Y OF MEDIC
`
`6716 b
`
`-7103
`36 (cid:9)
`W1 flR62SF
`pt,,,` NO.R (cid:9)
`
`1997
`B35530000
`IIRITIsH JOURNAL OF
`RREUMATOLOGY (cid:9)
`
`09/09/97
`
`• 1 JM (cid:9)
`
`V114.z.;;;i
`
`• , •
`mush
`
`e36
`rilber 8
`gust1997
`
`Editorials:
`genq‘ss@pse
`Can mutated
`and C. Williams
`C
`D, McLain
`EULAR—time
`role of
`
`Prockop,
`osteoarthritis?
`aRo and. S.
`
`c ange?
`
`okko,
`
`etzatrglii
`
`Essay, 1997.
`Prize
`The Mic eel Mason
`gas
`w a a
`Niiric oxrde and bone.
`
`Ralston
`
`Papers:
`Ongna
`ad esion olecu e-1
`.9 •loteinas,-3,me iate expression of intercell ar
`Algid es
`Pasquier
`rdt, 0. Me er, J. ak7m and C.
`CD 54) • DF
`
`ir (cid:9)( I atiol,
`HLA.,DRIW typing an• cartilag%,oligomeric matrix,protein COMP)las‘pre• ictors.of
`• iirmwor-ro ,--
`joint hWtRictlorrih'IMIIMet rireirmitOrdInfillir A A. ollheiSK. B. Eb erhardt,
`h.,.....", (cid:9)
`U. Jahnsninvirrt. Saxne
`Blackwell and G.
`
`ropathy
`
`.a
`
`rhAr
`
`rF
`
`Original Clinica Papers:
`Rrdiograpiiirdi amade in argejoints e@rty,rheum@toi• arthri is. re Opp
`DgridsTriefe@t, dis@pse actiliity,.pnd p ysicalrdisIalit
`r@didgrAiliiCda—rrItre (cid:9)
`H. Kuper, M. A. van Lee wen, P. L. C. M. yap, Riel, M. L L. Piro°,
`P. M. Hallman, W. F. L'Olkema and M. H. van Rijslitijk
`Persistent:synovitiLtreatedAwith ra • is ion synoyectorra sing yttrj. m-90.
`retro@pectenlaion of 83 proce• urps1,45.7iiients ZIALIEJahangier,
`J. W G. Jacobs, J. W art Isserfir9PawJ, VV. J.TBijIsma
`Auranofin isLsaf@andtsuperior to placebpotin elderly-onsetgheuma o • a hrit s
`lerrties A. G, T. OKtitien, CIPAndrup, b. Clarke-Jenssen, Karstensen an • U, Bro
`
`ic,
`RACIo.‘,: a (cid:9)
`Theirs iability. an • construct:yalidity of he
`derffleijoeiPS. P. McKenWd
`q aglqf life Instrument,Z, "Ong, D.
`D Whalley
`TarsavaaztOzza de ong
`r er matold
`Qua ityof life in
`D, van-Ter Heigle
`ga grene In
`cases poqitiveAfrpr anti-centromere antibodies
`andrH,Rondo
`extremitlesYM, ilkahas 1, J. Okada
`Diseases:
`Medicine and Rheumatic
`Occ •ational
`in the workplace
`aspects of musc loskeletal prob ems
`Legal
`Paediatric R e matplogy:
`R. Southwoo
`Brit-fib Paediatric Rherirhatology Gro p
`chronicarthritls?
`role inijuvenile
`intolerance. •,a
`Does food
`Saigrn1Hoeufft
`and H. M. S.
`M.P. Vries
`C. Marcel's,
`no•osa
`L9Dgiterm folio -up.refijuven le-onsocutaneo s po yarteritis
`withiTtreptococcal infection S. H. Till andrf?, STAthos
`complicated
`Severejuvenile dermatomyositis
`M.-Rooneynd P. Woo
`prev!ously.undpscribpd s in
`Palmar pla..92.5,tLyperkeratosis—a
`M. Rooney and P. oo
`jtivenile dermatorri7Ogliis Y. See,
`
`oward
`
`manifes ation of
`
`884
`
`909
`
`International Le ter:
`
`ood healthfat 50
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`oil elm
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`Con In ed on
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`Ir
`
`Ex. 1056 - Page 1
`
`(cid:9)
`

`

`BRITISH JOURNAL OF RHEUMATOLOGY
`
`Official Journal of the British Society for Rheumatology
`
`Editor
`H. A. Bird
`
`Editor Elect
`D. L. Scott
`
`Editorial Assistant (cid:9)
`W. Johnson (cid:9)
`
`Editorial Manager Elect
`J. A. Mazo
`
`Editorial Office
`41 Eagle Street
`London WC1R 4AR
`Tel 0171 242 3313 Fax 0171 242 1841
`E-mail: jmazo(wbritjrheum.demon.co.uk
`
`Assistant Editors
`
`D. L. Scott
`King's College Hospital
`London
`
`Editorial Board
`M. Bayliss, London, UK
`C. Black, London, UK
`F. Breedveld, Leiden, Netherlands
`F. Brennan, London, UK
`P. Brooks, Darlinghurst, Australia
`H. Capell, Glasgow, UK
`F. Cavalcanti, Pernambuco, Brazil
`R. Clague, Isle of Man, UK
`P. Davis, Alberta, Canada
`P. Dawes, Stoke-on-Trent, UK
`J-M. Dayer, Geneva, Switzerland
`C. Deighton, Nottingham, UK
`A. M. Denman, London, UK
`M. Dougados, Paris, France
`
`Ex-officio
`R. Sturrock (BSR President)
`
`M. Walport
`Hammersmith Hospital
`London
`
`F. Wollheim
`University Hospital of Lund
`Sweden
`
`P. Emery, Leeds, UK
`H. Gaston, Birmingham, UK
`T. Gibson, London, UK
`I. Griffiths, Newcastle upon Tyne, UK
`D. Haskard, London, UK
`E. Hess, Cincinnati, OH, USA
`M. Hochberg, Baltimore, MD, USA
`N. Hurst, Edinburgh, UK
`D. Isenberg, London, UK
`R. Jubb, Birmingham, UK
`A. Keat, London, UK
`L. Klareskog, Stockholm, Sweden
`T. Kvien, Oslo, Norway
`R. N. Maini, London, UK
`
`G. Mody, Congella, South Africa
`A. Mowat, Oxford, UK
`G. Murphy, Cambridge, UK
`G. Panayi, London, UK
`E. Pascual, Alicante, Spain
`T. Pullar, Dundee, UK
`P. van Riel, Nijmegen, Netherlands
`D, G. I. Scott, Norwich, UK
`A. Silman, Manchester, UK
`J. Smolen, Vienna, Austria
`M. Snaith, Sheffield, UK
`K. Whaley, Leicester, UK
`P. Woo, London, UK
`P. Wordsworth, Oxford, UK
`
`N. Sheehan (BSR Honorary Treasurer) D. E. Bax (BSR Honorary Secretary)
`
`The journal is listed in Current Contents/Life Sciences/Clinical Practice • Index Medicus • Medline • Excerpta Medica/Excerpta Medici)
`EMBASE • Chemical Abstracts
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`SUBSCRIPTIONS
`A subscription to British Journal of Rheumatology comprises 12 issues, with an Annual Author and Subject Index. Subscriptions are entered
`on a calendar year basis only. Prices include air-speeded delivery to Australia, Canada, India, Japan, New Zealand and the USA. Delivery
`elsewhere is by surface post.
`
`Annual subscription rate (Volume 36, 1997):
`Institutional rate: Europe £225; rest of World, USS390. Subscribers in Europe (EC) please either send details of sales tax (VAT) registration/
`exemption or add local sales tax to the prices quoted, Subscribers in Canada please add 7% GST to the prices quoted.
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`© British Society for Rheumatology 1997
`
`All rights reserved; no part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means,
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`Special requests, such as copying for general distribution, or for advertising or promotion purposes, should be addressed to the Production
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`
`Tfi= man'ial
`
`Ex. 1056 - Page 2
`
`(cid:9)
`(cid:9)
`

`

`4*044,41
`777:
`
`Editorial Announcement
`
`From 1 July 1997* all original submissions to
`the British Journal of Rheumatology should be
`sent to the new editorial office:
`
`The Editor
`British Journal of Rheumatology
`The British Society for Rheumatology
`41 Eagle Street
`London WC1R 4AR
`UK
`Tel: +44 (0)171 242 3313
`Fax: +44 (0)171 242 1841
`
`Submission of manuscripts to the former editorial office (in
`Leeds) after this date may cause delay.
`
`*This supersedes the previously announced date of 1 August 1997.
`
`iz (cid:9)
`d (cid:9)
`att.- = (cid:9)
`Subject LE :cc..., (cid:9)
`
`::ciad
`ce
`C LBWS
`
`Ex. 1056 - Page 3
`
`

`

`p
`
`ritish Journal of
`
`umatolog
`
`Volume 36
`\lumber 8
`august 1997
`
`CONTENTS
`
`Editorials:
`Can mutated genes cause common osteoarthritis? D. J. Prockop, L. Ala-Kokko,
`D. A. McLain and C. Williams (cid:9)
`The role of EULAR—time for a change? R. D. Sturrock and S. van der Linden (cid:9)
`
`The Michael Mason Prize Essay, 1997:
`Nitric oxide and bone: what a gas! S. H. Ralston (cid:9)
`
`Original Scientific Papers:
`Antibodies to proteinase-3 mediate expression of intercellular adhesion molecule-1
`(ICAM-1, CD 54) M. De Bandt, 0. Meyer, J. Hakim and C. Pasquier (cid:9)
`H LA DR B1* typing and cartilage oligomeric matrix protein (COMP) as predictors of
`joint destruction in recent-onset rheumatoid arthritis F. A. Wollheim, K. B. Eberhardt,
`U. Johnson and T. Saxne (cid:9)
`Faecal flora in spondyloarthropathy G. W. Smith, C. C. Blackwell and G. Nuki (cid:9)
`
`827
`829
`
`831
`
`839
`
`847
`850
`
`855
`
`861
`
`Original Clinical Papers:
`Radiographic damage in large joints in early rheumatoid arthritis: relationship with
`radiographic damage in hands and feet, disease activity, and physical disability
`H. H. Kuper, M. A. van Leeuwen, P. L. C. M. van Riel, M. L. L. Prevoo,
`P. M. Houtman, W. F. Lolkema and M. H. van Rijswijk (cid:9)
`Persistent synovitis treated with radiation synovectomy using yttrium-90: a
`retrospective evaluation of 83 procedures for 45 patients Z. N. Jahangier,
`J. W. G. Jacobs, J. W. van Isselt and J. W. J. Bijlsma (cid:9)
`Auranofin is safe and superior to placebo in elderly-onset rheumatoid arthritis
`A. Glennas, T. K. Kvien, 0. Andrup, 0. Clarke-Jenssen, B. Karstensen and U. Brodin 870
`The reliability and construct validity of the RAQoL: a rheumatoid arthritis-specific
`quality of life instrument Z. de Jong, D. van der Heijde, S. P. McKenna and
`D. Whalley (cid:9)
`Quality of life in rheumatoid arthritis D. Whalley, S. P. McKenna, Z. de Jong and
`D. van der Heijde (cid:9)
`Six cases positive for anti-centromere antibodies with ulcer and gangrene in the
`extremities M. Takahashi, J. Okada and H. Kondo (cid:9)
`
`878
`
`884
`
`889
`
`Occupational Medicine and Rheumatic Diseases:
`Legal aspects of musculoskeletal problems in the workplace G. Howard (cid:9)
`Paediatric Rheumatology:
`British Paediatric Rheumatology Group News T. R. Southwood (cid:9)
`
`894
`
`904
`
`Continued overleaf
`
`This matsrial
`att.' s (cid:9)
`Sri (cid:9)
`
`tS
`
`Ex. 1056 - Page 4
`
`

`

`Does food intolerance play a role in juvenile chronic arthritis? J. J. P. Schrander,
`C. Marcelis, M. P. de Vries and H. M. S. van Santen-Hoeufft (cid:9)
`Long-term follow-up of juvenile-onset cutaneous polyarteritis nodosa associated
`with streptococcal infection S. H. Till and R. S. Amos (cid:9)
`Severe juvenile dermatomyositis complicated by pancreatitis Y. See, K. Martin,
`M. Rooney and P. Woo (cid:9)
`Palmar plantar hyperkeratosis—a previously undescribed skin manifestation of
`juvenile dermatomyositis Y. See, M. Rooney and P. Woo (cid:9)
`
`International Letter:
`Swedish rheumatology in good health at 50 F. A. Wollheim (cid:9)
`
`Letters to the Editor:
`H LA-B51 negative monozygotic twins discordant for Behcet's disease A. GOI,
`M. Inanc, L. Ocal, 0. Aral, M. Garin and M. Konice (cid:9)
`Autoantibodies against cardiolipin and endothelial cells in Takayasu's arteritis:
`prevalence and isotype distribution S. Nityanand, K. Mishra, S. Shrivastava, G. Holm
`and A. K. Lefvert (cid:9)
`Von Willebrand factor antigen and angiotensin converting enzyme levels in
`Takayasu arteritis P. Kadioglu, V. Hamuryudan, N. Hekim, F. Ozbakir, S. Yurdakul
`and H. Yazici
`Madelung's deformity from a rheumatologist's point of view J. A. Tlacuilo-Parra,
`M. Salazar-Paramo, I. P. Davalos and I. Garcia-de la Torre (cid:9)
`Shared DMARD monitoring P. Helliwell and M. O'Hara (cid:9)
`Calendar (cid:9)
`Announcements (cid:9)
`
`905
`
`909
`
`912
`
`917
`
`920
`
`922
`
`923
`
`924
`
`925
`926
`928
`928
`
`Please visit the journal's World Wide Web site at http://www.oup.co.uk/bsr
`
`This ma7i-iE1 ,..:Ez
`at "AV
`
`Ex. 1056 - Page 5
`
`(cid:9)
`

`

`nwe.;::r.t"..T.: •
`
`Vt.ZSr.r
`
`f--
`
`British Journal of Rheumalology 1997;36:870-877
`
`rTh
`
`AURANOFIN IS SAFE AND SUPERIOR TO PLACEBO IN ELDERLY-ONSET
`RHEUMATOID ARTHRITIS
`
`A. GLENNAS, T. K. KVIEN, 0. ANDRUP, 0. CLARKE-JENSSEN, 13. KARSTENSEN
`and U. BRODIN"
`N-03I9 OsIoLNorit'ay and
`(Oslo City Department of Rheumatology, Diakonldentmet (cid:9)
`*Department of Medical Information Processing, Karolinska ln.tifihnel, Stockholm„civeden
`
`SUMMARY
`
`The efficacy, toxicity and possible steroid-sparing properties of auranofin in the treatment of elderly-onset rheumatoid arthritis
`(EORA) were studied in a 2 yr prospective double-blind placebo-controlled clinical trial. Sixty-five patients with onset of arthritis
`after the age of 60 yr were randomized to either auranofin 3 mg b.i.d. [n ---,III, age 70 (61 84) yr, median (range)] or placebo
`tablets [iz = 34, age 72 (60-81) yr]. Oral prednisolone, starting dose 7.5 or 20 mg daily, was used as a rescue drug in patients
`with intolerable joint pain and stiffness and with C-reactive protein (CRP) (cid:9)
`20 20 ing/1, and was tapered down according to
`protocol guidelines. Patients receiving auranofin continued therapy for a longer period of time (55% completers) than those
`on placebo medication (18% completers). The auranofin group consumed significantly less prednisolone, 2.64 (0 -11.85) inglday
`[median (range)], compared to 5.0 (0-18.33) mg/day in the placebo group [P = 00)6). No group differences at 2 yr follow-up
`were found for changes in joint pain (/' = 0.49), number of swollen joints (I' = 0.61), I Iealth Assessment Questionnaire score
`(P = 0.18) and radiographic damage score (Larsen-Dale index) of the hands (/' = 0.84). Within-group changes in radiographic
`scores were also insignificant. The drop-out rate due to adverse events was surprisingly higher in the placebo group (41%) than
`in the auranofin group (10%) and, as expected, higher due to lack of effect (29 and 16%). The results indicate that auranofin
`is safe, superior to placebo and has steroid-sparing capacity in the treatment of FORA. The favourable radiographic Outcome
`in both groups needs confirmation in future studies.
`
`KEY woRps: Clinical trial, Auranofin, Rheumatoid arthritis, Elderly-onset arthritis.
`
`ELDERLY-ONSET rheumatoid arthritis (FORA, onset
`at age ?60 yr) has been suggested as being distinctive
`from younger-onset RA (YORA) by representing
`heterogeneous polyarthritis syndromes, ranging from
`rheumatoid factor-positive polyarthritis to polymyal-
`gia rheumatica (PM R) including arthritis [I, 2]. Clinical
`features reported to be typically associated with FORA
`are a more equal sex distribution, more frequent
`involvement of large joints and a lower frequency of a
`positive test for rheumatoid factor [1]. Since FORA
`represents a group of diseases that differ clinically from
`YORA, extrapolations of results from clinical trials on
`YORA are uncertain and, consequently, clinical trials
`specifically addressing the use of drugs in FORA
`patients are required. Furthermore, age is recognized as
`a predisposing factor to drug toxicity due to altered
`drug pharmacokinetics, polypharntacy, and increased
`number of co-morbidities and compliance problems
`associated with old age.-Thus, drug therapy of arthritis
`in the elderly represents a particular challenge,
`administering potentially toxic drugs to a high-risk
`population.
`Auranofin has proven to be a safe and moderately
`effective disease-modifying anti-rheumatic drug
`(DMARD) in the treatment of RA, as judged by
`randomized placebo-controlled trials, different age
`
`Submitted 16 July 1996: revised version accepted 3 February 1997.
`Correspondence to: A. Glennas, Oslo City Department of
`Rheumatology, Diakonhjemmet Hospital, PO Box 23 Vinderen,
`N-0319 Oslo, Norway.
`
`groups not considered [3-9]. Meta-analyses of pla-
`cebo-controlled and comparative clinical trials focus-
`ing on either the efficacy or the toxicity of different
`DMA R Ds in the treatment of RA, suggested that
`auranofin was less efficacious than most other
`DMA R Ds, but had a low toxicity-related drop-out
`rate: 11.3% (range 8.5 29.9% for all DM A RDs
`tested) [10]. Fries el al. [II], however, found that
`auranofin scored the worst of the DMA R Ds com-
`pared for toxicity in 2727 consecutive patients, but
`that the poor ranking was almost entirely due to
`minor symptoms such as diarrhoea or loose stools.
`Studies addressing the efficacy and toxicity of
`auranofin in the elderly with either YORA or FORA
`are limited. Two post hoc analyses of controlled
`trials including auranofin, stratifying outcomes by
`patient age, showed no significant age-related differ-
`ences in efficacy outcomes of arthritis or in with-
`drawal rates chie to adverse drug reactions [12, 13].
`One prospective trial has compared the efficacy and
`toxicity or, gold-containing drugs in FORA and
`YORA 'patients, but included parenteral gold only
`[14]. No differences between the groups were found.
`Thus, the clinical benefit of auranofin in FORA is
`not yet fully clarified.
`In the present trial, we examined in a prospective and
`placebo-controlled design the 2 yr efficacy and toxicity
`of auranofin in the treatment of patients with FORA.
`We investigated whether auranofin was better than
`placebo, judged by clinical and radiographic outcome
`measures, and whether auranofin was safe and had
`steroid-sparing properties.
`
`Cc) 1997 British Society for Rheumatology
`
`870
`
`This material ivsz
`at the NLM
`2.
`Subje:-. UE
`
`
`
`Ex. 1056 - Page 6
`
`

`

`GLENNAS El' AL.: AURANOFIN IN ELDERLY-ONSET ARTHRITIS
`
`871
`
`MATERIAL AND METHODS
`
`Patients
`Patients with disease onset after the age of 60 yr,
`having either rheumatoid arthritis (RA) according to
`the ACR 1987 criteria [15] or oligoarthritis (at least
`three swollen joints) associated with PM R [16] or
`PM R-like symptoms, were included. Patients were
`considered eligible for the study if they had active
`disease defined as more than three swollen joints and
`elevated acute-phase reactants [erythrocyte sedimenta-
`tion rate (ESR) 28 mm/h or C-reactive protein
`(CRP) ;?, 20 mg/1]. Steinbrocker functional class I—III
`[17] was required. Patients with temporal arteritis or
`PM R without arthritis were excluded, as were patients
`with major arthropathies other than EORA, patients
`previously treated with gold-containing drugs, patients
`on oral prednisolone for other reasons than EORA or
`in doses exceeding 20 mg daily within the 4 preceding
`weeks, patients with chronic inflammatory bowel
`disease, liver or kidney disease, or other diseases which
`contraindicated the use of the study drug, prednisolone
`or non-steroidal anti-inflammatory drugs (NSAIDs).
`
`Study design
`The study was a randomized double-blind controlled
`clinical trial with a prospective and parallel group
`design with 2 yr follow-up. The intervention assign-
`ment schedule was generated by block randomization
`(blocks of four), stratifying for the presence of myalgias
`and rheumatoid factor (Waaler titre 64). The
`intervention assignment was concealed until the
`statistical analyses were completed, unless adverse
`reactions or the subsequent drug treatment necessitated
`the disclosure. Inclusion started in April 1990 and was
`concluded in 1993.
`
`Drugs
`Patients in the active drug arm received auranofin
`3 mg s.i.d. for the first week, followed by 3 mg b.i.d.
`The placebo medication was physically indistinguish-
`able from auranofin. The study drugs were handled by
`the hospital pharmacist.
`Oral prednisolone was introduced or the previous
`concomitant prednisolone dose was increased and used
`as rescue medication on the following indication:
`intolerable joint pain and stiffness, and CRP > 20 mg/l.
`The initial dose of prednisolone given was either 7.5 or
`20 mg s.i.d., according to the clinician's judgement and
`based on the assessment of current disease activity. The
`prednisolone dose was tapered down according to the
`following guidelines: dose reduction by 25% or a
`minimum 1.25 mg/week when the CRP decreased to
`<20 mg/I and the pain was tolerated by the patient.
`When the dose reductions led to a relapse in the
`symptoms and signs of disease activity, the pred-
`nisolone dose was increased to one step above the dose
`which gave no symptoms, before further tapering. In
`cases with intolerable pain and stiffness but
`CRP < 20 mg/1, therapy with NSAIDs was introduced.
`
`Paracetamol 3000 mg/day was allowed as rescue
`analgesic medication.
`No concomitant drugs with known interaction with
`the trial drugs were allowed. No patients received
`corticosteroids for other reasons than the EORA.
`Intra-articular steroid injections were allowed and
`recorded.
`
`Assessments
`Each patient was followed by the same assessor
`throughout the study. Patients were seen by the
`rheumatologist for safety and efficacy assessment every
`third month, and by a metrologist for safety reasons
`every second week for the first 3 months, followed by
`4 week intervals. In periods of prednisolone tapering,
`the patients were seen every other week. The
`physician's assessments every third month included
`general clinical examination, joint assessment (number
`and distribution of swollen joints), pain score [visual
`analogue scale (VAS) 0-100 mm], duration of morning
`stiffness, and physical disability assessed by the Health
`Assessment Questionnaire (HAQ, scale 0-3) [18]. All
`concomitant drugs used were recorded. Blood tests
`included disease activity measures (blood counts, ESR,
`CRP and serum protein electrophoresis) and safety
`parameters (liver and kidney function tests, dipstick
`and microscopic urine analysis). At every visit, the
`patients were asked whether they had experienced any
`event which they perceived as a possible adverse drug
`effect. Radiographic examination of the hands and
`wrists, when clinically affected, was performed at
`baseline and after 2 yr. The films were read blindly and
`without knowledge of the order in which they were
`taken, by one radiologist, and scored for damage
`according to the Larsen—Dale method [19], the index
`range being 0-150.
`
`TrCahnent elkel
`The following parameters were considered as the
`primary efficacy variables: number of swollen joints,
`pain score, HAQ and change in the Larsen—Dale index.
`In addition, the cumulative dose of prednisolone
`(AUC) in the two treatment groups, corrected for time
`in the study, was compared.
`
`Withdrawals and drop-outs
`The patients were considered as treatment failures
`and prematurely withdrawn from the study on the
`occurrence of adverse reactions to the trial drug or lack
`of efficacy according to the following guidelines:
`leucopenia (WBC < 2.0 x 109), thrombocytopenia
`(platelets 100 x 109), progressive anaemia, intolerable
`diarrhoea, serious rash, proteinuria ( >0.5 g/24 h) or
`persistent abnormality (equal or exceeding twice the
`upper limit of the normal range) of more than one liver
`function test, intolerable clinical deterioration in spite
`of the use of prednisolone rescue equal to 20 mg daily
`for >2 weeks during months 0-6 of the trial or 10 mg
`daily for >4 weeks during months 6-24 of the trial.
`Patients withdrawn due to treatment failure were
`offered treatment including other DMARDs according
`
`This mate•ial *MI ::
`atthe iNL".1B,3
`
`3WS
`
`Ex. 1056 - Page 7
`
`(cid:9)
`

`

`872 (cid:9)
`
`BRITISH JOURNAL OF RHEUMATOLOGY VOL,. 36 NO. 8
`
`to the physician's evaluation. All the patients, including
`those withdrawn, were called to a complete assessment
`at month 24. Patients were classified as drop-outs on
`premature termination of the study due to violation of
`the protocol, serious intercurrent disease or on
`discontinuation by their own request.
`
`Ethics
`The study was performed according to the
`Declaration of Helsinki of the World Medical
`Association. The patients received oral and written
`information on the study and gave verbal and written
`consent.
`
`Statistical analysis
`Only those patients completing at least the first 3
`months were included in the effect evaluation study.
`Patients, who for any reason, stopped taking the drug
`before month 3 were only included in the adverse event
`evaluation. The main clinical variables were analysed
`(1) for all patients followed up (last observation carried
`forward) and (2) for completers and withdrawals at 24
`months (intention-to-treat analysis).
`The treatment effect was investigated according to a
`regression model with treatment as the independent
`variable and the baseline status as a covariate. The
`Mann-Whitney test was used for a test of trend over
`the trial period for CRP and ESR, and for an overall
`intention-to-treat analysis, after 24 months. Calculated
`individual trends over time formed the basic values for
`this analysis. Differences in the cumulative closes of
`prednisolone, corrected for time in the study and
`differences in the radiographic damage scores, were
`evaluated by the Mann-Whitney test. Survival analyses
`(log-rank test) were used to evaluate the difference
`between the treatments with respect to time to
`discontinuation of study medication. An explorative
`analysis, using Cox's proportional hazards model, was
`performed to investigate the time to withdrawal as
`explained by the status at baseline, where the number
`of swollen joints, HAQ, log(CRP), the use of
`prednisolone and a dichotomized Waaler's reaction
`(Waaler > 64/Waaler < 64) were used as prognostic
`factors. I' values <0.05 for a type 1 error were
`considered significant.
`
`RESULTS
`Baseline conwarability
`Sixty-six patients were included and randomized for
`the study. All but one, who was incorrectly included
`due to previous aurothiomalate treatment, received
`intervention as allocated. Of the 65 patients followed
`up, 23 completed 24 months therapy. Descriptive
`statistics for demographic and other baseline data are
`shown in Table I. The treatment groups were similar
`with respect to important clinical variables, except for
`a slightly higher median value of HAQ score and a
`higher frequency of co-morbidities and the subsequent
`use of concomitant non-anti-rheumatic drugs in the
`placebo group. The total number of co-morbidities
`
`This -_._
`
`was: cardiovascular disease (21 patients), diabetes
`mellitus (3), mild asthma (3) and others (9).
`
`Clinical variables
`Treatment effect was assessed by the primary
`variables joint pain, number of swollen joints and HAQ
`score. The development of the primary variables for
`patients still on the trial medication is illustrated by box
`plots in Fig. la-c. No systematic differences between
`the treatment groups could be demonstrated statist-
`ically (P > 0.5) during the treatment period. This
`lack of systematic difference was also seen in the
`intention-to-treat analysis (Table 11). However, evalu-
`ations according to the last observation carried
`forward indicated a difference between the treatment
`groups for the pain score, auranofin giving the greatest
`improvement (P = 0.046). This was considered clin-
`ically significant, as even the consumption of
`prednisolone was lower for the auranofin group (see
`below). The Mann-Whitney test for the trend of CRP
`and ESR was in accordance with the clinical results, in
`that no differences between the treatment groups were
`found (I' = 0.40 for CRP). However, an indication of
`a greater increase in ESR (/' = 0.06) was found in the
`placebo group.
`
`Prednivolone consumption
`The total consumption of oral prednisolone, as long
`as the patients stayed in the study, was measured as the
`total use of prednisolone (AUC) corrected for time in
`the study, i.e. treatment intensity. The difference
`between the treatment groups was evaluated by a
`Mann--Whitney test. The auranofin-treated group
`consumed significantly less prednisolone than the
`placebo group: 2.64 (0 -11.85) mg/day [median (range)]
`and 5.0 (0-18.33) mg/clay, respectively (P = 0.006).
`Patients in the auranofin group received altogether 14
`intra-articular steroid injections and the placebo group
`received 11 injections during the 2 yr trial period. The
`difference in close of intra-articular steroids between the
`
`TABLE I
`Descriptive statistics of baseline data [median (range) values for
`continuous, counts ("/,,) for categorical variables]
`
`Auranolm
`31)
`
`Placebo
`= 34)
`
`10/11
`Female/male ratio
`Age (yr)
`70 (61-84)
`RA (according to ACR 1987 criteria [15]) 27 (87)
`Oligoarthritis with PMR or rnyalgias
`4 (13)
`Presence of myalgia at baseline
`19 (61)
`Waaler positive (.,64)
`10 (32)
`Arthritis duration (weeks)
`16 (4-520)
`Joint pain (mm, VAS)
`54 (3-100)
`Number of swollen joints
`17 (3-54)
`HAQ score (0-3)
`1.0 (0-2.8)
`Previous prednisolone
`3 (cid:9) (I())
`Previous DMARD
`3 110)
`Concurrent disease
`14 (45)
`Concomitant drugs
`(non-anti-rheumatic) MO
`
`13 (42)
`
`24/10
`72 (60-81)
`34 (100)
`0 (0)
`18 (53)
`12 (35)
`25 (3-780)
`52 (5-99)
`21 (cid:9) (4-39)
`1.6 (0-3.0)
`1 (cid:9) (3)
`2 (6)
`22 (65)
`
`19 (56)
`
`Ex. 1056 - Page 8
`
`

`

`GLENNAS ET L AURANOFIN IN ELDERLY-ONSET ARTHRITIS (cid:9)
`
`873
`
`(a)
`
`100.0
`Joint
`pain
`
`80.0
`
`0
`
`60.0
`
`40.0
`
`20.0
`
`0.0
`
`0
`0
`
`0
`
`0
`
`No. of (cid:9)
`swollen
`joints (cid:9)
`
`60
`
`so
`
`(b)
`
`0
`
`18 (cid:9)
`
`24
`months
`
`0 (cid:9)
`
`8
`
`0
`
`1
`
`0
`
`) (cid:9)
`
`--
`
`0 (cid:9)
`
`8
`
`0 (cid:9)
`
`
`6 (cid:9)
`
`12 (cid:9)
`
`18 (cid:9)
`
`24
`months
`
`0
`
`0
`
`0
`0 (1
`
`0 (cid:9)
`
`0
`
`0
`
`0
`
`0
`
`40
`
`30
`
`20
`
`10
`
`0
`
`3.s
`FIAQ
`3.0
`
`(c)
`
`2.5
`
`2.0
`
`1.5
`
`1.0
`
`(cid:9)1121
`
`18 (cid:9)
`
`0.0
`
`0
`
`0
`
`24
`months
`FIG, I. - (a) Development of joint pain (VAS. 0-100 min), (b)
`number of swollen joints and (c) 11AQ score (scale 0 3) during 2 yr
`follow-up on either auranofin (hatched boxes) or placebo (open
`boxes). Box and whisker plots show median values, 25 -75% boxes,
`10 -90% whiskers and individual observations X90% and
`
`cent of the patients on auranofin and 41 % of the
`patients on placebo withdrew prematurely for that
`reason. Additionally, 16% On auranofin and 29% on
`placebo treatment withdrew due to lack of effect
`(Table IV). Of those withdrawn, three patients in the
`auranofin group and 12 in the placebo group were put
`on other DMARDs. A few patients dropped out due
`to intercurrent disease or at their own request. The
`intercurrent diseases in the auranofin group were
`temporal arteritis (I), herpes zoster (1), nephrolithiasis
`with urosepsis (1) and cardiac infarction (1, lethal), and
`in the placebo group temporal arteritis (1). Of those
`who terminated the study for other reasons, five
`patients died before month 24. No patients died due to
`reasons related to the study medication.
`
`Duration of therapy
`As less than half of the patients (23/65) completed
`the study, one main piece of information was
`considered to be the duration of adherence to the
`assigned treatment. This was evaluated by a life table
`analysis (Fig. 2). A systematic and increasing difference
`between the treatment groups was demonstrated
`statistically from about 111011111 4 and onwards with
`respect to time in the study (P < 0.01). At month 24,
`55% of the auranofin group and 18% of the placebo
`group were completers. Furthermore, the withdrawals
`and drop-outs were assessed and ordered according to
`the (cid:9)
`scale: completers > lack of effect > adverse
`events > drop-outs. A Mann—Whitney test for inde-
`pendent groups yielded a significant difference between
`the treatments (P < 0.01). Other factors possibly
`influencing the length of time in the study were
`explored by a Cox's proportional hazard model for
`multiple regression. The following variables, measured
`at baseline, were analysed: age, sex, Steinbrocker index,
`I-1AQ, number of swollen joints, pain score, use of
`prednisolone, Waaler > 64/ <64 and log(CRP). The
`treatment effect was present in all models and evaluated
`as the, most important predictive variable. In addition,
`some influence of pain (P = 0.02) and Waaler's titre
`(P = 0.03) at baseline was indicated. A high pain score
`implied an increased risk of an early termination. The
`relative risk was 2.8 for Waaler > 64 rs Waaler < 64.
`
`RadiOgraphic changes
`Altogether, 51 patients had arthritis in the wrist or
`finger • joints. of these, two did not show up for
`radiographic examination. Thus, standard hand and
`wrist radiograms were obtained at baseline and at
`month 24 from 49 (75%) of 65 patients (completers and
`withdrawals). The Larsen—Dale indexes at