (ACR) core set of RA disease activity measures and shows how the GST combines the unique contributions of each outcome to provide an overall estimate of treatment effect. The GST allows inclusion of outcome measures in addition to the ACR core set, but with greater statistical power, and provides clinicians with another assessment tool for clinical trials relating to RA and other rheumatic diseases.

1889

Lower Prevalence of Chlamydia pneumoniae DNA Compared with Chlamydia trachomatis DNA in Synovial Tissue of Arthritis Patients

H. Ralph Schumacher, Jr., Herve C. Gerard, Thurayya K. Arayssi, Jose A. Pando, Patrick J. Branigan, Diego L. Saaibi, and Alan P. Hudson

Infection with Chlamydia pneumoniae usually occurs at a higher prevalence than that of Chlamydia trachomatis. This study demonstrates that C pneumoniae DNA is present in synovial tissue from patients with reactive arthritis, undifferentiated oligoarthritis, and other arthritides, although at a lower prevalence than that of C trachomatis. Patient histories of respiratory infection were not useful predictors of synovial polymerase chain reaction positivity for the organism. These results do not demonstrate a causal relationship between C pneumoniae and any specific type of arthritis, but they show that the organism can and does disseminate to the joints, indicating that further studies are warranted.

1894

Ciprofloxacin Treatment Does Not Influence Course or Relapse Rate of Reactive Arthritis and Anterior Uveitis

Denis Wakefield, Peter McCluskey, Manju Verma, Karim Aziz, Barrie Gatus, and Gregory Carr

This study assessed the efficacy of ciprofloxacin in the treatment of ReA and AU in a double-blind, randomized, placebo-controlled trial. It was shown that long-term treatment of ReA and AU patients with ciprofloxacin made no statistically significant difference to the natural history of these diseases or their severity. Further large, prospective studies with well-defined patient and control samples are needed to determine the role of antibiotics in the treatment of ReA and AU.

1898

Hepatitis C Virus but Not GB Virus C/Hepatitis G Virus has a Role in Type II Cryoglobulinemia

Fanghua Liu, Glenn B. Knight, and Vincent Agnello

The results of this study of US patients with mixed cryoglobulinemia reveal that, in contrast to high prevalences of HCV and HGV coinfection in type II cryoglobulinemia that have been reported in some studies from Europe, the prevalence in the US is low. When coinfection occurs, HCV, but not HGV, is concentrated in the cryoglobulins and correlates with cryoglobulinemia. After elimination of HCV and cryoglobulins from the serum following therapy with interferon-[ga], high titers of HGV may persist in the asymptomatic patient.

1902

Confirmation of Genetic Linkage Between Human Systemic Lupus Erythematosus and Chromosome 1q41

Kathy L. Moser, Courtney Gray-McGuire, Jennifer Kelly, Neeraj Asundi, Hua Yu, Gail R. Bruner, Monique Mange, Robert Hogue, Barbara R. Neas, and John B. Harley

Results of this linkage analysis indicate that at least 1 genetic effect near the D1S229 locus is important for lupus susceptibility in European Americans. Identifying the linkages and then the genes that increase the susceptibility for lupus will assist in the diagnosis, prognostication, and identification of therapeutic opportunities for better treatments of lupus. The clinical rheumatologist will be interested in the developing utility of these genes.

1908

Diminished Levels of T Cell Receptor [gz] Chains in Peripheral Blood T Lymphocytes from Patients with Systemic Lupus Erythematosus

Veronika Brundula, Liliana J. Rivas, Ana M. Blasini, Magdalena Par|fis, Susana Salazar, Ivan L. Stekman, and Martin A. Rodr|figuez

T lymphocytes are known to play a fundamental role in the pathogenesis of murine and human lupus. Recent evidence suggests a dysregulated response of SLE T cells on stimulation via the TCR/CD3 pathway. This study examined the expression of several molecules that participate in the coupling of early tyrosine phosphorylation events triggered by TCR/CD3 engagement. Diminished expression of TCR[gz] chains was found in unstimulated SLE PB lymphocytes. Abnormalities in postreceptor signaling on antigen receptor ligation may lead to unbalanced T lymphocyte gene expression and may contribute to the triggering and perpetuation of autoimmune responses in patients with SLE. The unraveling of potential signaling abnormalities in lupus T lymphocytes may open new perspectives of drug intervention in this disease.

1917

Differential Regulation of Rheumatoid Synovial Cell Interleukin-12 Production by Tumor Necrosis Factor [ga] and CD40 Signals

Minetake Kitagawa, Hiroshi Mitsui, Hiroshi Nakamura, Shinichi Yoshino, Shunpei Miyakawa, Naoyuki Ochiai, Makoto Onobori, Hiroshi Suzuki, and Takayuki Sumida

This study shows that IL-12 production by synovial cells from RA patients is regulated by 2 different pathways. One pathway is T cell dependent, predominantly through CD40-CD154 interaction, while the other is T cell independent, mediated through TNF[ga]. These results indicate that treatment of RA may require independent effects on CD40-CD154 interaction leading to IL-12 production and on TNF[ga] production leading to direct induction of inflammation.

1927

Treatment with Sulfasalazine or Sulfapyridine, but Not 5-Aminosalicylic Acid, Inhibits Basic Fibroblast Growth Factor-Induced Endothelial Cell Chemotaxis

Michael V. Volin, Lisa A. Harlow, James M. Woods, Phillip L. Campbell, M. Asif Amin, Michihide Tokuhira, and Alisa E. Koch

This study investigates the effects of SSZ and its metabolites, SP and 5-ASA, on components of angiogenesis, i.e., EC chemotaxis and proliferation, as well as on EC chemokine and soluble adhesion molecule expression. The study sheds light on a new mechanism of action for SSZ as a potential inhibitor of angiogenesis in chronic inflammatory diseases such as rheumatoid arthritis, and identifies decreases in cytokine-stimulated EC expression of chemokines and soluble adhesion molecules with SSZ, SP, and 5-ASA treatment. The inhibition of angiogenesis is potentially a very powerful tool for treating arthritis patients.

1936

Induction of [ga]1-Antitrypsin Synthesis in Human Articular Chondrocytes by Interleukin-6-Type Cytokines: Evidence for a Local Acute-Phase Response in the Joint

Dagmar-Christiane Fischer, Barbara Siebertz, Eddy van de Leur, Karl-Heinz Schiwy-Bochat, Lutz Graeve, Peter-C. Heinrich, and Hans-Dieter Haubeck

This study analyzed whether different IL-6-type cytokines induce the synthesis of [ga]1-antitrypsin, a major inhibitor of serine proteinases, in human articular chondrocytes. The results clearly demonstrate the induction of [ga]1-antitrypsin synthesis by IL-6-type cytokines at the mRNA and protein levels. Stimulation of human articular chrondrocytes with IL-6 or oncostatin M led to a 5-10-fold increase in [ga]1-antitrypsin synthesis and secretion. Furthermore, oncostatin M and IL-6 were found to stimulate IL-6 synthesis in chrondrocytes, resulting in an autocrine amplification loop. These data strongly suggest the existence of a local acute-phase response in the joint, which may be an important protective mechanism of articular chondrocytes to prevent cartilage damage in inflammatory joint diseases.

1946

Up-Regulation of MDC15 (Metargidin) Messenger RNA in Human Osteoarthritic Cartilage

Beate B. Bohm, Thomas Aigner, Angelika Gehrsitz, Carl P. Blobel, Joachim R. Kalden, and Harald Burkhardt

Members of the metalloproteinase disintegrin (metalloproteinase/disintegrin/cysteine-rich [MDC], or ADAM) protein family are considered to play an important role in protein ectodomain processing, matrix degradation, and integrin-mediated cell-matrix interactions, processes that are characteristically disturbed in OA cartilage remodelling. In this study, the expression of MDC15 (metargidin) in normal versus OA articular cartilage was investigated. The results show a strong up-regulation of MDC15 messenger RNA in OA cartilage, indicating the potential importance of MDC15 as an effector molecule in cartilage degeneration.

1951

Evidence for Neurogenic Transmission Inducing Degenerative Cartilage Damage Distant from Local Inflammation

Elvire Decaris, Corinne Guingamp, Mireille Chat, Lionel Philippe, Joel-Paul Grillasca, Amr Abid, Alain Minn, Pierre Gillet, Patrick Netter, and Bernard Terlain

The results of this study show that in inflammation, the nervous system not only contributes to pain phenomena but also, acting through innervated areas such as synovium, can provoke degeneration in distant articular cartilage. Such articular degenerative effects involve neurogenic mechanisms, in particular neuropeptide release, and may be provoked by the induction of inflammatory cytokines. This phenomenon has long been suspected in osteoarticular diseases such as algodystrophy and neurogenic arthropathy and may be of great importance in research on degenerative osteoarticular disease.

1961

Association Analysis Between the MIC-A and HLA-B Alleles in Japanese Patients with Behcet's Disease

Nobuhisa Mizuki, Masao Ota, Yoshihiko Katsuyama, Kazuro Yabuki, Hitoshi Ando, Kaori Goto, Satoshi Nakamura, Seiamak Bahram, Shigeaki Ohno, and Hidetoshi Inoko

Investigation of the genetic background of Behcet's disease at the DNA level is important for elucidating the molecular mechanism underlying the development of the disease and is also useful for clinical rheumatologists in diagnosing the disease. Recent studies have pinpointed the critical region for Behcet's disease in the major histocompatibility complex to be a 46-kb segment between the MIC-A gene and the HLA-B gene. In the present study, MIC-A genotyping and HLA-B testing were performed in Behcet's disease patients and controls, and the findings indicated that the HLA-B*51 allele is the more critical disease susceptibility gene. Secondary association with the MIC-A009 allele results from its linkage disequilibrium with HLA-B*51.

1967

Th1 Polarization of the Immune Response in Behcet's Disease: A Putative Pathogenetic Role of Interleukin-12

Maria Antonia Frassanito, Rosanna Dammacco, Paola Cafforio, and Franco Dammacco

This study demonstrates a strong polarization of immune response toward a Th1 pathway characterized by 1) increased percentages of peripheral Th1 lymphocytes and 2) increased serum levels of IL-12 in patients with active Behcet's disease. The highest proportion of Th1 lymphocytes was associated with a clinical flare, whereas a slight improvement or worsening of clinical signs coincided with a reduction or rise in peripheral CD3+/interferon-[gg]+. These results indicate that a quantitative evaluation of Th1 lymphocytes is a useful marker of Behcet's disease activity. Furthermore, apoptotic analysis revealed an increased susceptibility of patients' peripheral blood lymphocytes to spontaneous and Fas-mediated apoptosis and suggested a chronically active state of the immune system. Addition of recombinant IL-12 rescued phytohemagglutinin-activated peripheral blood lymphocytes from activation-induced cell death. Based on these results, overproduction of IL-12 by antigen-presenting cells can be postulated to play a central role in the pathogenesis of Behcet's disease.

1975

Modulation at Multiple Anchor Positions of the Peptide Specificity of HLA-B27 Subtypes Differentially Associated with Ankylosing Spondylitis

Jose R. Lamas, Alberto Paradela, Fernando Roncal, and Jose A. Lopez de Castro

This study is of interest because it analyzes in depth the peptide properties of HLA-B27, which is thought to be related to the pathogenesis of spondylarthropathy. In particular, the differences in peptide specificity between B*2704 and B*2706, as characterized in this report, are likely to be critical for the differential association between these 2 subtypes and ankylosing spondylitis.

1986

Differential Mechanisms of Inorganic Pyrophosphate Production by Plasma Cell Membrane Glycoprotein-1 and B10 in Chondrocytes

Kristen Johnson, Sucheta Vaingankar, Ying Chen, Allison Moffa, Mary B. Goldring, Kimihiko Sano, Piao Jin-Hua, Adnan Sali, James Goding, and Robert Terkeltaub

Increased cartilage PPi production and elevated PPi-generating nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity in chondrocytes are central changes that promote calcium pyrophosphate dihydrate (CPPD) crystal deposition in aging and osteoarthritis. This report defines a selective mechanism by which the PC-1, but not the closely related B10, NTPPPH activity functions to markedly increase the extracellular PPi concentration in chondrocytes. The results point to potential means to control PPi supersaturation in cartilage, and thereby to potentially inhibit the development of CPPD crystal deposition.

1997

Errata

Errors in Articles by McGonagle et al (Arthritis Rheum, June 1999), Wilson et al (Arthritis Rheum, July 1999), and Del Rincon and Escalante (Arthritis Rheum, July 1999)

1998

The Relationship Between Pityriasis Rubra Pilaris and Inflammatory Arthritis: Case Report and Response of the Arthritis to Anti-Tumor Necrosis Factor Immunotherapy

Philip G. Conaghan, Sabine Sommer, Dennis McGonagle, Douglas Veale, Herman Waldmann, Geoffrey Hale, Mark Goodfield, Paul Emery, and John Isaacs

2002

Hypertrophic Osteoarthropathy Can Indicate Recurrence of Whipple's Disease

Isabelle Marie, Herve Levesque, Marc-Henri Levade, Nicole Cailleux, Frederic Lecomte, Arnaud Francois, Josette Metayer, Eric Lerebours, and Hubert Courtois

2007

Mixed Cryoglobulinemia Secondary to Visceral Leishmaniasis

Milvia Casato, Francesco G. De Rosa, Leopoldo P. Pucillo, Ignazio Ilardi, Bruno Di Vico, Lelio R. Zorzin, Maria Laura Sorgi, Pamela Fiaschetti, Rossella Coviello, Bruno Lagana, and Massimo Fiorilli

2011

Acute Gout in a Young Man with Osteochondromatosis

Mir M. Ali and Catherine Meyer

2012

Fluorosis and Osteomalacia

P. D. W. Kiely, J. Chow, J. B. Eastwood, and B. E. Bourke

2014

Increased Expression of Multidrug Resistance of P-Glycoprotein on Th1 Cells Correlates with Drug Resistance in Rheumatoid Arthritis

Kazuo Yudoh, Hiroaki Matsuno, Fujio Nakazawa, Tamon Yonezawa, and Tomoatsu Kimura

2015

The HLA-DRB1 QR/KRAA Sequence Cannot Alone Explain the Rheumatoid Arthritis Susceptibility in the Corsican Population

P. Cucchi-Mouillot, J. P. Amoros, B. Genetet, and D. Haras

2017

Single Nucleotide Polymorphic Haplotypes of the Interleukin-10 5` Flanking Region are Not Associated with Renal Disease or Serology in Caucasian Patients with Systemic Lupus Erythematosus

Esther Crawley, Patricia Woo, and David A. Isenberg

2019

Intravenous Pulse versus Oral Administration of Cyclophosphamide: Comment on the Article by Haubitz et al

Caroline O. S. Savage, and David R. W. Jayne

2020

Reply

Marion Haubitz and Reinhard Brunkhorst

2021

Sensitivity and Specificity of Tests for Autoantibodies: Comment on the Article by Tan et al

A. S. Russell

2021

Reply

Eng M. Tan

2021

What Constitutes a Mortality Study? Comment on the Article by Uramoto et al

Daniel J. Wallace

2022

Reply

Sherine E. Gabriel

25A

ACR Announcements