(cid:9) (cid:9)
`
`W1 AR95163
`1996
`NO.1 (cid:9)
`V.39 (cid:9)
`. SEQ: A68430000
`C.DI
`ARTHRITIS AND RHEUMATISM
`03/21/96
`
`rc...+6. a ,r (cid:9)
`
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`L
`LIBRARY OF
`MEDICINE
`
`Ex. 1100 - Page 1
`
`

`

`Arthritis & Rheumatism
`
`Official Journal of the American College of Rheumatology
`
`Editor
`William P. Arend, MD
`University of Colorado Health
`Sciences Center, Box B-117
`4200 East Ninth Avenue
`Denver, CO 80262
`
`Clinical Associate Editor
`Sterling G. West, MD, Denver
`
`Associate Editors
`J. Woodruff Emlen, MD, Denver
`Richard Hamman, MD, DrPH, Denver
`V. Michael Holers, MD, Denver
`J. Roger Hollister, MD, Denver
`Halsted R. Holman, MD, Palo Alto
`Ray Kilcoyne, MD, Denver
`Brian L. Kotzin, MD, Denver
`Jerome Wiedel, MD, Denver
`
`Consultant Biostatistician
`Anna E. Bar6n, PhD, Denver
`
`Committee for the Publication of A&R
`David A. Fox, MD, Chair, Ann Arbor
`Ellen M. Gravallese, MD, Boston
`Nancy J. Olsen, MD, Nashville
`Joel M. Kremer, MD, Albany
`Paul H. Plotz, MD, Bethesda
`Carolyn L. Yancey, MD, Landover
`
`Editorial Staff
`Jane S. Diamond, MPH, Managing Editor, Atlanta
`Patricia K. Higgins, Assistant Managing Editor, Atlanta
`Lesley W. Allen, Manuscript Editor, Atlanta
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`Elisa C. Schulz, Production Editor, Philadelphia
`
`Advisory Editors
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`Ferdinand C. Breedveld, MD, Leiden
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`Thomas R. Cupps, MD, Washington
`Lawren H. Daltroy, DrPH, Boston
`Maxime Dougados, MD, Paris
`Marc Feldmann, MB, BS, PhD, London
`Gary S. Firestein, MD, San Diego
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`Arthur P. Hall, MD, Boston
`David A. Horwitz, MD, Los Angeles
`Osvaldo Hubscher, MD, Buenos Aires
`
`Gunnar Husby, MD, Oslo
`Joachim R. Kalden, MD, Erlangen
`Jeffrey N. Katz, MD, Boston
`Klaus E. Kuettner, PhD, Chicago
`Edward V. Lally, MD, Providence
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`Roland W. Moskowitz, MD, Cleveland
`Haralampos M. Moutsopoulos, MD, Ioannina
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`Gerald T. Nepom, MD, PhD, Seattle
`Kusuki Nishioka, MD, Kawasaki
`Nancy J. Olsen, MD, Nashville
`Gabriel S. Panayi, MD, MRCP, London
`Christine Parker, MD, Boston
`Jean-Pierre Pelletier, MD, Montreal
`Michelle Petri, MD, Baltimore
`Rosalind Ramsey-Goldman, MD, DrPH, Chicago
`Thomas J. Schnitzer, MD, PhD, Chicago
`
`Yuichi-Y Shiokawa, MD, Tokyo
`Leonard H. Sigal, MD, New Brunswick
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`Josef S. Smolen, MD, Vienna
`Leon Sokoloff, MD, Stony Brook
`Alan M. Solinger, MD, San Diego
`Virginia D. Steen, MD, Pittsburgh
`Robert Terkeltaub, MD, San Diego
`Daniel E. Tracey, PhD, Cambridge
`L.B.A. van de Putte, MD, Nijmegen
`Wim B. van den Berg, PhD, Nijmegen
`Michael H. Weisman, MD, San Diego
`Cornelia M. Weyand, MD, PhD, Rochester
`Patience H. White, MD, Washington
`H. James Williams, MD, Salt Lake City
`Frederick Wolfe, MD, Wichita
`Morris Ziff, PhD, MD, Dallas
`
`AMERICAN COLLEGE OF RHEUMATOLOGY
`Arthur L. Weaver, MD, Lincoln, President
`William J. Koopman, MD, Birmingham, First Vice-President and President-Elect
`Ronald L. Kaufman, MD, MBA, Los Angeles, Secretary-Treasurer
`Mark Andrejeski, Atlanta, Executive Vice-President
`
`Published for the College by Lippincott—Raven Publishers
`Arthritis & Rheumatism (ISSN 0004-3591) is published monthly for the American College of Rheumatology by Lippincott—Raven Publishers, at 12107
`Insurance Way, Hagerstown, MD 21740. Business offices are located at 227 East Washington Square, Philadelphia, PA 19106. Printed in the U.S.A.
`Copyright c) 1996 by the American College of Rheumatology, Atlanta, Georgia. Printed on acid-free paper effective with volume 32, number 11. Second
`class postage paid at Hagerstown, Maryland, and additional mailing offices.
` orders, or nonmember changes of address: (except Japan) 12107 Insurance Way, Hagerstown, MD 21740, or call 1-800-638-3030;
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`in Maryland, call collect 301-714-2300. In Japan, contact Igaku-Shoin, Ltd, 1-28-36 Hongo, Bunkyo-ku, 113 Tokyo, Japan. Members' changes of address,
`'
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`90 days of the mailing date, both in the U.S. and worldwide. International subscriptions must be prepaid. In Japan, contact Igaku-Shoin, Ltd., 1-28-36
`Hongo, Bunkyo-ku, 113 Tokyo, Japan. The views expressed in articles, letters, and other communications published in Arthritis & Rheumatism are those
`of the authors and do not necessarily reflect the opinions of the editors, publisher, or American College of Rheumatology. The publisher and the
`American College of Rheumatology do not investigate the information contained in the classified advertisements in this journal and assume no
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`or service advertised in this journal.
`POSTMASTER: Send address changes to ARTHRITIS & RHEUMATISM, P.O. Box 1550, Hagerstown, MD 21741.
`
`Text printed on acid-free paper.
`
`Ex. 1100 - Page 2
`
`

`

`Arthritis tk Rheumatism
`
`Official Journal of the American College of Rheumatology
`
`VOLUME 39 (cid:9)
`
`JANUARY 1996
`
`NO. 1
`
`Special Articles
`Guidelines for the Initial Evaluation of the Adult Patient with Acute Musculoskeletal Symptoms
`American College of Rheumatology Ad Hoc Committee on Clinical Guidelines (cid:9)
`
`Review: Pathology and Pathogenesis of Vascular Injury in Systemic Lupus Erythematosus:
`Interactions of Inflammatory Cells and Activated Endothelium
`H. Michael Belmont, Steven B. Abramson, and J. T. Lie
`
`Review: The T Cell Enigma in Lupus
`A. K. Dayal and Gary M. Kammer (cid:9)
`
`Clinical Science
`Development and Validation of the European League Against Rheumatism Response Criteria for
`Rheumatoid Arthritis: Comparison with the Preliminary American College of Rheumatology and
`the World Health Organization/International League Against Rheumatism Criteria
`A. M. van Gestel, M. L. L. Prevoo, M. A. van 't Hof, M. H. van Rijswijk,
`L. B. A. van de Putte, and P. L. C. M. van Riel
`EULAR criteria for the assessment of individual treatment response in RA are presented. The validity
`of the EULAR, ACR, and WHO/ILAR response criteria is examined.
`
`Oral Type II Collagen Treatment in Early Rheumatoid Arthritis: A Double-Blind,
`Placebo-Controlled, Randomized Trial
`Joachim Sieper, Sonja Kary, Helmut Sorensen, Rieke Alten, Ulrich Eggens, Werner Huge,
`Falk Hiepe, Andrea Kiihne, Joachim Listing, Norbert Ulbrich, Jurgen Braun, Angela Zink, and
`Nicholas Avrion Mitchison
`This report describes the results of a trial of treatment of RA with oral type II collagen, which is
`potentially a highly selective and nontoxic therapy. Problems associated with such therapy and further
`perspectives for the application of oral tolerance therapy are discussed.
`
`Percentage of Anti-CD4 Monoclonal Antibody—Coated Lymphocytes in the Rheumatoid Joint is
`Associated with Clinical Improvement: Implications for the Development of Immunotherapeutic
`Dosing Regimens
`Ernest H. S. Choy, Costantino Pitzalis, Alberto Cauli, J. A. Bijl, Allen Schantz, J. Woody,
`Gabrielle H. Kingsley, and Gabriel S. Panayi
`After treatment with the chimeric anti-CD4 monoclonal antibody, cM-T412, the degree of CD4
`lymphopenia and the percentage of cM-T412—coated CD4+ cells in the peripheral blood and synovial
`fluid differed greatly. While peripheral blood CD4 lymphopenia was not associated with therapeutic
`efficacy, the percentage of cM-T412—coated CD4+ lymphocytes in the synovial fluid correlated with the
`degree of clinical improvement seen in patients.
`
`Treatment of Xerostomia with Polymer-Based Saliva Substitutes in Patients with Sjogren's
`Syndrome
`Willy A. van der Reijden, Hanneke van der Kwaak, Arjan Vissink, Enno C. I. Veerman, and
`Arie V. Nieuw Amerongen (cid:9)
`Salivary flow rates were found to influence patients' preferences for the different saliva substitutes,
`although no treatment was truly effective. It is recommended that individual salivary flow rates be
`considered in choosing saliva substitutes for Sjogren's syndrome patients. The development of a variety
`of new polymer-based saliva substitutes with different viscoelastic properties should increase the success
`of managing oral dryness in such complicated diseases as Sjogren's syndrome.
`
`
`
`1
`
`9
`
` 23
`
`34
`
`41
`
`52
`
` 57
`
`THE rata i a I.
`
`t (cid:9)
`
`LE,:z
`
`Ex. 1100 - Page 3
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`Clinical Science (Cont'd)
`Relationship of Running to Musculoskeletal Pain with Age: A Six-Year Longitudinal Study
`
`James F. Fries, Gurkirpal Singh, Dianne Morfeld, Peter O'Driscoll, and Helen Hubert (cid:9)
`The rheumatologist needs to understand risk factors for musculoskeletal pain and disability with age,
`and their relationship to clinical osteoarthritis. This report presents a model for musculoskeletal aging,
`and longitudinal data relating vigorous physical exercise to these end points. The model strengthens the
`knowledge base for "preventive rheumatology."
`
`Distal Extremity Swelling with Pitting Edema in Polymyalgia Rheumatica: Report of Nineteen
`Cases
`Carlo Salvarani, Sherine Gabriel, and Gene G. Hunder (cid:9)
`Distal extremity swelling with pitting edema is a manifestation of polymyalgia rheumatica. Recognition
`of this manifestation will help facilitate appropriate diagnosis and therapy.
`
`
`
`Association of Radiographically Evident Osteoarthritis with Higher Bone Mineral Density and
`Increased Bone Loss with Age: The Rotterdam Study
`Hulbert Burger, Paulus L. A. van Dade, Else Odding, Hans A. Valkenburg, Albert Hofman,
`Diederick E. Grobbee, Henry E. Schiitte, Jan C. Birkenhager, and Hulbert A. P. Pols (cid:9)
`This study demonstrated that subjects with osteoarthritis have increased bone mineral density and,
`therefore, possibly lower fracture risk. However, the accompanying increase in bone loss with age may
`cancel out this benefit in the long run.
`
`
`
`The Epidemiology of Wegener's Granulomatosis: Estimates of the Five-Year Period Prevalence,
`Annual Mortality, and Geographic Disease Distribution from Population-Based Data Sources
`Mary Frances Cotch, Gary S. Hoffman, Diane E. Yerg, Gerald I. Kaufman, Paul Targonski,
`and Richard A. Kaslow (cid:9)
`A population-based estimate of the prevalence of Wegener's granulomatosis may be useful to clinicians
`and researchers in identifying communities where prevalence of the disease is high. Conducting in-depth
`epidemiologic investigations of individuals in such communities may facilitate further studies that
`attempt to address the issues of etiology and pathogenesis.
`
`Cross-Cultural Adaptation of a Brief Outcome Questionnaire for Spanish-Speaking Arthritis
`Patients
`Agustin Escalante, Dionisio Galarza-Delgado, Thomas D. Beardmore, Bruce A. Baethge,
`Jorge Esquivel-Valerio, Ana Laura Marines, and Michelle Mingrone
`This report demonstrates the adaptation of the Activities of Daily Living Index of the Modified Health
`Assessment Questionnaire to the Spanish language. The original English version of this brief
`quesionnaire has been shown to be valid and reliable, and yet very easy to implement in clinical
`practice. Questionnaires such as the one presented will prevent the systematic exclusion of a large
`proportion of Hispanic patients from studies examining the outcome of arthritis and allied conditions.
`
`Barriers to Return to Work Among Persons Unemployed Due to Arthritis and Musculoskeletal
`Disorders
`Karin V. Straaton, Richard Maisiak, J. Michael Wrigley, Mary B. White, Philip Johnson, and
`Philip R. Fine (cid:9)
`
`This prospective study determined barriers to work return among a group of persons with established
`unemployment due to arthritis and musculoskeletal disorders. The results provide insight into potentially
`modifiable factors influencing return to work among this group.
`
`Basic Science
`The Presence of Costimulatory Molecules CD86 and CD28 in Rheumatoid Arthritis Synovium
`Ming Fei Liu, Ilitoshi Kohsaka, Hiroshi Sakurai, Miyuki Azurna, Ko Okumura, Ichiro Saito,
`andNobuyuki Miyasaka (cid:9)
`
`In rheumatoid synovium, a subset of synoviocytes express CD86 costimulatory molecules, and surround
`CD28+ lymphoid aggregates. Their interaction might contribute to the aberrant immune activation seen
`in rheumatoid synovitis.
`
`Synovial Tissue Macrophage Populations and Articular Damage in Rheumatoid Arthritis
`Diarmuid Mulherin, Oliver FitzGerald, and Barry Bresnihan (cid:9)
`The relative contribution of individual cell populations in the synovium to polyarticular destruction in
`RA remains controversial. This study related synovial immunohistologic features in 28 patients with RA
`to their radiologic course over a mean of 6 years and implicated synovial macrophages as critical
`mediators of articular destruction in these patients. These results have important implications for the
`development of new therapies which target synovial macrophages and their products.
`
`64
`
`73
`
`81
`
` 87
`
`93
`
`
`
`101
`
` 110
`
` 115
`
`111.1z mats ria I ...
`
`• _
`
`Ex. 1100 - Page 4
`
`(cid:9)
`

`

`Basic Science (Cont'd)
`Responsiveness of Human T Lymphocytes to Bacterial Superantigens Presented by Cultured
`Rheumatoid Arthritis Synoviocytes
`Carlene Tsai, Luis A. Diaz, Jr., Nora G. Singer, Lan Lan Li, Antia H. Kirsch, Raj Mitra,
`Brian J. Nickoloff, Leslie J. Crofford, and David A. Fox (cid:9)
`This study demonstrated that synovial fibroblasts from patients with RA can serve as accessory cells for
`activation of T lymphocytes by superantigens, and also by the lectin phytohemagglutinin. If synovial
`fibroblasts can mediate initiation of immune responses in vivo as well as in vitro, this mechanism could
`be important in the pathogenesis of early RA.
`
`Cutaneous Lymphocyte Antigen—Positive T Lymphocytes Preferentially Migrate to the Skin but
`Not to the Joint in Psoriatic Arthritis
`Costantino Pitzalis, Alberto Cauli, Nicolo Pipitone, Catherine Smith, Jonathan Barker,
`Antonio Marchesoni, Ghada Yanni, and Gabriel S. Panayi (cid:9)
`This study found that CLA+ T cells preferentially accumulate in the skin, but not the joint, of patients
`with PsA, and also predominate in the delayed-type hypersensitivity skin lesions and epidermal skin
`blisters of patients with rheumatoid arthritis. This pattern of T cell infiltration is regulated by both
`organ-specific homing and general inflammation-related mechanisms. These findings have notable
`pathogenetic implications for the formation of skin and synovial lesions in PsA and, in general, for the
`generation of the inflammatory/immune cell infiltrate in different tissues.
`
`Autoantibodies to Glycyl—Transfer RNA Synthetase in Myositis: Association with
`Dermatomyositis and Immunologic Heterogeneity
`Michito Hirakata, Akira Suwa, Yoshihiko Takeda, Yasuo Matsuoka, Shoichiro Irimajiri,
`Ira N. Targoff, John A. Hardin, and Joe Craft (cid:9)
`Antibodies to aminoacyl-tRNA synthetases are the most common autoantibodies found in individuals
`with polymyositis and dermatomyositis, and are valuable aids in the diagnosis of these diseases. This
`report describes the presence of novel autoantibodies to glycyl-tRNA synthetase in a patient with
`dermatomyositis and emphasizes that, based on this finding and a review of published work, this
`specificity is associated with the illness. Moreover, this work underscores the fact that autoantibodies to
`aminoacyl-tRNA synthetases may be more immunologically variable than originally recognized,
`suggesting that there are diverse mechanisms for their genesis.
`Clinical Images
`Mees' Lines
`David R. Finger and Martin B. Giandoni (cid:9)
`Case Reports
`The Coexistence of Systemic Sclerosis and Rheumatoid Arthritis in Five Patients: Clinical and
`Immunogenetic Features Suggest a Distinct Entity
`Terumi Horiki, Junko Moriuchi, Masatoshi Takaya, Mitsuaki Uchiyama, Yuichi Hoshina,
`Kenichi Inada, Hidetoshi Inoko, Kmiyoshi Tsuji, and Yukinobu Ichikawa (cid:9)
`
`The Antiinflammatory and Antiviral Effects of Hydroxychloroquine in Two Patients with
`Acquired Immunodeficiency Syndrome and Active Inflammatory Arthritis
`Matthew H. Ornstein and Kirk Sperber (cid:9)
`
`Healing Phenomena of Erosive Changes in Rheumatoid Arthritis Patients Undergoing
`Disease-Modifying Antirheumatic Drug Therapy
`Rolf Rau and Gertraud Herborn (cid:9)
`
`Splinter Hemorrhages Following Arterial Puncture
`Peter B. Martens, James A. Levine, and Gene G. Hunder (cid:9)
`
`Complete Remission of Multicentric Reticulohistiocytosis with Combination Therapy of Steroid,
`Cyclophosphamide, and Low-Dose Pulse Methotrexate: Case Report, Review of the Literature,
`and Proposal for Treatment
`George C. Liang and Arthur S. Granston (cid:9)
`
`Rocky Mountain Spotted Fever Presenting with Acute Monarticular Arthritis
`John S. Sundy, Nancy B. Allen, and Daniel J. Sexton (cid:9)
`
` 125
`
` 137
`
` 146
`
` 151
`
` 152
`
` 157
`
` 162
`
` 169
`
` 171
`
` 175
`
`attt (cid:9)
`
`El3
`LE -
`
`Ex. 1100 - Page 5
`
`

`

`Concise Communication
`Evaluation of Two Interventions to Reduce the Ancillary Costs of Outpatient Care for
`Rheumatoid Arthritis
`Jeffrey N. Katz, Elizabeth A. Wright, Kari D. Lynch, and Michael E. Weinblatt (cid:9)
`
`Letters
`The Paradoxical Association Between Immunodeficiency and Autoimmunity: Comment on the
`Article by Atkinson
`Nikolai Petrovsky (cid:9)
`
`Reply
`John P. Atkinson (cid:9)
`
`Treatment of Scleroderma Lung Disease: Comment on the Article by Steen et al
`Michael J. Fairfax (cid:9)
`
`Fibromyalgia or Multi-Organ Dysesthesia?
`Arthur F. Kavanaugh (cid:9)
`
`Synovial Tissue Responses Following Treatment of Rheumatoid Arthritis with the Humanized
`Monoclonal Antibody CAMPATH-1H
`Enrique R. Soriano, Jonathan Dixey, Nicolas D. Hall, Joan Davies, and Peter J. Maddison (cid:9)
`ACR Announcements (cid:9)
`
` 177
`
` 179
`
` 180
`
` 180
`
` 180
`
` 181
`
` 6A
`
`This ^ ata•ial •.,a==__ia
`
`attt (cid:9)
`T
`
`Ex. 1100 - Page 6
`
`

`

`34
`
`ARTHRITIS & RHEUMATISM
`Vol. 39, No. 1, January 1996, pp 34-40
`0 1996, American College of Rheumatology
`
`DEVELOPMENT AND VALIDATION OF THE EUROPEAN LEAGUE
`AGAINST RHEUMATISM RESPONSE CRITERIA FOR
`RHEUMATOID ARTHRITIS
`
`Comparison with the Preliminary American College of Rheumatology and the
`World Health Organization/International League Against Rheumatism Criteria
`
`A. M. VAN GESTEL, M. L. L. PREVOO, M. A. VAN 'T HOF, M. H. VAN RIJSWIJK,
`L. B. A. VAN DE PUTTE, and P. L. C. M. VAN RIEL
`
`Objective. To validate the European League
`Against Rheumatism (EULAR), the American College
`of Rheumatology (ACR), and the World Health Or-
`ganization (WHO)/International League Against Rheu-
`matism (ILAR) response criteria for rheumatoid arthri-
`tis (RA).
`Methods. EULAR response criteria were devel-
`oped combining change from baseline and level of
`disease activity attained during followup. In a trial
`comparing hydroxychloroquine and sulfasalazine, we
`studied construct (radiographic progression), criterion
`(functional capacity), and discriminant validity.
`Results. EULAR response criteria had good con-
`struct, criterion, and discriminant validity. ACR and
`WHO/ILAR criteria showed only good criterion validity.
`Conclusion. EULAR response criteria showed
`better construct and discriminant validity than did the
`ACR and the WHO/ILAR response criteria for RA.
`
`Rheumatoid arthritis (RA) is a chronic systemic
`disease, with polyarthritis as its main feature. Chronic
`inflammation of the joints often leads to joint damage
`
`Supported by the Het Nationaal Reumafonds (the Dutch
`League against Rheumatism).
`A. M. van Gestel, MSc, M. L. L. Prevoo, MSc, L. B. A.
`van de Putte, MD, PhD, P. L. C. M. van Riel, MD, PhD: University
`Hospital Nijmegen, Nijmegen, The Netherlands; M. A. van 't Hof,
`PhD: Nijmegen University, Nijmegen, The Netherlands; M. H. van
`Rijswijk, MD, PhD: University Hospital Groningen, Groningen,
`The Netherlands.
`Address reprint requests to A. M. van Gestel, MSc, Uni-
`versity Hospital Nijmegen, Department of Rheumatology, P. 0.
`Box 9101, 6500 HB Nijmegen, The Netherlands.
`Submitted for publication March 14, 1995; accepted in
`revised form August 4, 1995.
`
`and functional impairment. Because the pathogenesis
`of RA is still unknown, antirheumatic therapies are
`focused on nonspecific suppression of disease activity.
`Patients with RA have various manifestations of the
`disease, and therefore, disease activity cannot be
`expressed by a single parameter of inflammation. An
`index of disease activity should combine measure-
`ments representing several aspects of the disease (1).
`The Disease Activity Score (DAS) is such a validated
`index. It combines the Ritchie articular index (2), a
`count of swollen joints, the erythrocyte sedimentation
`rate (ESR), and an assessment of the patient's general
`health (3).
`In general, the efficacy of a treatment is deter-
`mined by comparing group means of changes in dis-
`ease activity variables. However, a significant differ-
`ence between groups does not indicate the actual
`number of patients who responded to treatment.
`Therefore, in addition to disease activity, the response
`of individual patients to antirheumatic therapy is an
`important measurement in clinical trials. Response
`criteria should include the relevant change in disease
`activity since the start of treatment, and the level of
`disease activity attained during followup (4).
`Recently, 2 sets of response criteria were pro-
`posed: the American College of Rheumatology (ACR)
`preliminary criteria for improvement (5), and the World
`Health Organization (WHO)/International League
`Against Rheumatism (ILAR) criteria for decreased
`inflammatory synovitis (6). The components of these
`criteria were selected using a judgmental approach
`rather than a statistical approach (7). On behalf of the
`EULAR Standing Committee for International Clini-
`
`•-•-•
`at t- (cid:9)
`
`"„L",
`LE
`
`Ex. 1100 - Page 7
`
`(cid:9)
`

`

`RESPONSE CRITERIA FOR RA (cid:9)
`
`35
`
`Table 1. Response criteria defined by the WHO/ILAR and the ACR*
`
`WHO/ILAR response criteria
`
`ACR response criteria
`
`1. >20% improvement in swollen joint count
`2. >20% improvement in tender joint count, or (cid:9)
`is between 16 and 20
`3. >20% improvement in at least 2 of the following 3 measures:
`A. Patient's or physician's assessment of global disease activity
`B. Pain
`C. ESR
`
`if the count
`
`improvement in swollen joint count
`1. (cid:9)
`2..-20% improvement in tender joint count
`3. _20% improvement in at least 3 of the following 5 measures:
`A. Patient's global assessment of disease activity
`B. Physician's global assessment of disease activity
`C. Patient's assessment of pain
`D. Acute-phase reactant
`E. Disability
`
`* WHO = World Health Organization; ILAR = International League Against Rheumatism; ACR = American College of Rheumatology; ESR
`= erythrocyte sedimentation rate.
`
`cal Studies including Therapeutic Trials, it was de-
`cided to develop response criteria based on a combi-
`nation of the judgmental and statistical approaches.
`The validity of the newly developed EULAR criteria
`and the ACR and WHO/ILAR response criteria was
`also studied. Our findings are presented herein.
`
`PATIENTS AND METHODS
`
`Development of response criteria. Patients and mea-
`surements. Response criteria were developed using a cohort
`of patients with recent-onset (<1 year) definite or classic RA
`(8) who were attending the outpatient clinic at the University
`Hospital Nijmegen. Between 1985 and 1994, 227 patients
`were included in the study.
`Slow-acting antirheumatic drugs (SAARDs) were
`prescribed when treatment with nonsteroidal antiinflamma-
`tory drugs (NSAIDs) alone was not sufficiently effective.
`Sulfasalazine (SSZ), hydroxychloroquine (HCQ), or aurano-
`fin (AUR) were regarded as first-option SAARDs. In case of
`treatment failure, aurothioglucose or methotrexate could be
`prescribed. A third option was treatment with D-penicilla-
`mine or azathioprine. Oral prednisone (10 mg) and intra-
`articular injections of steroid were allowed as adjuvant ther-
`apy. Rheumatologists decided about all changes in therapy.
`Patients were seen every 3 months by specially
`trained research nurses. The nurses collected clinical and
`laboratory data, including the Ritchie articular index (RAI),
`number of swollen joints, erythrocyte sedimentation rate
`(ESR, in mm/hour), and general health status (by 100-mm
`visual analog scale). On the basis of these measurements, we
`calculated the Disease Activity Score (DAS) (3):
`
`DAS = 0.54(VRAI) + 0.065(SwJts) + 0.33(ln ESR) + 0.0072(GH)
`
`where SwJts = the number of swollen joints and GH =
`general health status.
`The measurement error of the DAS was estimated,
`using interperiod correlation matrix analysis, in patients with
`->-.3 years of followup (n = 78). With this method, the
`assumption was made that the correlation between 2 DAS
`measurements declines as the interval in between increases.
`The intercept of the regression line (y axis: interperiod
`Pearson correlations between DAS measurements; x axis:
`intermediate time interval) was used for estimating the
`
`measurement—remeasurement correlation ro (correlation be-
`tween DAS measurements with intermediate time interval =
`0) (9). From this r0, the measurement error (e) can be
`calculated:
`
`e2/SD2 = (1/ro) — 1
`
`where SD = the standard deviation of the DAS.
`Definition of response. Response was defined as
`both: (a) change in disease activity from baseline and (b) the
`level of disease activity attained during followup. The fol-
`lowing criteria for change and attained disease activity were
`used. (a) For good response, a statistically significant de-
`crease in disease activity from baseline (i.e., more than 2
`times the measurement error [2e] [95% confidence interval =
`DAS ± 2e]), was necessary. (b) For good response, the DAS
`level attained must correspond to low levels of disease
`activity.
`Periods of low disease activity were defined as either
`the time during which the rheumatologist recommended that
`SAARD treatment be stopped because of remission, or
`periods of at least 1 year during which SAARD treatment
`was not started or the existing SAARD treatment was not
`changed. A high level of disease activity was defined as the
`time at which the rheumatologist decided that the patient
`should start SAARD treatment, or that the SAARD being
`taken should be changed (after a washout period of >1
`month for SSZ or methotrexate, and >2 months for the
`remaining SAARDs). Medical records were checked to
`correct for reasons other than high or low levels of disease
`activity that could bias the rheumatologist's decision regard-
`ing treatment (noncompliance, refusal of therapy, etc.). In
`the analyses, 5_2 periods of high disease activity and .-52
`periods of low disease activity per patient, with a time period
`between high and low activity of >I year, were randomly
`chosen.
`Validation of response criteria. Patients and measure-
`ments. In a 48-week double-blind trial comparing SSZ and
`HCQ in 60 patients with recent-onset RA (10), the EULAR
`response criteria and 2 other newly developed response
`criteria, the WHO/ILAR and the ACR criteria (Table 1),
`were validated. Twenty-five patients in the SSZ—HCQ trial
`were also included in the open (development) study. How-
`ever, the overlap existed only during the first year of the
`open study (<10% of the data); thereafter, no overlap was
`present.
`
`att.- (cid:9)
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`E (cid:9)
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`'1E7
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`Ex. 1100 - Page 8
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`(cid:9)
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`36 (cid:9)
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``Yo of moments
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`30
`
`25
`
`20
`
`15 t-
`
`10
`
`5
`
`0
`
`
`
`1 I Low disease activ.
`
`High disease activ.
`
`Li Overlap
`
`2 (cid:9)
`
`3 (cid:9)
`
`4 (cid:9)
`
`5 (cid:9)
`
`6
`
`7 (cid:9)
`
`8
`
`Disease Activity Score (DAS)
`Figure 1. Distribution of Disease Activity Scores at moments of
`low (n = 89) or high (n = 189) disease activity, according to
`treatment decisions made by rheumatologists in the cohort study of
`patients with rheumatoid arthritis. The vertical lines divide the DAS
`into low (2.4), moderate (>2.4 and -.53.7), and high (>3.7) levels of
`disease activity (activ.).
`
`Disease activity variables were measured every 12
`weeks. Radiographs of the hands and feet were taken at
`baseline and at 48 weeks. Films were scored using a modi-
`fication of the method of Sharp et al (11). At weeks 0, 12, 24,
`36, and 48, a Dutch equivalent of the Stanford Health
`Assessment Questionnaire (HAQ) was used to measure
`functional capacity in the last 41 consecutive patients of the
`trial (12).
`Response was retrospectively assessed every 12
`weeks. Because the physician's global assessment of disease
`activity was not included in the original trial, we modified the
`ACR criteria, such that patients had to fulfill 3 of the 4
`remaining measures as well as have improvement in the
`tender and swollen joint counts to be considered a re-
`sponder.
`Validation procedures (7). Criterion validity tests the
`accuracy of the criteria. Because no gold standard for
`response was available, we compared the criteria with each
`other and with the true clinical status, as determined by the
`functional capacity (from the HAQ). To correct for baseline
`values, the relative change in the HAQ score was evaluated
`at weeks 12, 24, 36, and 48.
`Construct validity is an aspect of validity that inves-
`tigates the association of the criteria with the expected
`results (the outcome). Radiographic progression represents
`an observable biologic end point resulting from inflammation
`and enzymatic degradation of cartilage and subchondral
`bone (13). Therefore the association between response (ev-
`ery 12 weeks) and radiographic progression (total number of
`new erosions and joint space narrowing at week 48 com-
`pared to baseline) was analyzed.
`Discriminant validity refers to the ability of the
`criteria to detect clinically important differences. Therefore,
`the proportion of responders in both treatment categories
`(HCQ and SSZ) was compared every 12 weeks.
`
`VAN GESTEL ET AL
`
`Statistical analysis. Missing disease activity data were
`supplied by interpolation when measurements were avail-
`able within 2 weeks from the missing moment. Tests were
`performed using patient moments of response: response at
`weeks 12, 24, 36, and 48 for each of the 60 patients. To
`equalize the number of patient moments available for the
`analyses of each set of response criteria, we used 186
`moments of the original 240 (4 x 60), excluding moments
`with missing EULAR, modified ACR, or WHO/ILAR re-
`sponses. Radiographic progression was transformed (square
`root) to "normality." The association between response
`(week 12, 24, 36, 48) and radiographic progression (week 48)
`was tested with analysis of variance. The association be-
`tween response (week 12, 24, 36, 48) and relative change in
`HAQ score (week 12, 24, 36, 48) was analyzed with Kruskal-
`Wallis tests. Differences in response in both treatment
`groups were tested with Wilcoxon rank sum tests (EULAR
`response criteria: good response = 1, moderate response =
`2, no response = 3; WHO/ILAR and modified ACR response
`criteria: good response = 1, insufficient response = 0).
`
`RESULTS
`
`Development of the EULAR criteria. The esti-
`mated Pearson's correlation coefficient for remeasure-
`ments was 0.80, and the standard deviation of the DAS
`was 1.17, leading to a measurement error of 0.6. For
`good response, a change from baseline that exceeded
`1.2 (or 2 x 0.6) DAS points was necessary.
`Disease Activity Scores during moments of
`high and low disease activity, according to the rheu-
`matologists, were calculated. In 142 patients, 189
`moments of high disease activity were defined. The
`DAS ranged from 1.38 to 7.15, with a mean of 4.32.
`Eighty-nine moments of low disease activity in 56
`patie