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`olume
`Number
`December
`
`1998
`
`Editorial:
`urnping
`syndrome
`
`splitting autoimm ne
`earie2
`M. Moutsopoulos
`
`disorders Lessons
`Manoussakis
`
`Sjogre
`
`1263
`
`Review:
`Heber en Oration 1997.
`taw:AIM
`Brooks
`relief to potentia
`
`d/
`r euma oid
`
`from symptomatic
`
`Original Papers:
`Electron
`microscopy
`capillaroscopical y
`connective
`biopsy
`gui•ed
`nailfold
`4WD
`diseases:
`detection
`of ultrastructural
`of'the microcircu atory
`changes
`=Ma=
`/140ex/saw
`Cba tifilidi Meta
`Bierbrauer,
`Baerwald,
`C.
`ta,
`Schmidt
`double-blind,
`randomized,
`moclobemide
`placebo-controlled study
`Riigbili3201200
`tiatallaB
`without
`psychiatric
`amitriptyline
`fibromyalgia
`enalIS
`Hannonen, Ci (cid:9)
`MI
`Isomer! and Roponen 1279
`U. Yli-Kerttula,
`disorder
`syndrome: prevalence
`cytoplasmic antibodies
`Antineutrophil
`SjOgren's
`primary
`Bosch,
`Font,
`R. Cervera,
`Ramos-Casals,
`significance
`clinical
`Garcfa-Carrasco,
`Ingelmo
`Mirapeix,
`M.
`glaMorla
`M.
`emegomo
`IlitMWROimakzema
`vasculitides
`necrotizing
`systemic
`a Cohen, 12
`Gumwat
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`Bogard, Delaugerre,
`calla?
`restricted
`movement to
`arge-vessel
`disease
`: tno aetiology caw
`McRorie,
`Ruckley
`ulceration
`rheumatoid
`Nuki
`memo=
`
`ankylosing
`
`different
`
`Kle•siella serotypes
`K. Granfors
`CID
`markedly elevated
`dab
`Reynolds,
`Ponting,
`
`factor
`
`antibodies against three
`Maki-lkola,
`spondylitis
`endothelial growth
`of vascular
`granulomatosis
`with Wegener's
`patients
`lZha
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`ill r
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`rheumatoid
`antibody
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`Ligier,
`Long-term outcomes ealBagilb
`self-management
`a P. wawa a
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`co pericardial
`of the frequency
`study
`Pope
`and J.
`4t
`Thompson
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`rheumatoi
`in patients
`early
`remission
`course
`cav@ip213133 Eberhardt
`and E.
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`outcom
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`pneumoniae lipopolysaccharide
`Klebsiella
`Anti • odies
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`systemic
`interleukin-16
`Circulating
`a
`and
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`Hashimoto
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`physical
`training
`long-term
`polymyositis/dermatomyositis
`months
`Benefit
`au, Wiesinger,
`Quittan,
`Graninger,
`A. Seeber, Q, Ebenbichler,
`patients
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`
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`fig SHED
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`
`Kaneko,
`
`Co tinued
`
`inside
`
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`
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`
`4 _h i..4li'
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`
`1320
`
`1330
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`1338
`
`Ex. 1034 - Page 1
`
`(cid:9)
`

`

`BRITISH JOURNAL OF RHEUMATOLOGY
`
`Official Journal of the British Society for Rheumatology
`
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`D. L. Scott
`
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`J. A. Mazo
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`
`r,- it atsrial
`at t- s (cid:9)
`a- d (cid:9)
`u bj =:tL_:=_
`
`
`c s
`
`Ex. 1034 - Page 2
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`Volume 37
`Number 12
`December 1998
`
`ritis Jour all of
`
`CONTENTS
`
`Editorial:
`Lumping or splitting autoimmune rheumatic disorders? Lessons from Sjogren's
`syndrome H. M. Moutsopoulos and M. N. Manoussakis
`
`1263
`
`Review:
`The Heberden Oration 1997. Treatment of rheumatoid arthritis: from symptomatic
`1265
`relief to potential cure P. M. Brooks
`
`Original Papers:
`Electron microscopy and capillaroscopically guided nailfold biopsy in connective
`tissue diseases: detection of ultrastructural changes of the microcirculatory
`vessels A. von Bierbrauer, P. Barth, J. Willert, C. Baerwald, H. D. Mennel and
`J. A. Schmidt (cid:9)
`
`1272
`
`A randomized, double-blind, placebo-controlled study of moclobemide and
`amitriptyline in the treatment of fibromyalgia in females without psychiatric
`disorder P. Hannonen, K. Malminiemi, U. Yli-Kerttula, R. Isomeri and P. Roponen 1279
`
`Antineutrophil cytoplasmic antibodies in primary Sjogren's syndrome: prevalence
`and clinical significance J. Font, M. Ramos-Casals, R. Cervera, X. Bosch,
`E. Mirapeix, M. Garcia-Carrasco, R. M. Mode and M. Ingelmo (cid:9)
`
`GB virus C in systemic medium- and small-vessel necrotizing vasculitides
`A. Servant, M. Bogard, C. Delaugerre, P. Cohen, P. Deny and L. Guillevin (cid:9)
`
`1287
`
`1292
`
`The relevance of large-vessel vascular disease and restricted ankle movement to
`the aetiology of leg ulceration in rheumatoid arthritis E. R. McRorie, C. V. Ruckley
`and G. Nuki (cid:9)
`IgA class serum antibodies against three different Klebsiella serotypes in
`ankylosing spondylitis 0. Maki-/kola, M. Nissila, K. Lehtinen and K. Granfors (cid:9)
`
`1295
`
`1299
`
`Serum levels of vascular endothelial growth factor (VEGF) are markedly elevated
`in patients with Wegener's granulomatosis C. G. Li, I. Reynolds, J. M. Ponting,
`P. J. L. Holt, M. C. Hillarby and S. Kumar (cid:9)
`
`A new antibody in rheumatoid arthritis targeting glycated IgG: IgM anti-IgG-AGE
`S. Ligier, P. R. Fortin and M. M. Newkirk (cid:9)
`Long-term outcomes of an arthritis self-management programme J. H. Barlow,
`A. P. Turner and C. C. Wright (cid:9)
`
`A study of the frequency of pericardial and pleural effusions in scleroderma
`A. E. Thompson and J. E. Pope (cid:9)
`
`Clinical course and remission rate in patients with early rheumatoid arthritis:
`relationship to outcome after 5 years K. Eberhardt and E, Fex (cid:9)
`
`1303
`
`1307
`
`1315
`
`1320
`
`1324
`
`Continued overleaf
`
`mate-iak..Bz (cid:9)
`
`ed
`
`Ex. 1034 - Page 3
`
`

`

`Antibodies to Klebsiella pneumoniae lipopolysaccharide in patients with
`ankylosing spondylitis K. Ahmadi, C. Wilson, H. Tiwana, A. Binder and
`A. Ebringer
`Circulating interleukin-16 in systemic lupus erythematosus S. Lee, H. Kaneko,
`I. Sekigawa, Y. Tokano, Y. Takasaki and H. Hashimoto
`Benefit of 6 months long-term physical training in polymyositis/dermatomyositis
`patients G. F. Wiesinger, M. Quittan, M. Graninger, A. Seeber, G. Ebenbichler,
`B. Sturm, K. Kerschan, J. Smolen and W. Graninger
`
`1330
`
`1334
`
`1338
`
`Grand Rounds in Rheumatology:
`Post-streptococcal reactive myalgia: a novel syndrome secondary to infection with
`group A or G streptococci T. L. Th. A. Jansen, M. Janssen, J. D. Macfarlane and
`A. J. L. de Jong (cid:9)
`
`Case Report:
`Hypothyroid myopathy as a complication of interferon alpha therapy for chronic
`hepatitis C virus infection G. Ghilardi, J.-J. Gonvers and A. So
`
`1343
`
`1349
`
`1352
`
`1353
`
`Letters to the Editor:
`Digital gangrene and anticentromere antibodies without scleroderma U. Picillo,
`
`M. R. Marcialis, A. Matarazzo, G. Italiano and A. Petti (cid:9)
`Sternum tumour revealing a chronic myeloid leukaemia E. Blot, J. Miguel,
`F. Heron, H. Tilly, H. Levesque and H. Courtois (cid:9)
`Unusual occurrence of acute low back pain in a patient with ruptured urachal cyst
`A. Ambro2io, S. Praprotnik and B. Rozman (cid:9)
`Cerebral calcification in a patient with systemic lupus erythematosus and a
`monoclonal IgG reactive with glial fibrillary acidic protein B. M. Stuart and
`
`N. A. Gregson (cid:9)
`Haemophagocytic syndrome in a patient with dermatomyositis S. Yasuda,
`A. Tsutsumi, T. Nakabayashi, T. Horita, K. Ichikawa, M. leko and T. Koike
`Successful treatment with antithymocyte globulin and cyclosporin A of a severe
`aplastic anaemia associated with an eosinophilic fasciitis B. Bonnotte,
`B. Chauffert, D. Caillot, F. Martin and B. Lorcerie
`Aortitis in relapsing polychondritis U. A. Walker, S. M. Weiner, P. Vaith, M. Uhl
`and H. H. Peter
`
`1354
`
`1355
`
`1357
`
`
`1358
`
`
`1359
`
`1361
`
`1362
`
`1363
`
`1364
`
`1365
`
`1365
`
`Infection with an unenveloped DNA virus (TTV) associated with non-A to G
`hepatitis in patients with rheumatoid arthritis D. Hirata, N. Kaneko, M. Iwamoto,
`T. Yoshio, H. Okazaki, A. Mimori, J. Masuyama and S. Minota
`Outcome in systemic vasculitis R. Luqmani, R. Moots and L. Guillevin
`Sensorineural hearing loss, iritis and ankylosing spondylitis K. Raza, D. Karokis,
`F. Wilson and J. P. Delamere (cid:9)
`
`Review of book
`
`Calendar
`
`Announcements
`
`Please visit the journal's World Wide Web site at http://www.oup.co.uk/brheum/
`
`Ex. 1034 - Page 4
`
`

`

`British Journal of Rheumatology 1998;37:1324-1329
`
`CLINICAL COURSE AND REMISSION RATE IN PATIENTS WITH EARLY
`RHEUMATOID ARTHRITIS: RELATIONSHIP TO OUTCOME AFTER 5 YEARS
`KIEBERHARDT and E.1 FEX*
`inepartment of Rheumatology, Lund University Hospital, Lund,1 Sweden )
`
`SUMMARY
`Objective. To investigate the clinical course in early rheumatoid arthritis (RA) patients followed prospectively, to relate
`course to outcome after 5 yr, and to try to identify prognostic features.
`Methods. A total of 183 patients with definite RA and a mean disease duration of 11 months were included. Of these, 75
`were rheumatoid factor (RF) positive; 85% carried the shared epitope, 32% on both alleles. Most patients were assessed every
`6 months. Disability was evaluated with the Health Assessment Questionnaire (HAQ) and radiographic findings according to
`Larsen. Remission was defined in two ways: with the American Rheumatism Association (ARA) criteria and as 'no arthritis
`at least at one follow-up visit'.
`Results. Twenty per cent achieved ARA-defined remission periods of at least 6 months duration; 21 were spontaneous and
`18 drug induced. Average length of remission was 20.5 months. The remission periods constituted 7% of follow-up for all
`patients. Another 36% achieved remission according to the second definition. All 56% were considered to have a relapsing-
`remitting disease pattern, in contrast to the remaining 44% with a persistent disease pattern. More patients with persistent
`disease were treated with disease-modifying anti-rheumatic drugs (DMARDs) and had also received a larger number of
`different drugs. Outcome after 5 yr regarding disability, joint inflammation and joint damage was worse for patients with
`persistent disease. Neither ARA-defined remission nor disease pattern could be accurately predicted.
`Conclusions. Long-term ARA-defined remission was rare, constituting 7% of follow-up for the entire cohort. For those 20'/,
`achieving remission, this period represented 34% of their follow-up. A total of 56% had a relapsing-remitting disease pattern
`and 44% had a persistent disease pattern. This classification had prognostic implications with persistency being a bad
`prognostic sign.
`
`KEY woRps: Rheumatoid arthritis, Remission, Disease course, Prognosis, Outcome.
`
`THE prognosis for patients with rheumatoid arthritis
`(RA) varies considerably. Early prediction of outcome
`has, therefore, been the subject of numerous investi-
`gations focusing on, for example, sociodemographic,
`clinical or laboratory variables. No features of early
`disease have so far shown sufficient power to allow
`clinically meaningful prediction [1, 2]. In most studies,
`prognosis of RA was related to the state of the disease
`at a certain defined end point. However, prognostic
`information may also be gained by evaluation of the
`disease course up to that point in time.
`The most desirable patient outcome is probably
`achievement of stable remission. The length of remis-
`sion periods during the course of the disease is con-
`sequently a relevant prognostic measure. Remission
`can be defined according to the rigorous American
`Rheumatism Association . (ARA) criteria shown in
`Table 1 [3]. More clinical definitions like 'being symp-
`tom free' or 'no arthritis on examination' have also
`been used. Remission criteria can either be examined
`at a single point in time or during a longer time period.
`Reported cross-sectional remission rates in early RA
`patients vary from 32% [4] to 7% after —6 yr [5, 6].
`Various methods to define remission and different
`patient selection are factors that contribute to the wide
`variation of remission rate. The length of time spent
`
`Submitted 30 March 1998; revised version accepted 24 August
`1998.
`Correspondence: K. Eberhardt, Department of Rheumatology,
`Lund University Hospital, S-221 85 Lund, Sweden.
`*Deceased.
`
`in remission is rarely reported. However, in a retro-
`spective study of established RA patients, the median
`length of remission was 10 months [7].
`Different patterns of disease have been described.
`The two main patterns are chronic persistent and the
`relapsing-remitting disease course. Twenty-six per cent
`of patients in the Middlesex early RA study were
`chronic persistent over 3 yr [8], while in a Canadian
`study of a 1985 inception cohort 40% had a persistent
`disease course during 6-7 yr. The disease pattern may
`have prognostic implications. In the Canadian study,
`patients with chronic persistent disease had worse
`outcome at study finish [9].
`In this study, we examined the disease course in our
`cohort of early RA patients especially regarding ARA-
`defined remission and different disease patterns. The
`disease course was related to outcome after 5 yr follow-
`up and the prognostic value of different features.
`including rheumatoid factor (RF) and shared epitope,
`was investigated.
`
`TABLE 1
`Preliminary ARA remission criteria
`
`Five or more of the following criteria must be fulfilled
`for at least two consecutive months:
`Duration of morning stiffness not exceeding 15 min
`No fatigue
`No joint pain (by history)
`No joint tenderness or pain on motion
`No soft-tissue swelling in joints or tendon sheaths
`Erythrocyte sedimentation rate (Westergren method) <30 mm
`after 1 h for a female or <20 mm after 1 h for a male
`
`1998 British Society for Rheumatology
`
`i= (cid:9)
`
`1324
`az :apied
`
`Ex. 1034 - Page 5
`
`

`

`EBERHARDT AND FEX: CLINICAL COURSE IN EARLY RA
`
`1325
`
`PATIENTS AND METHODS
`
`Patients
`The patients were taking part in an ongoing pro-
`spective study of course and outcome of RA at the
`Lund University Hospital in Southern Sweden [10].
`The inclusion criteria were definite RA with disease
`duration of <24 months and age > 18 yr. Disease
`duration was defined as time from onset of symptoms.
`Most patients were referred from primary care as a
`result of a special campaign to recruit cases of recent
`onset. One hundred and eighty-three patients were
`enrolled during the years 1985-1989.
`The study group consisted of all the 183 patients,
`67 men and 116 women, with a mean (s.D.) age of 51.4
`(12.4) yr at onset. Mean (s.D.) duration of joint symp-
`toms at inclusion in the study was 11.1 (6.1) months.
`
`Clinical assessment
`The patients were assessed at least every 6 months
`with the exception of a few patients in sustained
`remission who were seen once a year. These patients
`were told to make contact with the clinic earlier if they
`gotjoint symptoms. Joint tenderness was estimated
`according to Ritchie et al. [11]. Joint inflammation
`Was assessed by an active joint count (defined as
`swollen and either tender or painful on motion). The
`50 joints evaluated included all but two from the
`Ritchie index, namely the neck and subtalar joints.
`Disability was evaluated with a Swedish version of the
`Stanford Health Assessment Questionnaire (HAQ)
`disability index [12]. Radiographs of hands and feet
`Were taken at study start and annually thereafter. We
`used standard film and an anterior—posterior projec-
`tion. The radiographic findings were scored by the
`Larsen method, grading changes from 0 (normal) to 5
`(maximal damage) [13]. Thirty-two joints were evalu-
`ated. The wrist score was multiplied by five, then all
`scores were added to give a joint damage score with a
`theoretical range of 0-200. Clinical and laboratory
`information was not available at the time of the
`radiological evaluation. The erythrocyte sedimentation
`rate (ESR) was measured according to Westergren.
`Rheumatoid factor of IgM class was analysed with an
`enzyme-linked immunosorbent assay (ELISA) [14].
`HLA-DRB alleles were typed by restriction fragment
`length polymorphism analysis with sequence-specific
`Primers as previously described [15].
`
`Clinical course
`Remission was defined according to the ARA criteria
`[3] as shown in Table I. Fatigue was not measured in
`this study, and remission was therefore considered
`Present if a patient fulfilled four of the remaining five
`criteria. Concomitant use of disease-modifying anti-
`rheumatic drugs (DMARDs) and/or oral cortico-
`steroids was allowed. The patients had to fulfil
`remission criteria at least at two consecutive follow-up
`visits (6 months apart).
`The course of the disease was regarded as relapsing
`remitting if the patient had no active joints on examin-
`
`ation at least at one follow-up visit, and persistent if
`the patient had active joints at all evaluation points.
`
`Statistical analyses
`Differences between groups regarding continuous
`variables were estimated by Mann—Whitney's test for
`independent samples. The e test was used for discrete
`variables. Logistic multiple regression analyses were
`performed in an attempt to predict ARA remission
`and clinical course, respectively. Demographics, RF
`status, genotype, and clinical and laboratory variables
`at baseline, were used as independent variables. All
`tests were two-tailed and the level of significance was
`set at P = 0.05.
`
`RESULTS
`
`Clinical features
`Table II shows some clinical and laboratory charac-
`teristics at study start. Fifty-two per cent of the patients
`had no erosions. Onset of the disease was acute (within
`1 day) for 33 patients, intermediate (within 1 week)
`for 32, insidious (within weeks to months) for 99, and
`palindromic for 19. One hundred and twenty-eight
`(75%) were RF positive. One hundred and seventy
`patients were genotyped, 145 (85%) of these carried
`the shared epitope. Fifty-four (32%) carried the epitope
`on both alleles.
`Patients with active disease were offered treatment
`with DMARDs and 114 (62%) received this treatment
`some time during follow-up. Sixty-seven received one
`drug, 27 two drugs and 18 received 3-5 drugs.
`Most commonly used was chloroquine (68 patients),
`followed by D-penicillamine (51), gold compounds
`(25), sulphasalazine (21) and methotrexate (6).
`Twenty-nine (16%) were treated with oral cortico-
`steroids. Active disease was defined as the presence of
`six or more swollen joints and at least two of following
`features: (i) ?)9 tender joints; (ii) morning stiffness
`lasting at least 45 min; (iii) an ESR of 28 mm/h.
`During a follow-up time of 5 yr, seven patients were
`lost. Five died (three had malignant disease; two
`carcinoma in the lungs and one in the uterus; one had
`cardiovascular disease and one committed suicide).
`One patient moved to another part of the country and
`one stopped attending due to psychiatric disease.
`
`Remission
`Twenty per cent (37 patients: 16 men/21 women)
`had 39 remission periods of at least 6 months. Mean
`(s.D.) remission time was 20.5 (12.9) months with a
`range of 6-48 months. The patients were in remission
`
`TABLE II
`Some clinical and laboratory features at the start of the study in
`183 RA patients with -1 yr disease duration. All values arc given
`as the median (interquartile range)
`
`Active joint count (0-50)
`I-IAQ disability index (0-3)
`Joint damage score (0-200)
`(available for 151 patients)
`ESR (mm/h)
`
`6 (4-10)
`0.8 (0.5-1.3)
`6 (3-11)
`
`29 (14.5-52)
`
`This .7'
`
`C.,`IEr L
`
`Ex. 1034 - Page 6
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`

`1326 (cid:9)
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`BRITISH JOURNAL OF RHEUMATOLOGY VOL. 37 NO. 12
`
`free episode within the first study year, and another
`20% within 2 yr.
`Most patients had during the course of the 5 yr
`both large and small joint involvement (82% in the
`relapsing-remitting group and 86% in the persistent
`group). Twenty-nine patients (16%) had involvement
`of hands and feet only. Nine of them had a limited
`disease with involvement of four or less small joints.
`Five of the nine with limited disease, compared to 32
`of 142 with more widespread disease, had remission
`periods of 6 months or more (P < 0.02).
`Table III shows a comparison of demographics and
`disease characteristics between patients with persistent
`and relapsing-remitting disease. The only significant
`finding was that patients with persistent disease were
`more often RF positive (P = 0.04). No clinical or
`laboratory variable at baseline differed between the
`two groups. We obtained no logistic regression model
`that could predict the disease course with any accuracy.
`Seventy-two per cent of the patients with persistent
`disease had received DMARD therapy compared to
`58% of the patients with relapsing-remitting disease.
`Patients with persistent disease had also received a
`larger number of different drugs (P = 0.01). Ten
`patients with relapsing-remitting disease and 19
`patients with persistent disease had oral corticosteroid
`treatment some time during the 5 yr. This difference
`was significant (P = 0.02).
`Table IV shows some clinical and laboratory features
`for the 176 patients who remained at study finish,
`subdivided according to clinical course. Patients with
`persistent disease fared significantly worse in all
`respects. They were more disabled, had more joint
`inflammation and more erosive radiographic changes.
`Table V displays the relationship between remission
`and DMARD treatment. More non-treated patients
`went into remission according to either definition.
`
`DISCUSSION
`In this early RA cohort, the patients were followed
`prospectively with standardized measures. The follow-
`up period was the same for all the patients, and the
`drop-out rate was only 4%. Remission was defined
`according to the rigorous ARA criteria. However, the
`required observation period of 2 months was prolonged
`to 6 months due to our study design. Twenty per cent
`of our patients achieved remission some time during
`the 5 yr follow-up time. Remission was mostly lont
`lasting with an average length of almost 2 yr. One-
`third of the follow-up time for these patients was spent
`in remission. However, the remission periods consti-
`tuted only 7% of the entire follow-up time for the
`cohort. Other authors applying similar methods to
`calculate remission rates have reported findings in
`accord with ours both in early and established RA
`[7, 16].
`In other studies of early RA patients, remission
`criteria were applied at a single point in time. The
`highest cross-sectional rates were found in a Finnish
`study [4] where 27% of the patients were in ARA-
`defined remission at the 2 yr follow-up and 32% at
`
`34% of their follow-up time. Mean (s.D.) disease dura-
`tion at achievement of the first remission period was
`36.2 (14.3) months with a range of 9-64 months.
`Twenty-one remissions were spontaneous and 18 drug
`induced (chloroquine 8, D-penicillamine 6, aurothio-
`malate 3, and sulphasalazine 1).
`Figure 1 illustrates the remission rate over time. The
`number of patients moving in and out of remission
`during each 6 month period in the study is displayed.
`Figure 2 shows the starting point and length of remis-
`sion for each individual patient during the course of
`follow-up.
`The time spent in remission constituted 7.0% of
`follow-up for all patients.
`Cross-tabulation comparing patients with (n = 37)
`and without remission periods of at least 6 months
`(n = 146) showed that remitting patients were signifi-
`cantly less often RF positive (P = 0.01) and less often
`carried two shared epitopes (P = 0.05). Age, gender
`and mode of onset did not differ between the two
`groups. Comparison between the clinical and labora-
`tory variables at onset displayed in Table II showed
`that patients with remission periods had a significantly
`lower active joint count (P = 0.05). Prediction of
`remission by means of logistic regression analysis did
`not yield any clinically meaningful model, only 26% of
`the patients with remission periods could be correctly
`classified.
`
`Clinical course
`One hundred and two patients (56%) had a
`relapsing-remitting disease course and 81 (44%) had a
`persistent disease course. Forty per cent of patients
`with relapsing-remitting disease had their first arthritis-
`
`CI In remission
`17777z1 Relapsing
`
`45AVA
`
`/.4
`
`6 (cid:9)
`
`12 (cid:9)
`
`18 (cid:9)
`
`24 (cid:9)
`
`30 (cid:9)
`
`.13. (cid:9)
`
`42 (cid:9)
`
`48 (cid:9)
`
`54 (cid:9)
`
`60
`
`183 (cid:9) 183 (cid:9) 179 (cid:9) 179 179 (cid:9) 178 (cid:9) 177 (cid:9) 177 (cid:9) 176 (cid:9) 176
`
`Months in
`the study
`
`Number of
`patients
`left in the study
`each 6 month's
`period
`
`25 —
`
`20 —
`
`15 —
`
`10 —
`
`5 -
`
`0
`
`10
`
`Number of patents
`
`FIG. 1. -ARA-defined remission rates over time in originally 183
`early-RA patients with a mean disease duration of —1 yr at study
`start. Altogether, 37 patients achieved 39 remission periods during
`follow-up. The numbers of patients moving in and out of remission
`during each 6 month period in the study are shown. The number of
`patients left in the study in each period is displayed below.
`
`at t-
`
`-t
`
`ie ": -ev's
`
`Ex. 1034 - Page 7
`
`(cid:9)
`(cid:9)
`

`

`EBERHARDT AND FEX: CLINICAL COURSE IN EARLY RA
`
`1327
`
`2
`3
`4
`5
`6
`7
`8
`9
`10
`1
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`
`6 12 18 24 30 36 42 48 54 60 Months
`
`2.—Remission periods (n = 39) for each individual patient (n = 37) during the course of follow-up. Each line denotes the starting point
`and length of remission. Mean (s.o.) remission time was 20.5 (12.9) months.
`
`TABLE III
`Demographic data and disease characteristics subdivided according
`to clinical course for all the 183 patients
`
`TABLE IV
`Clinical and laboratory features subdivided according to clinical
`course for 176 patients who remained in the study at the 5 yr follow-
`up. Median (intcrquartile range)
`
`Age at onset
`[yr; mean (s.0.)]
`Gender (% women)
`Single epitope
`(V positive)
`Double epitope
`(Y,' positive)
`Rheumatoid factor
`(V positive)
`Disease onset
`(% acute/intermediate/
`insidious/palindrome)
`
`*P = 0.04 (x2 test).
`
`Persistent
`disease
`= 81)
`
`Relapsing-remitting
`disease
`(ii = 102)
`
`50.7 (11.7)
`
`52 (13)
`
`67
`86
`
`28
`
`78*
`
`61
`84
`
`36
`
`64
`
`14/20/59/7
`
`21/16/50/13
`
`Persistent disease
`(n = 78)
`
`Relapsing-remitting
`disease
`= 98)
`
`Active joint count
`1-IAQ disability index
`Joint damage score
`ESR
`
`5 (2-8)
`1.2 (0.9-1.5)
`53 (32-74)
`31 (15-55)
`
`1 (0-4)**
`0.8 (0.3-1.2)**
`27 (12-53)**
`21 (9-31)*
`
`*P = 0.01, **P < 0.001; Mann-Whitney's test.
`
`TABLE V
`Relationship between remission and DMARD treatment during
`follow-up
`
`Treated (cid:9)
`(n = 114) (cid:9)
`
`Non-treated
`= 69)
`
`the 6 yr follow-up. Harrison et al. [17] studied a
`community-based cohort and found that 19% of their
`RA cases were in remission after 2 yr. Remission was
`defined as 'no arthritis on examination and no
`DMARD or steroid treatment within the previous 3
`months'. Two other studies reported a cross-sectional
`remission rate of —7% after 3 and 7 yr, respectively
`[5, 6]. Both studies used 'being symptom free' as a
`definition for remission. As illustrated in Fig. 1, remis-
`
`ARA remission n (%)
`No arthritis on examination n (%)
`
`18 (16)
`60 (53)
`
`21 (30)
`42 (61)
`
`sion was often a temporary state with new patients
`achieving remission or relapsing at any point in time.
`Cross-sectional remission rates do not measure this
`longitudinal aspect and are therefore less reliable, as
`also pointed out by Harrison et al. [17]. Comparisons
`between different studies are thus not only hampered
`
`Misr (cid:9)
`at':k•E
`
`:::ie5
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`
`by differences in defining remission and different
`patient referral and selection, the different methods to
`estimate remission rates are also rendering difficulties.
`Remission was more likely in seronegative patients
`having no or only a single shared epitope and fewer
`active joints at baseline. However, even in combination,
`these factors were not strong enough to allow accurate
`prediction of remission. Wolfe and Hawley [7] found
`that female sex, onset before the age of 60 yr and
`early development of erosions were associated with
`decreased proportions of remission periods. Harrison
`et al. [17] could confirm their finding of association
`with gender, but not with age. Like us, they found
`asso