'iv 6
`
`November 1974 Vol 33 No 6
`
`Complement metabolism in the seronegative arthritides
`K. Whaley, B. Canesi, A. Moseley, W. Morrow, R. Sturrock, W. Mitchell,
`and W. C. Dick
`
`Pig articular cartilage in organ culture. Effect of enzymatic depletion of the
`matrix on response of chondrocytes to complement-sufficient antiserum
`against pig erythrocytes
`S. J. Millroy and A. R. Poole (cid:9)
`
`Studies on synovial fluid lymphocytes in rheumatoid arthritis
`P. J. Sheldon, M. Papamichail, and E. J. Holborow (cid:9)
`Granulocyte-specific antinuclear factors in synovial fluids and sera from
`patients with rheumatoid arthritis
`A. Wiik, E. Jensen, and J. Friis
`Isotopic indices as a measure of inflammation in rheumatoid arthritis
`H. Berry and E. C. Huskisson
`Atlanto-axial subluxation in rheumatoid arthritis. A 5-year follow-up study
`J. A. Mathews
`Trial comparing D-penicillamine and gold in rheumatoid arthritis. Preliminary
`report
`E. C. Huskisson, T. J. Gibson, H. W. Balme, H. Berry, H. C. Burry,
`R. Grahame, F. Dudley Hart, D. R. F. Henderson, and J. A. Wojtulewski (cid:9)
`Tissue gold levels after chrysotherapy
`R. Grahame, R. Billings, M. Laurence, V. Marks, and P. J. Wood (cid:9)
`Liver disease in patients with joint symptoms
`A. M. Hilton, B. E. Boyes, P. J. Smith, J. Sharp, and I. W. Dymock (cid:9)
`Thiopurinol and purine metabolism. Metabolic and radioisotope studies
`H. A. Simmonds, A. Cadenhead, J. S. Cameron, T. J. Rising, R. Grahame,
`and B. M. Dean
`Abnormal regulation of carbohydrate metabolism in primary gout
`H. S. Diamond, A. C. Carter, and E. B. Feldman
`Pseudogout in acute neuropathic arthropathy. A.-elue to pathogenesis?
`- . (cid:9) R. M. Bennett, J. C. Mall, and D. J. McCarty . i_
`
`
`• Notice to Contributors: SI units! (cid:9)
`The use of SI units
`V. Wright
`
`Heberden Society
`
`Note
`
`Index
`
`ASTM CODEN : ARDIAO 33 (6) 495-590 (1974)
`
`495
`
`500
`
`509
`
`515
`
`523
`
`526
`
`532
`
`536
`
`540
`
`548
`
`554
`
`563
`
`567
`
`568
`
`573
`
`578
`
`579
`
`This materia I was copied
`atthe NLM and maybe
`Subject LI S Copyright Laws
`
`Ex. 1080 - Page 1
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`Annals of the Rheumatic Diseases
`
`A journal of clinical rheumatology and connective tissue research
`
`This Journal, founded by the Empire Rheumatism Council, now the Arthritis and Rheumatism
`Council for Research in Great Britain and the Commonwealth, is also supported by the
`Heberden Society.
`
`Advice to contributors
`Communications This journal exists to publish work
`on all aspects of rheumatology and disorders of connec-
`tive tissue. Laboratory as well as clinical studies are
`welcome. In addition brief communications, for example
`reports of single cases, will be printed if of exceptional
`interest.
`Papers, which will be accepted on the understanding
`that they have not been and will not be published else-
`where and are subject to editorial revision, should be
`addressed to The Editor, Annals of the Rheumatic Diseases,
`B.M.A. House, Tavistock Square, London, WC1H 9JR.
`Two copies should be supplied.
`The author should make adequate reference to previous
`work on his subject, and provide a full summary of his
`observations and conclusions.
`Articles must be typewritten on one side of the paper
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`Diagrams should be drawn in black ink on smooth
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`Legends should be listed on a separate sheet.
`References In the text, the year of publication must
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`abbreviated as in World Medical Periodicals, 3rd ed., 1961,
`B.M.A.), volume number (bold type, Arabic), first page
`number (ordinary type, Arabic), and title of article (in
`parentheses) thus:
`KIDD, C. B. (1965) Brit. .1. prey. soc. Med., 19, 4 (Psychia-
`tric morbidity among students)
`For books the author's name and initials, year (in
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`
`Proofs Contributors will receive ONE proof, and should
`read it carefully for printers' errors, and check the tables,
`figures, legends, and any numerical, mathematical, or
`other scientific expressions. Alterations to the original
`text should be kept to a minimum.
`
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`
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`From January 1, 1975, the annual subscription rate,
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`
`COPYRIGHT 0 1974 by the
`Annals of the Rheumatic Diseases
`
`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, electronic, mechanical,
`photocopying, recording, or otherwise, without the prior
`permission of the Annals of the Rheumatic Diseases.
`
`This material wascopied
`at the NLA4 and may be
`Subject US Copyright Laws
`
`Ex. 1080 - Page 2
`
`

`

`Ann. rheum. Dis. (1974), 33, 532
`
`Trial comparing D-penicillamine and gold in
`rheumatoid arthritis
`
`Preliminary report'
`
`E. C. HUSKISSON, T. J. GIBSON, H. W. BALME, H. BERRY, H. C. BURRY,
`R. GRAHAME, F. DUDLEY HART, D. R. F. HENDERSON, AND J. A.
`WOJTULEWSKI
`From the Department of Rheumatology, St. Bartholomew's Hospital; Guy's Arthritis Research Unit; and
`the Department of Rheumatology, Westminster Hospital, London
`
`The Multicentre Trial Group (1973) showed that
`penicillamine was superior to placebo in a double-
`blind trial against placebo. In this trial penicillamine
`was compared with gold.
`There are three reasons why a double-blind trial of
`penicillamine and gold was not attempted; first, gold
`is given by injection and penicillamine orally;
`secondly, both drugs have distinctive side effects
`which might `unblind' the observer; and thirdly,
`because some side effects are potentially dangerous,
`it is essential that the physician knows which drug his
`patient is receiving. For these reasons, the patients
`were treated by their usual physicians who super-
`vised dosage and documented side effects. Before the
`trial and at 3-monthly intervals after the start of
`treatment, the patients were seen by a 'blind' observer
`from another hospital.
`
`Methods
`Eighty-nine patients from three centres were admitted to
`the trial. All had definite or classical rheumatoid arthritis
`by the A.R.A. criteria (Committee of the American
`Rheumatism Association, 1959) of at least 6 months'
`duration, with an articular index (Ritchie, Boyle, McInnes,
`Jasani, Dalakos, Grieveson, and Buchanan, 1968) of at
`least eight, and an ESR of at least twenty-five. All were
`outpatients.
`Patients were allocated to treatment with either gold or
`penicillamine according to a randomized schedule
`stratified for age, sex, steroid therapy, and type of anti-
`inflammatory drug therapy. As far as possible, patients
`were given aspirin alone; when this was not possible, they
`were given one other drug only; phenylbutazone was not
`permitted and patients who had received either gold or
`penicillamine in the past were excluded.
`Gold was given in the form of sodium aurothiomalate
`(Myocrisin) in a dose of 10, 20, 30, and 40 mg weekly for
`the first 4 weeks, then 50 mg weekly up to a total dose of
`
`1g, then 50 mg monthly. Penicillamine was given in an
`initial dose of 250 mg daily of base or 300 mg, daily of
`hydrochloride, increasing by 250 mg or 300 mg, respec-
`tively, every fortnight up to a total dose between 1 and 1.8g
`daily according to response.
`The following measurements were made before the
`start of treatment and at 3-monthly intervals thereafter:
`pain using a visual analogue scale; duration of morning
`stiffness; an assessment of progress (worse, unchanged,
`slightly, moderately, and much better); joint size (Board-
`man and Hart, 1967); grip strength; articular index
`(Ritchie and others, 1968); nodule count; ESR; latex test;
`sheep cell agglutination test.
`Clinical measurements were made by two observers and
`all measurements of a particular patient were made by the
`same observer. The observer did not know which treat-
`ment the patient was receiving and patients were asked not
`to discuss their treatment or their side effects with the
`observer.
`The results were analysed by Student's t-test ; this was
`applied to differences between measurements at the start
`of the trial and after 3 and 6 months of treatment. Differ-
`ences within treatment groups were analysed by Student's
`t-test applied to paired data. Correlation coefficients were
`used to examine relationships between different measure-
`ments and their significance tested by Student's t-test.
`
`Results
`
`Eighty-six patients completed at least 3 months'
`treatment. Three who were withdrawn in the first 3
`months of the trial have not been included in the
`following analysis because no assessments were
`carried out; two were withdrawn for reasons un-
`related to treatment, and one was unable to tolerate
`even one tablet of penicillamine.
`Table I shows that the forty patients receiving gold
`and forty-six receiving penicillamine were well
`matched for sex, age, and duration of rheumatoid
`
`Accepted for publication May 5, 1974.
`* Based on a paper read at the Heberden Society in November, 1973.
`Address correspondence to Dr. E. C. Huskisson, St. Bartholomew's Hospital, West Smithfield, London ECIA 7BE.
`
`This material wascopied
`at the NLM and may be
`Subject US Copyright Laws
`
`Ex. 1080 - Page 3
`
`

`

`Trial comparing D-penicillamine and gold in rheumatoid arthritis 533
`
`Table I Characteristics of patients receiving either
`gold or penicillamine
`
`Number (cid:9)
`male: female (cid:9)
`Age (yrs) (cid:9)
`Duration of
`disease (yrs) (cid:9)
`
`Gold (cid:9)
`
`40 (cid:9)
`12:28 (cid:9)
`51.9 (cid:9)
`
`6.0 (cid:9)
`
`Penicillamine
`
`46
`17:29
`52.4
`
`5.0
`
`There arc no significant differences between the groups.
`
`arthritis. There was no statistically significant differ-
`ence between the groups in any of these respects, nor
`in any of the initial measurements, which are shown
`in Tables I I and III.
`Tables II and III show the changes in various
`measurements made after 3 and 6 months' treatment.
`All have been analysed using Student's t-test applied
`to differences between measurements at 3 or 6
`months and those made before the start of the trial.
`In no case was a significant difference found between
`the effects of the two drugs.
`Student's t-test was also applied to changes
`within each treatment group. There were statistically
`highly significant improvements in all measurements
`at 3 months with both drugs. Between 3 and 6 months
`there were further highly significant improvements in
`grip strength and latex titre with both drugs, joint
`size in patients receiving gold, and articular index in
`patients receiving penicillamine; there were signifi-
`cant improvements in pain in patients receiving
`
`penicillamine and articular index in patients receiving
`gold. Most of the clinical improvement in both groups
`was achieved in the first 3 months of treatment.
`There was a statistically significant reduction in the
`number of nodules after 6 months treatment with
`both drugs (Table IV).
`Although a reduction in rheumatoid factor titres
`seems to be a feature of therapy with these drugs,
`there was no evidence that this reduction played any
`part in the therapeutic response. Fig. 1 shows that
`there was no significant correlation between changes
`in latex titre and pain relief in patients receiving
`penicillamine (r = 0.0; P > 0.1). Fourteen patients
`who were seronegative at the start of the trial ob-
`tained pain relief of similar degree to the remaining
`seropositive patients (t = 0.14; P > 0.1). There was
`no evidence that response was related to age (r = 0.14;
`P > 0.1), or duration of arthritis (r = 0.10; P > 01).
`Table V shows withdrawals from the trial in the
`first 6 months and these were significantly more fre-
`quent in patients receiving gold than in those receiving
`
`Table IV Changes in number of rheumatoid nodules
`after 6 months' treatment with penicillamine or gold
`
`Total No.
`of patients Increased Decreased Sign test
`
`9
`
`Gold (cid:9)
`Penicil-
`lamine 15
`
`0
`
`1
`
`6
`
`10
`
`P = 0.032
`
`P= 0.012
`
`Table II Mean initial levels and changes in clinical measurements after 3 and 6 months' treatment with penicil-
`lamine (P) or gold (G)
`
`Months (cid:9)
`of
`treatment
`
`0
`3
`6
`
`Pain (cid:9)
`
`Duration of
`morning stiffness
`
`Articular
`index
`
`Grip
`strength
`
`Joint
`size
`
`14.2
`+6.3
`+6.3
`
`141
`+6.2
`+7.7
`
`104.5
`+52.8
`+59.9
`
`99.6
`+48.8
`+60.6
`
`587.7
`585.3
`216.0
`25.8
`23.6
`228.0
`+10.4 +11.6 +47.3 +40.0 +11.2 +12.2
`+82.4 +80.8 +19.9 +17.4
`+11.8
`+14.1
`
`+ Figures indicate improvement.
`
`Table III Mean initial levels and changes in laboratory measurements after 3 and 6 months' treatment with
`penicillamine or gold
`
`Months (cid:9)
`of
`treatment
`
`0
`3
`6
`
`ESR (cid:9)
`
`52.2
`+15.7
`+28.7
`
`Latex*
`
`52.9
`+21.5
`+23.7
`
`4.0
`+1.2
`+1.5
`
`SCATt
`
`G (cid:9)
`
`3.6
`+1.1
`+1.4
`
`P
`
`4.5
`+1.5
`+2.0
`
`P
`
`4.5
`+1.1
`+1.8
`
`• Titres were scored: 1 (cid:9)
`<1/20; 2 (cid:9)
`<1/16; 2- 1/16; 3 (cid:9)
`t 1 (cid:9)
`1/32, etc.
`+ Figures indicate improvement.
`
`1/20; 3 (cid:9)
`
`1/40, etc.
`
`This material was copied
`at the NUM and may be
`Subject US Copyright Laws
`
`Ex. 1080 - Page 4
`
`(cid:9)
`

`

`534 (cid:9) Annals of the Rheumatic Diseases
`
`+15 (cid:9)
`
`Penicillamine
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`
`• •
`
`• •
`
`•
`
`• •
`
`+10 -
`
`0
`
`- 5
`
`•• (cid:9)
`•
`
`•
`•
`
`•
`
`• •
`
`•
`
`•
`• •
`•
`
`• •
`
`•
`
`00
`
`•
`•
`
`•
`•
`05
`
`Penicillamine
`
`El Gold
`
`18
`
`16 -
`
`14 -
`
`12
`
`o 10
`8
`
`6
`
`•
`•
`
`•
`
`0 +1
`-
`Change in latex titre
`
`+i >2
`
`Lack of relationship between pain relief and changes
`FIG. 1 (cid:9)
`in latex titre in patients receiving penicillamine
`
`Rashes
`
`0
`
`1
`Months
`All side effects
`
`3
`
`6
`
`Flc. 2 Number of patients developing side effects while
`receiving either penicillamine or gold
`
`Table V (cid:9) Withdrawals in first 6 months of treatment
`
`Drop-out (cid:9)
`
`Survivors (cid:9)
`
`Total
`
`Gold (cid:9)
`Penicillamine (cid:9)
`
`Total (cid:9)
`
`14 (cid:9)
`3 (cid:9)
`
`17 (cid:9)
`
`25 (cid:9)
`40 (cid:9)
`
`65 (cid:9)
`
`39
`43
`
`82
`
`The difference between the gold and penicillamine groups is highly
`significant (x2 — 10.3; P < 0.01).
`
`penicillamine. (cid:9) Rashes (cid:9) or (cid:9) pruritus accounted for
`twelve of the fourteen gold withdrawals. Two
`patients receiving gold and two receiving penicil-
`lamine were withdrawn because of heavy proteinuria
`or nephrotic syndrome. One patient receiving
`penicillamine was withdrawn because of nausea and
`vomiting. Four patients were withdrawn for reasons
`unrelated to treatment.
`Fig. 2 shows the incidence of clinically important
`side effects and it is clear that there is a large excess of
`these attributable to penicillamine in the first 2 months
`of treatment. Of these side effects, rashes (Fig. 3) oc-
`curred in 32.5 % of patients receiving gold and in 24
`of those receiving penicillamine. The penicillamine
`rashes occurred earlier and in no case caused with-
`drawal of treatment for more than a week or two. All
`but one of the patients receiving gold who developed
`rashes were withdrawn; gold therapy was restarted
`in this patient, but the rash recurred after 3 months.
`Apart from rashes and two cases of heavy proteinuria,
`no other important side effects were noted in patients
`receiving gold.
`Fig. 4 shows the incidence of some other side effects
`
`4
`
`2
`
`-
`0
`
`I
`2
`(325°/0)
`
`4
`
`Gold
`
`°
`si5
`
`
`
`-1' E 4
`
`2
`
`O
`
`2
`Penicillamine (24%)
`
`4 (cid:9)
`
`5 (cid:9)
`
`6 Monthl
`
`Flo. 3 Number of patients developing rashes while
`receiving either penicillamine or gold
`
`of penicillamine. Loss of taste occurred in 24% of
`patients during the first 3 months of the trial, lasted
`4-8 weeks, and did not necessitate withdrawal of
`treatment. Gastrointestinal disturbances occurred in
`33 % of patients, also commonly in the first 3 months
`of treatment, with nausea and anorexia being the
`commonest symptoms. 27 % of these episodes were
`associated with loss of taste. In the 4th, 5th, and 6th
`months, six patients (13%) developed thrombo-
`cytopenia with levels between 46,000 and 110,000
`platelets/mm3; in one case this was associated with
`haemoptysis and in another with haematuria. In all
`cases, the platelet count returned rapidly to normal
`with prompt withdrawal of penicillamine and treat-
`ment was later restarted at a lower dose. Transient
`slight proteinuria was common in patients receiving
`
`This material wascopied
`at the NLM and may be
`Subject LIS Copyright Laws
`
`Ex. 1080 - Page 5
`
`(cid:9)
`(cid:9)
`

`

`Trial comparing D-penicillamine and gold in rheumatoid arthritis 535
`
`both drugs, but did not necessarily herald the develop-
`ment of serious proteinuria.
`
`Discussion
`
`On present evidence, there is little to choose between
`penicillamine and gold therapy in the management of
`patients with active rheumatoid disease which has
`failed to respond to simpler measures; in the first 6
`months of treatment, gold and penicillamine were
`equally effective. Gold treatment had to be withdrawn
`much more frequently than penicillamine because of
`rashes which occurred in about one third of cases.
`However, there were more side effects on penicil-
`lamine, particularly loss of taste, rashes, gastro-
`intestinal disturbance, and thrombocytopenia; these
`were usually transient and did not prevent the
`continuation of treatment. The incidence of heavy
`proteinuria was equal in the two groups, but since
`penicillamine nephropathy is commonly encountered
`after 9 months of treatment, more cases may be
`expected in the next 6 months of the trial.
`
`Penicillamine
`6 -
`
`4
`
`2
`
`O
`
`2 (cid:9)
`1 (cid:9)
`3 (cid:9)
`Loss of taste ( 24%)
`
`4 (cid:9)
`
`5
`
`6 (cid:9)
`
`6-
`
`4 -
`
`2 -
`
`0-
`
`1 (cid:9)
`3 (cid:9)
`4
`2
`Gastrointestinal disturbance (33%)
`
`E771
`
`6 (cid:9)
`
`Number of cases
`
`42
`
`0
`
`1
`2 (cid:9)
`3 (cid:9)
`4
`Thrombocytopenia (13%)
`
`Ti
`6 Months
`
`5
`
`FIG. 4 Number of patients developing loss of taste, gastro-
`intestinal disturbance, or thrombocytopenia while receiving
`penicillamine
`
`Summary
`
`In the first 6 months of a comparative study in patients
`with rheumatoid arthritis, penicillamine and gold
`were equally effective. Penicillamine caused more side
`effects but the side effects which occurred in patients
`receiving gold were more likely to require with-
`drawal of treatment.
`
`References
`
`BOARDMAN, P. L., AND HART, F. D. (1967), Brit. med. J., 4, 264 (Clinical measurement of the anti-inflammatory
`effects of salicylates in rheumatoid arthritis)
`ComminEE OF THE AMERICAN RHEUMATISM ASSOCIATION (1959) Ann. rheum. Dis., 18, 49 (Diagnostic criteria for
`rheumatoid arthritis: 1958 revision)
`MULTICENTRE TRIAL GROUP (1973) Lancet, 1, 275 (Controlled trial of D-penicillamine in severe rheumatoid
`arthritis)
`RrrcHit., D. M., BoYLE, J. A., TvlcINNEs, J. M., JASANI, M. K., DALAKOS, T. G., GRIEVESON, P., AND BUCHANAN,
`W. W. (1968) Quart. J. Med., 37, 393 (Clinical studies with an articular index for the assessment of joint
`tenderness in patients with rheumatoid arthritis)
`
`This material wascopiet1
`atthe NLM arid may be
`Subject LISCopyright Laws
`
`Ex. 1080 - Page 6
`
`