17,
`
`V. 350
`C-o1
`TI: LANCET
`
`WI LA453
`NO.9074 (cid:9)
`1997
`SEO: L01840000
`
`10,10/97 ANCET
`
`Volume 350, Number 9074 • Founded 1823 • Published week!} • Saturday 2 August 1997
`
`EDITORIAL
`303 How do you sleep at night, Mr Broughton?
`
`COMMENTARY
`304 Rheumatoid arthritis: not yet curable with early intensive
`therapy
`P Emery
`305 Watchful waiting or drug therapy for benign prostatic
`hyperplasia? D E Neal
`306 Hypersensitivity vasculitis—not always benign?
`R A Swerlick, T J Lawley
`307 Listeria meningitis in adults
`J A M Calder
`308 Dearing—a report to be embraced G Remuzzi, A Schieppati
`
`ARTICLES
`309 Randomised comparison of combined step-down prednisolone,
`methotrexate, and suiphasalazine with sulphasalazine alone in
`early rheumatoid arthritis
`M Boers and others
`319 Should women be advised against pregnancy after breast-
`cancer treatment?
`N Kroman and others
`323 Resistance to methicillin and other antibiotics in isolates of
`Staphylococcus aureus from blood and cerebrospinal fluid,
`England and Wales, 1989-95
`D C E Speller and others
`326 Language bias in randomised controlled trials published in
`English and German
`M Egger and others
`
`EARLY REPORT
`330 Cytogenetic effect of chronic low-dose, low-dose-rate -y-radiation
`in residents of irradiated buildings
`W P Chang and others
`
`CASE REPORT
`334 A pain in the groin K Harris and others
`
`NEWS
`Science & medicine
`341 Changing insulin sensitivity
`Retrovirus in IDDM
`342 (cid:9) Nurturing intelligence in the
`womb
`US warns on zafirlukast
`SLE immune response
`343 Sex and coronary care
`Cyclospora plagues USA
`DOTS works with nomads
`
`Feature
`344 Predicting El Nino's effects
`
`Dispatches
`345 (cid:9) Algeria's quiet violence
`Policy & people
`346 (cid:9) Gulf War sarin exposure
`US Congress' tobacco habit
`Stem-cell separator fight
`347 WHO gets tough with leprosy
`Treatment of Filipino lepers
`Robinson takes up UN post
`Review of Canada's research cuts
`348 British medical students' debt
`Russia embraces DOTS
`Ireland learns from child abuse
`
`See contents list inside
`
`REVIEW AND OPINION
`Seminar:
`Psoriasis
`Issues in imaging:
`Interventional radiology
`Literature & medicine:
`Narratives of mental
`illness
`
`CORRESPONDENCE
`nit" TING ROOM
`ooks, Art
`abs & jibes
`
`336 (cid:9)
`
`RESEARCH LETTERS
`335 (cid:9) Thrombospondin-related adhesive
`protein (TRAP) of Plasmodium (cid:9)
`berghei and parasite motility
`R Spaccapelo and others (cid:9)
`Subretinal haemorrhage after (cid:9)
`granulocyte colony-stimulating
`factor
`T Matsumura and others (cid:9)
`Presenilin-I, presenilin-II, and VLDL-R
`associations in early onset (cid:9)
`Alzheimer's disease
`A J Brookes and others
`337 (cid:9) Autologous bone-marrow (cid:9)
`transplantation for rheumatoid (cid:9)
`arthritis (cid:9)
`D J L Joske
`
`36 (cid:9)
`
`338 Chronic progressive leptomeningitis
`associated ./ith measles virus
`P Luzi and others
`339 Anophthalrria and agenesis of optic
`chiasma associated with adapalene
`gel in early pregnancy
`E Autret and others
`339 Neural innervation and healing
`A M Richards and others
`340 Antibiotic prophylaxis after
`swan bite
`R J Ebrey and others
`340 Aberrant infernal carotid artery
`in the mouth
`K Tsunoda and others
`
`All literary matter in The Lancet is copyright. ,Q The Lancet Ltd, 1997. Registered as a newspaper. ISSN 0140-6736.
`4:3.50
`
`This material was copied
`atthe NLM and may be
`Subject US CDDyright Laws
`
`Ex. 1062 - Page 1
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`THE LANCET
`
`Volume 350, Number 9074 • Founded 1823 • Published weekly • Saturday 2 August 1997
`
`EDITORIAL OFFICES
`LONDON
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`London WC1B 3SL, UK
`Telephone (+44) (0) 171 436 4981
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`Internet address
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`
`SEMINAR
`349 Psoriasis R S Stern
`
`ISSUES IN IMAGING
`Interventional radiology K R Thomson
`354 (cid:9)
`
`LITERATURE AND MEDICINE
`359 (cid:9) Literature and medicine: narratives of mental illness
`A Hudson Jones
`
`CORRESPONDENCE
`Severity of malaria and level of
`362 (cid:9)
`Plasmodium falciparum transmission
`U D'Alessandro;
`V Moorthy, D Wilkinson;
`P N Soni, B L Sharp;
`A F Fleming
`
`364 (cid:9)
`
`364 (cid:9)
`
`Severe hepatitis in patients with
`AIDS and haemophilia B treated
`with indinavir
`J Matsuda and others
`
`Primary hyperparathyroidism
`G S Spathis;
`A Al Zahrani, M A Levine;
`F J Fernandez-Fernandez
`
`365 (cid:9) Breast cancer genetics
`M Swift;
`K N Naresh;
`W D Foulkes
`
`366 (cid:9) AIRE Extension (AIREX) Study
`G Tognoni, M G Franzosi;
`P Dunkley, K Hodgson;
`A Hall and others
`
`368 (cid:9) Autolmmune (idiopathic)
`thrombocytopenic purpura
`S Hauser;
`S J Proctor and others
`
`368 (cid:9) Leishmaniasis mimicking collagen
`disease
`E Galanakis and others
`
`369 (cid:9) Growth factors in saliva
`R J Playford, C E Macdonald
`
`369 (cid:9)
`
`Polymorphism of m-adducin and
`hypertension
`N lwai and others
`
`370 (cid:9) Good manners for the
`pharmaceutical industry
`M Gore and others;
`T Perren;
`G J S Rustin, D Crowther;
`H Calvert and others
`
`371 (cid:9) Health impact of human rights
`violations in Haitian refugees
`M C Smith Fawzi and others
`
`372 (cid:9) Organ transplant waiting-list
`in France
`P Romano and others
`
`DISSECTING ROOM
`373 (cid:9) Hormones in and out of the delivery room A Levy
`373 Endoscopy H Ellis
`374 (cid:9) And so to sleep ... perchance? G Murphy
`Jungle law D Feenan
`374 (cid:9)
`376 Lifeline R David
`376 (cid:9) How about a filling? D Davis
`
`DEPARTMENT OF ERROR
`372 (cid:9) A woman who had a stroke, then a
`myocardial infarction
`372 Olanzapine: a novel atypical
`neuroleptic agent
`372 (cid:9) Activin A and inhibin A as possible
`endocrine markers for pre-eclampsia
`
`Writing for The Lancet
`Guidelines for authors are published in the
`first issue of every month, immediately
`after Dissecting Room.
`
`This material was copied
`at th e NLM and may be
`Subject US Copyright Laws
`
`Ex. 1062 - Page 2
`
`

`

`THE LANCET
`
`Articles
`
`Randomised comparison of combined step-down prednisolone,
`methotrexate and sulphasalazine with sulphasalazine alone in early
`rheumatoid arthritis
`
`Maarten Boers, Arco C Verhoeven, Harry M Markusse, Mart A F J van de Laar, Rene Westhovens,
`J Christiaan van Denderen, Derkjen van Zeben, Ben A C Dijkmans, Andre J Peeters, Piet Jacobs,
`Hans R van den Brink, Hubert J A Schouten, Desiree M F M van der Heijde, Annelies Boonen, Sjef van der Linden
`
`Summary
`
`Background The value of intensive combination therapy in
`early rheumatoid arthritis is unproven. In a multicentre,
`double-blind, randomised trial (COBRA), we compared the
`combination of sulphasalazine (2 g/day), methotrexate (7.5
`mg/week), and prednisolone (initially 60 mg/day, tapered in
`6 weekly steps to 7.5 mg/day) with sulphasalazine alone.
`
`Methods 155 patients with early rheumatoid arthritis
`(median duration 4 months) were randomly assigned
`combined treatment (76) or sulphasalazine alone (79).
`Prednisolone and methotrexate were tapered and stopped
`after 28 and 40 weeks, respectively. The main outcomes
`were the pooled index (a weighted change score of five
`disease activity measures) and the Sharp/Van der Heijde
`radiographic damage score in hands and feet. Independent
`health-care professionals assessed the main outcomes
`without knowledge of treatment allocation.
`
`Findings At week 28, the mean pooled index was 1.4 (95%
`CI 1.2-1.6) in the combined treatment group and 0.8
`(0.6-1.0) in the sulphasalazine group (p<0.0001). At this
`time, 55 (72%) and 39 (49%) patients, respectively, were
`improved according to American College of Rheumatology
`criteria. The clinical difference between the groups
`decreased and was no longer significant after prednisolone
`was stopped, and there were no further changes after
`methotrexate was stopped. At 28 weeks, the radiographic
`damage score had increased by a median of 1 (range 0-28)
`in the combined-therapy group and 4 (0-44) in the
`sulphasalazine group (p<0.0001). The increases at week 56
`(2 [0-43] vs 6 [0-54], p=0.004), and at week 80 (4 [0-80]
`vs 12 [0-72], p=0.01) were also significant. Further analysis
`suggests that combined therapy immediately suppressed
`
`University Hospital, Maastricht (M Boers MD, A C Verhoeven mo,
`H J A Schouten, DM FM van der Heijde, A Boonen,
`S van der Linden); Zulderzlekenhuis, Rotterdam
`(H M Markusse mo); Medisch Spectrum Twente and Twenteborg
`Hospital, Enschede and Almelo, Netherlands
`(M A F J van der Laar mo); Pellenberg Hospital, Catholic University,
`Louvain, Belgium (R Westhovens mo); Jan van Breemen Instituut,
`Amsterdam (J C van Denderen mo); Bronovo Hospital, The Hague
`(D van Zeben Mo); University Hospital, Leiden (B A C Dijkmans mo);
`Reinier de Graaf Gasthuis, Delft (A J Peeters mo); Sint Laurentius
`Hospital, Roermond (P Jacobs mo); Medisch Centrum Alkmaar,
`Netherlands (H R van den Brink mo)
`Correspondence to: Dr Maarten Boers, Department of Clinical
`Epidemiology, Free University Hospital, PO Box 7057, 1007 MB
`Amsterdam, Netherlands
`
`damage progression, whereas sulphasalazine did so less
`effectively and with a lag of 6 to 12 months. There were
`fewer withdrawals in the combined therapy than the
`sulphasalazine group (6 [8%) vs 23 [29%]), and they
`occurred later.
`
`Interpretation This combined-therapy regimen offers
`additional disease control over and above that of
`sulphasalazine alone that persists for up to a year after
`corticosteroids are stopped. Although confirmatory studies
`and long-term follow-up are needed, this approach may prove
`useful in the treatment of early rheumatoid arthritis.
`
`Lancet 1997; 350: 309-18
`See Commentary page 304
`
`Introduction
`The treatment of rheumatoid arthritis is traditionally
`characterised by escalation. The first step is non-steroidal
`anti-inflammatory drugs (NSAIDs), and then if necessary a
`sequence of progressively toxic second-line drugs (disease-
`modifying antirheumatic drugs) is introduced.' There is
`evidence that some of these disease-modifying drugs
`provide a degree of disease control'—ie, decrease disease
`activity but also maintain or improve physical function and
`retard radiographic joint damage.' However, both patients
`and physicians are dissatisfied with the long-term results of
`traditional therapy. A 1996 study suggested that early
`introduction of disease-modifying antirheumatic drugs may
`be more beneficial than delayed introduction for patients
`with recently diagnosed rheumatoid arthritis.' Research is
`focused towards finding new, more effective drugs,
`reassessment and earlier use of existing drugs (such as
`corticosteroids5), and treatment with drug combinations.°
`The COBRA trial (Combinatietherapie Bij Reumatoide
`Artritis) is an adaptation of the latter two options—step-
`down bridge therapy with corticosteroids in early
`rheumatoid arthritis.' Our intention was to control disease
`rapidly at a very early stage, with agents that have
`overlapping windows of efficacy onset; and then, after 6
`months to taper and stop the more toxic components while
`retaining disease control. We devised a regimen comprising
`a short period of high-dose oral prednisolone, rapidly
`tapered to a low maintenance dose. As the other
`components we chose methotrexate, commonly used as the
`disease-modifying drug of first choice in the USA, and
`sulphasalazine as the anchor drug to remain after the other
`two drugs were withdrawn. In Europe, sulphasalazine is
`commonly used as the disease-modifying drug of first
`choice.
`We carried out a 56-week multicentre, randomised
`
`Vol 350 • August 2, 1997
`
`This material was copied
`at the NUM and may be
`Subject USCopyright Laws
`
`309
`
`Ex. 1062 - Page 3
`
`

`

`dm(
`
`THE LANCET
`
`controlled trial among patients with early, active
`rheumatoid arthritis to study the degree of disease control
`afforded by a combination of sulphasalazine, methotrexate,
`and high/low oral prednisolone given in the first 28 weeks,
`compared with that achieved with sulphasalazine alone;
`and to find out whether control could be maintained on
`sulphasalazine alone, after sequential tapering and
`withdrawal of prednisolone and methotrexate in the second
`
`28 weeks.
`
`Patient and methods
`
`Patients
`We recruited patients between May, 1993, and May, 1995, in ten
`centres (nine in the Netherlands, one in Belgium). To optimise the
`benefit/risk ratio in line with the study purpose, we applied strict
`eligibility criteria to include patients with early rheumatoid arthritis
`who had very active disease and were most likely to benefit from
`this intensive treatment, in whom effects could be easily measured,
`and in whom we believed adverse effects would be least likely. The
`inclusion criteria were: a diagnosis of rheumatoid arthritis
`(American College of Rheumatology criteria') with onset of disease
`at or after 16 years of age; active disease of the joints and
`inadequate control of arthritis (due to lack of efficacy or toxicity of
`treatment); and treatment with NSAIDs in adequate doses for at
`least 3 months. Such treatment could already have been initiated
`at the start of symptoms, not necessarily at the time of diagnosis.
`We defined disease activity as the presence of six or more actively
`inflamed joints, located at three or more different sites (a site is
`defined as either one large joint or a group of small joints: the
`joints of the wrist, the metacarpophalangeals, the proximal hand
`interphalangeals, the distal hand interphalangeals, ankles, the
`tarsometatarsals, the metatarsophalangeals, and the proximal and
`distal foot interphalangeals) and presence of at least two of the
`following: nine or more tender joints (irrespective of site), morning
`stiffness of 45 min or longer, and a Westergren's erythrocyte
`sedimentation rate (ESR) of 28 mm or more in the first hour.
`We excluded patients who had had rheumatoid arthritis for
`longer than 2 years, those previously or currently treated with any
`disease-modifying antirheumatic drug except antimalarials (eg,
`gold, d-penicillamine, azathioprine, or cyclophosphamide) or
`corticosteroids (for arthritis or another disease), serious
`comorbidity or recent (within the 3 months before enrolment)
`major surgery, or inability to comply with the protocol. Adequate
`contraception was required. Further exclusion criteria were age
`below 18 or over 70; hypersensitivity to study medication, sulpha-
`containing compounds, or aspirin; hypersensitivity to three or
`more drugs; active infectious disease; a history of tuberculosis,
`recurrent infections, recent (<3 months) gastritis or
`gastrointestinal ulceration; any history of gastrointestinal bleeding
`or neoplasia; diabetes mellitus; hypertension treated with more
`than one antihypertensive drug; significant cardiovascular disease;
`liver disease; cataract; glaucoma; haematological disorders; partial
`or total colectomy; reduced renal function (creatinine clearance
`<50 mUh) proteinuria (>0.5 g/day); hypoalbuminaemia; chronic
`dermatitis; treatment with phenytoin, phenylbutazone, salicylates,
`barbiturates, cholestyramine, probenecid, oral anticoagulants
`(dicoumarol derivatives); and a history of alcohol or substance
`abuse (ie, inability to limit alcohol intake to a maximum of 70 g
`weekly) or use of any experimental drug less than 2 months before
`inclusion.
`The study protocol was approved by research and medical
`ethics committees in all participating hospitals. The patients were
`fully informed about the potential side-effects of all the drugs. To
`maintain allocation concealment, they were told that response to
`treatment was variable in onset and efficacy with all three drugs.
`All patients gave written informed consent.
`
`Intervention
`Both groups received sulphasalazine (Salazopyrine enteric-coated
`tablets of 500 mg, Pharmacia & Upjohn, Uppsala, Sweden) 500
`
`mg/day, increased to 2000 mg/day over a period of 3 weeks. In
`addition, the combination therapy group received prednisolone
`and methotrexate; the control group received matching placebo
`tablets and capsules identical in appearance and taste. The daily
`prednisolone dose was 60 mg in week 1, 40 mg in week 2, 25 mg
`in week 3, 20 mg in week 4, 15 mg in week 5, 10 mg in week 6,
`and 7.5 mg thereafter (week 1-6--one gelatine capsule containing
`the daily dose, capsule compound by Bufa, Uitgeest, Netherlands;
`week 7 and later-5 mg tablets by CentraFarm Nederland by,
`Etten-Leur, Netherlands; some of these tablets were broken by the
`pharmacy so that 7.5 mg could be taken daily). The cumulative
`dose over the first 6 weeks was 1190 mg; over the first 28 weeks it
`was 2345 mg, corresponding to a mean of 12 mg daily. The
`methotrexate prescription was 7.5 mg in a single weekly dose
`(PharmaChemie by, Haarlem, Netherlands). If an adverse event
`occurred, the drugs were temporarily withdrawn, and reintroduced
`at lower doses according to a fixed protocol where possible.
`Prednisolone and methotrexate were stopped after 28 weeks
`and 40 weeks, respectively. Both drugs were gradually withdrawn
`to decrease the chance of a disease flare. Thus, from week 29 to
`35, a day of zero prednisolone dose was introduced each week:
`first week, no prednisolone on Wednesday; second week, no
`prednisolone on Tuesday and Saturday; third week, no
`prednisolone on Monday, Wednesday, and Friday; until after 6
`weeks, the prednisolone had been stopped. After 40 weeks of
`treatment, methotrexate was tapered: the drug was given at 5 mg
`per week for 3 weeks, then at 2.5 mg per week for 3 weeks, then
`stopped. If there was a flare in disease activity, the last medication
`stopped was reintroduced. A flare was defined per protocol as an
`increase of five in active joint count or an increase from zero to
`three compared with the situation at week 28 (an active joint is
`swollen or tender on pressure; counting of joint groups in one
`hand or foot as above). If the research medication had to be
`stopped for any reason and a consecutive disease-modifying
`antirheumatic drug was started, the protocol recommended that a
`drug not in the combination should be given, preferably
`intramuscular gold salts. After 56 weeks, the protocol ended, and
`the treating physician was at liberty to change second-line therapy,
`or to attempt a second tapering of methotrexate or prednisolone in
`those patients still on combination therapy. Where possible,
`blinded protocol treatment was continued. To maintain allocation
`concealment for other patients still in the protocol, the treatment
`code was revealed only for those patients still on combination
`therapy after 80 weeks.
`
`Concurrent therapy
`NSAIDs and simple analgesics were allowed; discontinuation was
`actively pursued. A maximum of two infra-articular steroid
`injections was allowed in two periods after week 38 of the protocol,
`but not in the 6-week period preceding independent assessment.
`Any other intervention with parenteral or oral corticosteroids was
`not permitted. All patients received folic acid (1 mg/day) during
`methotrexate or placebo prescription. Vitamin D deficiency
`apparent at the laboratory screening before inclusion was
`corrected.
`
`Treatment allocation
`Patients who met the eligibility criteria were entered into the study
`and assigned a unique study identification number by telephone.
`This number implied random allocation to one of the two
`treatments with stratification by centre. For each centre, a separate
`randomisation list was generated by an adaptive biased urn
`algorithm. In contrast to fixed blocks, this algorithm ensured that
`the rheumatologists would have no clue to the allocation of each
`subsequent patient in a setting where unblinding was possible; yet
`it also guaranteed an approximately equal distribution over the
`groups even in the centres with smaller numbers of patients." The
`assignment was known only by the employees of the Maastricht
`Hospital pharmacy who prepackaged the medication; it was
`disclosed to the treating physician only in case of an emergency.
`Primary analysis was done with coded group allocation after entry
`of all study data. The full randomisation codes remained
`
`310
`
`This material was copied
`at the NUM and may be
`Subject US Copyright Laws
`
`Vol 350 • August 2, 1997
`
`Ex. 1062 - Page 4
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`

`

`concealed until completion of the primary analysis.
`
`Organisation
`Each centre was staffed by a rheumatologist, a research nurse, and
`an independent assessor. The rheumatologist was responsible for
`the identification and inclusion of the patients, and for all medical
`policy decisions. The research nurse monitored safety through
`regular follow-up schedules (first weekly, then every 4 weeks) and
`also measured disease activity. Independent assessors (mostly
`physiotherapists) applied the outcome measures at baseline and at
`weeks 16, 28, 40, and 56; in almost every instance a patient was
`seen by the same assessor. These health professionals were not
`involved in care of patients; they were also asked not to discuss
`disease activity or the treatment with the patients. Independent
`assessment ensured optimum concealment of primary outcome
`assessments, especially important in the first 6 weeks of the
`protocol, when potential effects and side-effects of high-dose
`prednisolone would be most apparent. These assessments
`included all primary and core-set outcome measures except pain
`score, grip strength, and ESR. The follow-up schedule is
`continuing; all outcomes during the first 56 weeks are reported
`here. In response to criticism about the follow-up period for the
`radiographs, we read and analysed the 80-week radiographs at a
`later stage.
`Before the study and then once a year, all study personnel
`trained together to maintain assessment quality and agreement
`between observers. A specially designed manual of procedures and
`assessment techniques was available in each study centre. The trial
`was coordinated and data managed in the University Hospital
`Maastricht. Safety and toxicity were monitored by a safety
`committee of two independent rheumatologists, the Maastricht
`University pharmacist, and a statistician (HJAS). The pharmacy
`centre of the University Hospital Maastricht was responsible for
`drug production, packaging, and distribution.
`
`Assessment of endpoints
`The primary endpoint of the therapeutic intervention was a pooled
`index summarising the change in five measures after 28 weeks of
`treatment. Pooling is a validated method to increase sensitivity of
`separate measures.' To obtain the pooled index of one of the
`groups at week 28, we calculated a standardised change score of
`that group by dividing the mean change in one measure by its
`pooled SD of change at week 28. This procedure was repeated for
`each of the five measures; the pooled index is the mean of the
`standardised scores. To obtain pooled index values for another
`time point, change scores at that point were standardised through
`division by the same pooled SD at week 28. Finally, a constant
`was added to all index values so that the value at baseline was zero.
`We selected five measures for maximum sensitivity to change:1°
`Tender joint count (68 joints"); overall assessment by the
`independent assessor (on a 100 mm visual analogue scale, worst
`and best imaginable health status at the left and right anchor,
`respectively); grip strength (by vigorimetry; Martin, Tottlingen,
`Germany, range 0-150 kPa, mean of medians of three
`measurements in both hands);12 ESR (Westergren method); and
`McMaster Toronto arthritis questionnaire," which follows
`improvement in five impaired activities elicited and priority-ranked
`by the patient during a baseline interview, together with change
`scores for quality of life, psychological, social, and emotional
`wellbeing. The scores of this questionnaire reflect change, increase
`as disability improves, and vary from 10 (maximum deterioration)
`to 40 (maximum improvement). In its original format, the baseline
`questionnaire score differs from the follow-up scores because the
`change items are not available. To make these scores directly
`comparable, we added mock change items at baseline and scored
`them as "unchanged". Grip strength and ESR were assessed by
`the research nurses every week at the start of the protocol, then at
`least every 4 weeks.
`We assessed all remaining disease activity measures of the
`World Health Organisation/International League of Associations
`for Rheumatology core set as secondary endpoints.'" As well was
`tender joint count, assessor's overall assessment, and acute phase
`
`THE LANCET
`
`reactant (ESR) included in the pooled index, these measures are
`swollen joint count (48 joints: modified from American College of
`Rheumatology 66-joint count;" small foot joints as one joint site
`and no midfoot joints), pain (assessed by the patient on a 100 mm
`visual analogue scale; worst imaginable pain at the right anchor),
`and patient's overall assessment (on a 100 mm visual analogue
`scale, worst and best imaginable health status at the left and right
`anchor, respectively).To facilitate comparisons with other studies,
`the highly patient-specific McMaster Toronto arthritis
`questionnaire was complemented with the more generic health
`assessment questionnaire (Dutch validated version; scores 0-3, 3
`indicating a poor functional state)."
`We expressed improvement in individual patients by the
`American College of Rheumatology preliminary criteria for
`remission" (occurrence and duration; because no inquiry on
`fatigue was made we used the concept of a "probable remission'
`for instances in which a patient would be in remission when
`absence of fatigue was assumed). Furthermore, we used the
`American College of Rheumatology preliminary criteria for
`improvement in rheumatoid arthritis" (ie, minimum 20%
`improvement in tender and swollen joint counts plus a similar
`improvement in at least three of five remaining core-set measures).
`Before calculating improvement percentages, we ensured (by
`recoding if necessary) that all scales decreased on improvement.
`We also report improvement with application of a 50% threshold
`instead of the 20% in the American College of Rheumatology
`criteria.
`To facilitate comparison with other European studies, we report
`the disease activity score, a composite outcome measure
`containing the Ritchie tender joint index (RI), swollen joint count
`(JC), ESR, and patient's overall assessment
`Score=0-54VRI+0•065JC +0•331nESR+0•0070A
`The term disease-controlling has been suggested for
`antirheumatic treatment regimens that improve disease activity,
`retain or improve physical function, and decrease progression of
`radiographic damage.' A priori, we expected out study to be too
`small to detect small differences in radiographic progression
`between the two groups, since both were treated with the disease-
`controlling drug sulphasalazine. Nevertheless, two trained
`observers (AB and ACV) assessed radiographic damage, unaware
`of the identity of the patients. They separately scored radiographs
`of hands and feet according to van der Heijde's modification of
`Sharp's method.' This method reflects erosions and joint-space
`narrowing in 44 joints in the hands and feet. The principal
`measure, the total score, is the sum of erosion and narrowing
`scores, and ranges from 0 to 448. The method requires
`radiographs to be presented in ordered fashion (baseline, and
`weeks 28, 56, and 80). Scores can either be stable or increase;
`decrease (indicating improvement) is not possible. We report the
`mean of the two observers' erosion, narrowing, and total scores.
`As an exploratory analysis, we also report the cumulative
`number of joints free of erosions at baseline in which at least one
`erosion developed during follow-up. For this purpose, joints were
`grouped into four areas on each side: wrist (six joints),
`metacarpophalangeal (five joints); proximal interphalangeal (four
`joints); and foot joints (six joints). The first erosion in each area
`was counted. Furthermore, we explored the rate of radiographic
`change in each of the measurement periods by calculating not only
`the change scores from baseline, but also the change scores
`between week 28 and 56 and between week 56 and 80.
`
`Toxicity and monitoring
`Laboratory monitoring at every control visit comprised complete
`blood count, measurement of serum total bilirubin,
`aminotransferases, alkaline phosphatase, creatinine, blood urea
`nitrogen, and electrolytes, and urinalysis for glucose and albumin.
`Toxicity was assessed by counting of each adverse event reported
`and possible subsequent changes to treatment (eg, withdrawal).
`Each patient underwent pulmonary function tests (expiratory
`volume and carbon monoxide diffusion capacity) at baseline and
`twice yearly thereafter. Bone densitometry was done by an
`operator unaware of treatment assignment, in all centres where a
`
`Vol 350 • August 2, 1997 (cid:9)
`
`This material was copied
`atthe NLM and may be
`Subject US Copyright Laws
`
`311
`
`Ex. 1062 - Page 5
`
`(cid:9)
`

`

`THE LANCET
`
`156 patients enrolled
`
`Randomised
`
`77 assigned
`combined treatment
`
`1
`
`79 assigned
`sulphasalazine
`alone
`
`Numbers of patients who
`received treatment as
`allocated and were
`included in the analysis
`0-
`
`16
`
`to
`
`28
`
`1 ineligible
`at start
`
`1
`
`1 (1AE)
`
`76
`
`75 (cid:9)
`
`75 (cid:9)
`
`2 (1 AE, 1 LE)
`
`40
`
`73
`
`3(3 AE)
`
`79
`
`71
`
`62
`
`59
`
`Combined treatment
`protocol
`
`.0
`
`0 -
`
`',)
`
`qc?7c4.'p
`
`Prednisolone
`
`8 (4 AE*, 2 LE,
`2 AE+LE)
`
`16 -
`
`28 -
`
`To
`(r)
`CO
`0_
`
`9 (1 AE, 7 LE*,
`1 other*)
`
`3 (1AE, 2 LE*)
`
`40
`
`3(1 LE,
`2 other*)
`
`56
`
`70 completed trial
`
`56 completed trial
`
`56 -
`
`
`
`Figure 1: Trial profile
`*Patient lost to follow-up.
`AE=adverse events; LE-loss of efficacy; other includes protocol violations.
`dual-energy X-ray absorptiometer was available (Lunar, Hologic,
`or Norland, in eight centres). We report changes in bone mass for
`lumbar spine and femoral neck (mean of right and left hip).
`We assessed IgM rheumatoid factor serostatus in a time-
`resolved fluoroimmunoassay (rabbit IgC antigen; Nordic, Tilburg,
`Netherlands); values over 20 kU/L classified patients as positive for
`rheumatoid factor." Class II HLA genotype was identified by
`serological typing (Tissue Typing Laboratory, Maastricht
`University Hospital).
`
`Compliance
`We assessed compliance by tablet counts at every control visit, by
`questioning (including a quantification of the number of tablets
`missed), and by measurement of sulphapyridine (a sulphasalazine
`metabolite) in urine samples taken at weeks 16, 28, and 40. We
`classified as non-compliant all patients on protocol treatment who
`were negative for sulphapyridine once or who failed to return
`tablet boxes at control visits more than once. In the first 28 weeks,
`we made judgments at every control visit, and classified as
`"probably non-compliant" patients who in the first 28 weeks on
`average missed more than one daily dose per week of
`sulphasalazine or prednisolone, or more than one weekly dose of
`methotrexate over a period of 6 weeks.
`
`Analysis
`The target sample size was 168 patients. This number yields a
`power of at least 90% to detect a difference of 0.33 or greater in
`
`the pooled index (SD 0.45) between the treatment groups at two-
`sided oc=0.05, given a maximum dropout r