AN62
`NO.5
`1997
`-SEQ= A35415000
`ANNALS OF THE RHEUMATIC
`DISEASES
`06/04/97 997 VOI, 56
`
`
`
`
`
`
`
`
`:13», wk, 1»
`
`Ex. 1106 - Page 1
`
`

`

`Annals of the Rheumatic Diseases
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`
`this — at (cid:9) a I::rizd
`
`-taws
`
`Ex. 1106 - Page 2
`
`

`

`MAY 1997 VOL 56 NO 5
`
`Annals of the Rheumatic Diseases
`
`Leaders (cid:9)
`
`Hypothesis (cid:9)
`
`Notes/News (cid:9)
`
`281 (cid:9)
`
`285 (cid:9)
`
`Do sex hormones modulate the synovial macrophages in rheumatoid arthritis?
`M Cutolo
`Rheumatoid factors: where are we now? A J Soltys, J S Axford, B J Sutton
`
`287 (cid:9)
`
`Phenotypic modulation of chondrocytes as a potential therapeutic target in
`osteoarthritis: a hypothesis T Aigner, J Dudhia
`292 Notices • Forthcoming events
`
`Unusual but memorable 284 Case number 5: Series editor G D Wright
`Extended reports (cid:9)
`293 (cid:9) Osteoarthrosis of the hip in women and its relation to physical load at work and in
`the home E Vingard, L Alfredsson, H Malchau
`Synovial fluid chondroitin and keratan sulphate epitopes, glycosaminoglycans,
`and hyaluronan in arthritic and normal knees C Belcher, R Yaqub, F Fawthrop,
`M Bayliss, M Doherty
`Prevalence of shoulder pain in the community: the influence of case definition
`D P Pope, P R Croft, C M Pritchard, A J Silman
`Increase in age at onset of rheumatoid arthritis in Japan over a 30 year
`period T Imanaka, K Shichikawa, K Inoue, Y Shimaoka, Y Takenaka, S Wakitani
`Rheumatoid arthritis: autoreactive T cells recognising a novel 68k autoantigen
`St BI5l3, C Haferkamp, Ch Specker, M Schwochau, M Schneider, E M Schneider
`
`299 (cid:9)
`
`308 (cid:9)
`
`313 (cid:9)
`
`317 (cid:9)
`
`Concise reports (cid:9)
`
`323 (cid:9)
`
`326 (cid:9)
`
`330 (cid:9)
`
`333 (cid:9)
`
`336 (cid:9)
`336 (cid:9)
`
`337 (cid:9)
`
`Matters arising (cid:9)
`
`Serum concentrations of a tocopherol, (3 carotene, and retinol preceding the
`diagnosis of rheumatoid arthritis and systemic lupus erythematosus
`G W Comstock, A E Burke, S C Hoffman, K J Helzlsouer, A Bendich, A T Masi,
`E P Norkus, R L Malamet, M E Gershwin
`Prevalence of low body mass in rheumatoid arthritis: association with the acute
`phase response R Munro, H Capell
`Increased serum N°-hydroxy-L-arginine in patients with rheumatoid arthritis and
`systemic lupus erythematosus as an index of an increased nitric oxide synthase
`activity R Wigand, J Meyer, R Busse, M Hecker
`Subgroups of primary Sjogren's syndrome. Sjogren's syndrome in male and
`paediatric Greek patients A A Drosos, E K Tsiakou, N Tsifetaki, E N Politi,
`A Siamopoulou-Mavridou
`
`Pigmented villonodular synovitis W P Docken; M Zuber
`Combination DMARD therapy for rheumatoid arthritis. Full or low DMARD doses?
`G F Ferraccioli, L Casatta, E Di Poi, R Damato, E Bartoli, E Bartoli; J R O'Dell
`Tissue crosslinks concentrations in normal joints and chronic articular diseases
`L Sinigaglia, M Varenna, L Binelli, A Parafioriti, M Arrigoni, G Abbiati; M Takahashi
`
`Front cover: Synovial macrophages after double immunostaining with the anti-androgen monoclonal antibody
`and the anti-phagocytic cell antigen antibody in the lining of the rheumatoid synovial tissue (original
`magnification x500), see Leader p 281.
`
`TM: (cid:9)
`
`ial•.:aa__piav
`ar
`
`Ex. 1106 - Page 3
`
`

`

`326 (cid:9)
`
`Annals of the Rheumatic Diseases 1997;56:326 -\ 329
`
`Prevalence of low body mass in rheumatoid
`arthritis: association with the acute phase response
`
`R Munro, H Capell
`
`Abstract
`Objective—To ascertain the prevalence of
`low body mass in a rheumatoid arthritis
`(RA) population and to explore a possible
`relation with the acute phase response.
`Methods-97 patients who fulfilled the
`American College of Rheumatology
`(ACR) criteria for RA were recruited.
`Change in weight from initial presentation
`was noted. Body mass index (BMI), upper
`arm fat and muscle areas were recorded
`together with fat free mass calculated
`from the waist measurement. Blood sam-
`ples were taken for erythrocyte sedimen-
`tation rate (ESR), C reactive protein
`(CRP), and serum albumin.
`Results-13% of the RA group fell into the
`lowest 5th centile for BMI for the general
`population. The loss of body mass was
`greater for lean tissue than fat, with over
`50% of the RA group falling into the lowest
`10th centile of a reference population for
`the upper arm muscle area. Female
`patients who lost greater than 15% of their
`initial weight had higher health assess-
`ment questionnaire (HAQ) results than
`the rest of the group (p=0.020). In female
`patients there was a significant correla-
`tion between reduced fat free mass and the
`acute phase response (ESR p=0.016 and
`CRP p=0.003)
`is an increased
`Conclusions—There
`prevalence of low body mass, greatest for
`lean tissue, in the RA population. In the
`female group there was an inverse relation
`between the acute phase response and fat
`free mass. Female patients with RA who
`lose a significant amount of weight arc
`more disabled as assessed by IIAQ.
`
`(Ann Rheum Du 1997;56:326-329)
`
`Rheumatoid arthritis (RA) results in profound
`weight loss in some people. The association
`between weight loss and inflammatory joint
`disease has been recognised since the mid 19th
`century.' The proportion of RA patients, how-
`ever, who have significant but subclinical
`reduction in body mass is less clear.
`Weight loss and loss of lean body mass in
`particular are powerful predictors of health
`both in disease states and the general
`population.' Studies in patients with AIDS
`and chronic obstructive airways disease have
`shown a strong relation between weight loss
`and increased morbidity and mortality." The
`reasons for weight loss in RA are probably
`multi-factorial and include mechanical prob-
`lems leading to muscle wasting, poor appetite
`
`because of drug therapy and disease, and the
`metabolic burden of the inflammatory
`response. This study was designed to
`investigate the prevalence of low body mass its
`an RA population attending a rheumatoNy
`clinic and explore the relation, if any, with dis-
`ease activity.
`
`Methods
`PATIENTS
`Ninety six patients who fulfilled the ACR crite-
`ria for RA were recruited serially from a rentro
`rheumatology outpatient clinic. Patients who
`were pregnant, not ambulant or taking oral
`corticosteroids were excluded. Patients with
`bilateral shoulder surgery or severe shoulder
`disease were excluded as this may have
`interfered with the upper arm anthropometry
`results.
`None of the patients had co-morbid medical
`conditions that are known to affect body mass,
`Table 1 shows the demographic details of the
`study group. Functional status was assessed
`using the Health Assessment Questionnaire
`(I-IAQ) score. Social deprivation was assessed
`from the Carstairs Score.'
`
`ANTI I RO POM ETRY
`The subjects were weighed on balance beam
`scales to the nearest 0.1 kg. Initial weight at
`time of presentation to a specialist clinic Was
`noted if this was available. Standing height Was
`measured on a wall mounted stadiometer to
`the nearest centimetre. Body mass index Was
`calculated from: weight/height2(kg/m2). Knee
`height was also recorded with the patient
`seated and both the ankles and knees flexed to
`ninety degrees. The measurement was taken
`from the base of the heel pad to the superior
`pole of the patella. Knee height varies very lit-
`tle with age unlike standing height and is
`therefbre useful in comparing body composi-
`tion results across age groups.'
`Skin fold thickness using standard skin fold
`callipers was measured over the triceps at the
`midpoint between the acromion and
`olecranon. Upper arm circumference was
`taken at the same site. Measurements were
`made on the right arm unless patients had
`shoulder disease in which case the least
`affected arm was used. Upper arm muscle and
`fat areas were calculated from standard
`equations using triceps skin fold thickness and
`upper arm circumference.'
`Waist circumference to the nearest 0.1 cm
`was recorded at the midpoint between the
`superior iliac crest and lower costal margin. Fat
`mass was calculated from waist circumference,
`weight, and age. This method correlates well
`
`rnts
`
`z
`
`Centre for Rheumatic
`Diseases,
`Glasgow Royal
`Infirmary,
`Glasgow
`R Munro
`H Capell
`
`Correspondence to:
`Dr R Munro, Centre for
`Rheumatic Diseases,
`Glasgow Royal Infirmary,
`Castle Street, Glasgow, G4
`OSF.
`
`Accepted for publication
`20 February 1997
`
`Ex. 1106 - Page 4
`
`

`

`Prevalence of low body mass in RA (cid:9)
`
`"Rible 1 (cid:9) Demographic details
`
`Age (y)
`Disease duration (y)
`HAQ
`Body mass index
`Waist (cm)
`CRP (mg/1)
`ESR (mm/lst h)
`Albumin (gJI)
`
`Alen (n=36)
`
`Wnten (n=61)
`
`(46-60)
`56
`(7-17)
`10
`1.750 (1.250-2.375)
`26.0
`(21.3-28.4)
`94.0
`(81.6-100.2)
`15
`(7-49)
`28
`(16-40)
`44
`(43-46)
`
`(43-60)
`52
`(5-17)
`9
`1.875 (1.500-2.125)
`23.5
`(21.5-26.9)
`77
`(71.0-86.3)
`15
`(0-30)
`33
`(11-46)
`44
`(42-46)
`
`Medians and interquartile ranges are shown.
`
`Table 2 (cid:9) Characteristics of women divided by weight change since initial referral
`
`Wight change since referral
`
`>15% loss (n=7)
`
`< or = 15% loss (n=53)
`
`Mann-Whitney
`p Value
`
`Age (y)
`Initial BMI
`Actual BMI
`Disease duration (y)
`HAQ
`ESR (mm/lst h)
`CRP (mg/I)
`Albumin (g/1)
`
`52 (42-61)
`26.4 (19.3-27.4)
`21.5 (cid:9) (16.3-21.8)
`12 (cid:9) (6-17)
`2.625 (cid:9) (1.876-2.875)
`53 (36-61)
`31 (cid:9) (6-63)
`41 (cid:9) (41-42)
`
`(43-60)
`51
`(20.9-27.3)
`24.2
`(22.0-27.2)
`24.3
`(5-17)
`10
`1.875 (1.500-2.125)
`(9-41)
`24
`(0-27)
`14
`(44-46)
`45
`
`NS
`NS
`0.009
`NS
`0.020
`0.011
`0.120
`0.003
`
`Medians and interquartile ranges are shown.
`
`with results achieved using underwater
`weighing (r=0.839 to 0.868 dependent on sex)
`and is suitable for population studies.'
`All anthropometry measurements were
`made by one observer using the same
`equipment for each patient.
`
`LABORATORY INVESTIGATIONS
`C reactive protein (CRP), erythrocyte
`sedimentation rate (ESR), and serum albumin
`were recorded. Seropositivity for rheumatoid
`factor was ascertained.
`
`Results
`Table 1 shows the demographic details of the
`patients. Ninety eight per cent of the study
`group were white. The patients generally had
`moderately severe disease as can be seen from
`
`EMI Women
`F-1 Men
`
`327
`
`the median HAQ scores. There was a high pro-
`portion of seropositive erosive disease in our
`study group (87%), which is representative of
`the patients attending our review clinics.
`
`BODY MASS INDEX
`Figure 1 shows the distribution of BMI in the
`male and female populations.
`Age and sex matched median values of BMI
`are available for the British population.' In the
`RA group 13% of both men and women fell
`into the lowest 5th centile for the general
`population. There was no significant difference
`in BMI between smokers, ex-smokers, and
`non-smokers. Patients with low BMI were no
`more socially deprived than the rest of the
`patients.
`
`WEIGHT LOSS
`Initial weight was available in 60 of 61 women
`and 34 of 36 men. Thirteen per cent of the
`women had lost more than 15% of their initial
`weight compared with only 3% of the men.
`The women who had lost >15% of their initial
`weight were significantly different from the rest
`of the female group in a number of ways (table
`2). Despite being of a similar age and having a
`similar duration of disease they were
`significantly more disabled judging from their
`HAQ score. They also had significantly higher
`ESRs and lower serum albumin. No comment
`could be made regarding the male group as
`only one patient had lost >15% of their initial
`weight.
`Weight gain of >15% was seen in six women
`and four men. Their acute phase response and
`HAQ score was no different from the rest of
`the cohort.
`
`FAT AND MUSCLE MASS
`Age and sex reference ranges for upper arm
`muscle and fat areas are available from a large
`study of 19 097 white subjects."
`Figure 2 shows the percentage distribution
`of the RA patients compared with the expected
`percentile distribution of the control
`population. The distribution of upper arm fat
`area is very similar to the normal population.
`The distribution of muscle mass however is
`skewed to the left with 50% of the RA group
`falling into the lowest 10th centile for muscle
`mass of the reference population.
`
`ACUTE PHASE RESPONSE AND LEAN BODY MASS
`Fat free mass was calculated as outlined in the
`methods section. To allow for differences in
`stature a fat free mass index (FFMI) was
`calculated from fat free mass/knee height
`(kg/cm). In women reduced FFMI correlated
`moderately well with raised acute phase
`response (ESR r=-0.323, p=0.016 and CRP
`r=-0.413, p=0.003) and serum albumin
`(r=0.377, p=0.008) when the results were
`adjusted for age. There was no significant cor-
`relation with HAQ (r=-0.222, p=0.094) or
`disease duration (r=-0.150, p=0.261). There
`was no relation between any of the above vari-
`ables and low fat free mass index in the male
`group.
`
`It
`
`30
`
`20
`
`10
`
`0
`
`Patients (n)
`
`>15
`
`15-20
`
`20-25 (cid:9)
`
`25-30
`
`30-35
`
`>35
`
`Figure 1 Body mass index distribution.
`
`BMI
`
`Th‘ -
`att- N.L": a- a r- a7 rs
`
`Ex. 1106 - Page 5
`
`

`

`328
`
`a) (cid:9)
`cn
`ca
`cj
`a>
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`0 (cid:9)
`
`(cid:9) Normal
`•
`Muscle
`Fat
`
`20 (cid:9)
`
`40 (cid:9)
`
`60
`
`80
`
`100
`
`Figure 2 Arm muscle and fat area percentiles versus normal controls.
`
`Percentile
`
`Discussion
`The results of this study suggest that the preva-
`lence of low body mass in patients with RA
`may be under recognised. If one uses a defini-
`tion of being underweight as the lowest 5th
`centile of a reference population (possibly an
`overgenerous cut off point) one in eight RA
`patients would be considered underweight
`compared with one in 20 of the general popu-
`lation.
`Our results from upper arm anthropometry
`suggest that the reduction in body mass is
`greatest for lean tissue and that fat mass is
`comparatively well maintained. It is striking
`that over 50% of the RA group had arm mus-
`cle mass areas in the lowest 10th centile of the
`reference population. Muscle wasting resulting
`from local joint disease may be partly responsi-
`ble. These results are very similar, however, to
`those in a previously published smaller study of
`24 RA patients where body composition by
`upper arm anthropometry closely resembled
`results achieved using bio-electrical impedance
`methods.'`
`Body composition by waist measurement
`has recently been validated against the more
`cumbersome and time consuming method of
`underwater weighing and seems to be as accu-
`rate as the more traditional method using the
`sum of four skin folds.' In the female patients
`we studied there was a correlation with
`increased acute phase response judged by high
`ESR or CRP and low FFMI (calculated using
`waist measurements). These findings are in
`keeping with a previous study that found that
`RA patients classified as malnourished had
`higher ESR and CRP than normally nourished
`RA patients."
`A probable cause for the reduced body mass
`is weight loss since the onset of disease. A sig-
`nificant proportion of the female group had
`experienced considerable weight loss since
`presentation, one in eight had lost more than
`15% of their initial weight. These patients
`seemed to have a poorer functional outcome as
`judged by their HAQ scores despite similar
`disease duration and age to the remainder of
`
`that tats i
`at t (cid:9)
`• (cid:9)
`
`E' (cid:9) '
`
`Munro, Cape11
`
`the cohort under investigation. In addition
`patients with the most dramatic weight loss
`tended to have a higher acute phase response
`to their disease (although this did not quite
`reach significance for CRP).
`We could find no relation between disease
`activity and reduced lean body mass in the
`male population. One possible explanation
`may be a sampling error because of the smaller
`size of the male group. Alternatively true
`differences between the sexes may exist.
`FIormonal differences could play a part. The
`reduction of the androgens testosterone and
`dehydroepiandrosterone seen in patients with
`RA may be pertinent." The reduced values
`seen in men however may still be high enough
`to afford some protection against lean tissue
`loss. It may also be relevant that women tend to
`have a poorer outcome with RA than men"
`and the greater weight loss seen in the female
`group may be another marker of their
`increased morbidity. Further more specific
`studies in this area are warranted.
`The relation between active disease, reduced
`lean body mass, and weight loss in female
`patients is probably multifactorial. Although
`mechanical problems leading to secondary
`muscle wasting may contribute, this seems
`unlikely to be an important factor as there is no
`relation between the HAQ score (a measure of
`disability and not disease activity) and lower
`FFMI. The acute phase response seems to be
`more important, although we did not measure
`cytokine production they may play a pivotal
`part in RA cachexia. Interleukin 16 and inter-
`leukin 6 both may be systemically increased in
`RA.''" Interleukin 113 may cause reduced
`appetite while interleukin 6 participates in the
`production of acute phase reactants by the
`liver. The role of tumour necrosis factor in
`weight loss has been studied extensively.
`Animal studies have shown that infused
`tumour necrosis factor may cause increased
`protein degradation.'" Higher serum tumour
`necrosis factor concentrations have been
`detected in RA patients experiencing a flare of
`their disease and suffering from cachexia com-
`pared with patients without a cachectic flare.''
`In addition studies in RA and cystic fibrosis
`patients have shown a relation between raised
`tumour necrosis factor production and
`increased resting energy expenditure." Thus
`tumour necrosis factor may lead to increased
`energy expenditure and increased protein deg-
`radation both of which may lead to a reduction
`in lean body mass.
`In conclusion, there is clear evidence from
`this study that weight loss is a significant prob-
`lem in female patients with RA and is greatest
`in those patients with the highest acute phase
`response to their disease. Women with
`significant weight loss seem to have a poorer
`functional outcome.
`
`We are grateful to Miss A Tierney for typing the manuscript and
`Professor M Lean for his helpful comments.
`
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`Ex. 1106 - Page 6
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`(cid:9)
`(cid:9)
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