August 1981 Vol. 40 No, 4
`
`BRITISH MEDICAL ASSOCIATION TAVISTOCK SQUARE LONDON WC1H 9JR
`
`This material wascopied
`at the NMI and may be
`Subject US Copyright Laws
`
`Ex. 1072 - Page 1
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`

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`Annals of the Rheumatic Diseases
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`ill
`
`Esc,
`
`itra-
`
`This
`at the NLM arid may be
`
`
`
`Ex. 1072 - Page 2
`
`

`

`Annals of the Rheumatic Diseases August 1981 Vol. 40 No. 4
`
`Contents (cid:9)
`
`Systemic lupus erythematosus in childhood F. CAEIRO, F. M. C. MICHIELSON, R. BERNSTEIN, G. R. V.
`HUGHES, AND BARBARA M. ANSELL
`Arthrographic study of the rheumatoid knee. Part 1. Synovial proliferation KYOSUKE FUJIKAWA
`Arthrographic study of the rheumatoid knee. Part 2. Articular cartilage and menisci KYOSUKE
`FUJIKAWA, YOSHINORI TANAKA, TSUNEYO MATSUBAYASHI, AND FUJIO ISEK1
`Prostaglandin E1 infusions for vascular insufficiency in progressive systemic sclerosis M. F. R. MARTIN,
`P. M. DOWD, E. F. J. RING, E. D. COOKE, P. A. DIEPPE, AND J. 0. T. KIRBY
`Azathioprine in rheumatoid arthritis: double-blind study of full versus half doses versus placebo
`J. WOODLAND, D. M. CHAPUT DE SAINTONGE, S. J. W. EVANS, V. L. SHARMAN, AND H. L. F. CURREY
`Circulating immune complexes in polymyalgia rheumatica and giant cell arteritis J. R. PARK, J. G. JONES,
`G. D. HARKISS, AND B. L. HAZLEMAN
`
`Arthritis in psoriasis L. GREEN, 0. L. MEYERS, W. GORDON, AND 13. BRIGGS
`Polymorphonuclear cell function in rheumatoid arthritis and in Felty's syndrome G. B. HOWE, J. N.
`FORDHAM, K. A. BROWN, AND H. L. F. CURREY
`Synovial histopathology of Behget's syndrome T. GIBSON, R. LAURENT, J. II1GHTON, M. WILTON, M.
`DYSON, AND R. MILLIS
`Cellular phagocytic studies in rheumatoid arthritis patients treated with levamisole KATHERINE M.
`WYNNE, P. A. DIEPPE, JANE SCOTT, AND E. C. HUSKISSON
`Inflammatory synovial tissue monuclear cells release leucocyte migration inhibition factor in antigen-
`and mitogen-free Cultures TORSTEIN EGELAND, OVE J. MELL13YE, AND JAN A. PAHLE
`Polymorphonuclear granulocytes in rheumatic tissue destruction. 1 1 I. An electron microscopic study
`of PMNs at the pannus-cartilage junction in rheumatoid arthritis w. tomtit, II. WESTERHELLWEG,
`AND D. WESSINGHAGE
`
`Search for cross-reactivity between HLA B27 and Kleb.siella pneumennie J. R. ARCHER
`A comparison of serum biochemistry in ankylosing spondylitis, seronengative and seropositivc
`rheumatoid arthritis J. S. DIXON, H. A. BIRD, AND V. WRIGHT (cid:9)
`Prevalence of anti-beta-2 microglobulin autoantibodics in sera of rheumatoid arthritis patients with
`extra-articular manifestations ANDRAS FALUS, KATHERINE MERETEY, AND SANDOR 130ZSoKY (cid:9)
`Reiter's syndrome in association with enteritis due to Campylobacier fetus ssp. jejuni A. PONKA,
`J. MARTIO, AND T. U. KOSUNEN (cid:9)
`
`Spontaneous rupture of the Achilles tendon in a patient with gout PATRICK G. MAHONEY, PETER D.
`JAMES, CHRISTOPHER J. HOWELL, AND ANTHONY J. SWANNELL (cid:9)
`Polyarteritis nodosa associated with acute cytomegalovirus infection M. DOHERTY AND J. W. B.
`BRADFIELD (cid:9)
`
`A case of systemic lupus erythematosus with sideroblastic anaemia terminating in erythroleukaemia
`H. S. NG, H. W. NG, R. SINNIAH, AND P. H. FENG
`
`Coexistent rheumatoid arthritis and tophaceous gout: a case report D. RAMAN, A. M. ABDALLA, D. R. L.
`NEWTON, AND IAN HASLOCK
`
`Correspondence
`
`Notes
`
`,t
`
`L
`
`t
`
`Page
`
`325
`
`332
`
`344
`
`350
`
`355
`
`360
`
`366 (cid:9)
`
`370
`
`376
`
`382
`
`388
`
`396
`
`400 (cid:9)
`
`404
`
`409
`
`414
`
`416
`
`419
`
`422
`
`427
`
`430
`
`432
`
`ASTMS CODEN: ARD1A0 40 (4) 325-432 (1981) (cid:9)
`
`ISSN 0003-4967
`
`British Medical Association Tavistock Square London WC1H 9JR
`
`Published by British Medical Association, Tavistock Square, London WCI H 9JR, and
`printed in Englaff [S'erii-FM86§11i1l#Press Ltd., Torquay
`atthe NLM and may be
`Subject US Copy right Laws
`
`Ex. 1072 - Page 3
`
`

`

`Annals of the Rheumatic. Diseases, 1981, 40, 355-359
`
`Azathioprine in rheumatoid arthritis: double-blind
`study of full versus half doses versus placebo
`
`J. WOODLAND, D. M. CHAPUT DE SAINTONGE, S. J. W. EVANS,
`V. L. SHARMAN, AND H. L. F. CURREY
`
`From the London Hospital, London El IBB
`
`SUMMARY To test whether azathioprine is effective in rheumatoid arthritis in doses smaller than
`those normally used the drug was tested at 2 dosage levels, 2.5 and 1.25 mg/kg/day (2. 5 AZ and
`1.25 AZ), against placebo under double-blind conditions over 24 weeks. Dropouts were 7 out of 15
`in the 2.5 AZ group, 4 out of 14 in the 1.25 AZ group, and 2 out of 13 in the placebo group. Some
`significant improvement occurred in all 3 groups, including those on placebo. However, the 2.5 AZ
`group fared significantly better than the placebo group, while the 1.25 AZ group results tended to fall
`between the other 2 groups. We conclude that, in order to obtain the reported effectiveness of
`azathioprine in rheumatoid arthritis, it is necessary to start treatment with 2.5 mg/kg/day. Halving
`this dosage reduces the effectiveness of the drug
`
`Active and progressive rheumatoid arthritis is
`usually treated with one of the 'slow acting' group
`of drugs which includes gold, penicillamine, and the
`'immunosuppressive' (antiproliferative) agents. Po-
`tentially serious toxicity combined with the need for
`regular blood count monitoring limits the usefulness
`of these 'slow acting' drugs. Azathioprine is perhaps
`the easiest of this group to manage) However, the
`slight but probable oncogenic hazard remains a
`nnajor drawback to its usefulness.2 3 How anti-
`Proliferative drugs predispose to neoplasia is un-
`known. The risk has not been shown to be clearly
`related to dose,3 but it nevertheless seems sensible
`to limit the dosage level to that which will achieve
`a satisfactory therapeutic effect. Early studies in
`rheumatoid arthritis' used a dose of 2.5 mg/kg/day,
`based on the successful use of this drug in renal
`transplantation. Subsequent attempts to test the
`effectiveness of low doses have not given clear
`results.3-8 We have therefore tested the drug at 2
`doses-2.5 and 1.25 mg/kg/day—against placebo
`tinder double-blind conditions.
`
`the past 3 months. Their disease had to be severe
`enough to warrant treatment with azathioprine,
`either because of active and persistent inflammatory
`joint disease despite full anti-inflammatory and
`analgesic therapy or because of progression of radio-
`logical damage. A blood count obtained within 1
`month of entry had to satisfy the following minimum
`criteria: total leucocytes 4.0 x 102/1, platelets
`102/1, and haemoglobin of 10 g/dl. Patients
`175 (cid:9)
`previously treated with azathioprine, or who within
`the previous 3 months had received gold, corti-
`costeroids, penicillamine, or immunosuppressive
`drugs, were excluded. Other reasons for exclusion
`were age under 20, the possibility of pregnancy,
`persistent troublesome dyspepsia, and evidence of
`liver or renal disease (blood urea over 7 mmo1/1).
`There were 3 treatment groups: azathioprine
`2.5 mg/kg daily (2.5 AZ), azathioprine 1.25 mg/kg
`daily (1.25 AZ), and placebo. The drugs were
`prepared as matching tablets and given in 2 divided
`doses daily. Patients were stratified for duration of
`disease (less than or more than 5 years) and for the
`severity of arthritis (joint number less than 6, 6 to
`9, or more than 9). Allocation to a treatment group
`was balanced by the process of `minimisation'.9
`On entry to the trial patients were invariably on
`full dosages of anti-inflammatory drugs, and these
`were continued throughout the trial, which was
`carried out under double-blind conditions. A trial
`controller allocated treatment once the initial
`assessments (week —2) had been carried out.
`355
`
`patients and methods
`
`Patients admitted to the trial were required to have
`definite rheumatoid arthritis shown to be sero-
`Positive (latex test (cid:9)
`1:80) and erosive within the
`Accepted for publication 4 September 1980.
`Correspondence to Professor H. L. F. Currey, Bone and
`Joint Research Unit, Arthritis and Rheumatism Council
`Building, 25-29 Ashfield Street, London El 2AD.
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Ex. 1072 - Page 4
`
`

`

`356 Woodland, Chaput de Saintonge, Evans, Sharman, Currey
`
`The following clinical assessments were made at
`the beginning of the trial and at monthly intervals:
`functional capacity (Steinbrocker); duration of
`morning stiffness; patient's assessment of severity of
`joint symptoms over the preceding 7 days, both on a
`4-point scale (nil to severe), and a visual analogue
`scale. For both of these measurements higher scores
`indicate worse symptoms. Joint score was the
`number of limb joints painful on full active move-
`ment. With the hands and feet each counting as 1
`unit until the maximum score was 16. Grip strength
`was measured with a 200 mm circumference in-
`flatable bag. Drug toxicity was sought with the
`following question: 'Has the treatment upset you
`in any way since your last visit ?.' In addition direct
`questions were asked about sore throat, mouth ulcers,
`and purpura. All unused trial tablets were returned
`and counted, and a record was kept of analgesic con-
`sumption. Blood counts were performed at weeks
`-2, 0, +2, +4, then 4-weekly. Latex, SCAT, and
`SGOT tests were carried out 3-monthly.
`
`effect, and these were later used in an analysis Of
`covariance comparing changes between the treat.
`ments. This analysis corrected for the contribution
`to the treatment effect made by variables other th4n
`the treatment itself, particularly the values at entry,
`The value of changes in morning stiffness Wks
`transformed (loge) for the calculations because Of
`its skewed distribution. The effect of compliance
`was studied by using the number of tablets riOt
`returned as a covariate, thereby measuring the eft%
`of treatments independently of the effects of non_
`compliance.i° A few patients took so little of their
`allocated treatment that they effectively joined
`another group. The trial was further reanalYSQd
`after these patients had been reallocated to the
`appropriate treatment groups. A discriminaht
`analysis was performed on all variables on admis_
`sion to discover whether there were any early
`indications of treatment success or of dropout. The
`measure of treatment success was the physician's
`overall judgment of the changes in all trial variables,
`
`STATISTICAL ANALYSIS
`Analysis of the effects of treatment was carried out
`by comparing the mean values of the initial ob-
`servations (-2 and 0 weeks) with those at monthly
`intervals thereafter. Multiple regression analysis
`identified important determinants of the treatment
`
`Results
`
`Forty-two patients entered the trial. Fifteen wet•e
`allocated to 2.5 AZ, 14 to 1.25 AZ, and 13 10
`placebo. Patients allocated to each of these groUbs
`did not differ significantly with regard to duration of
`
`Table 1 (cid:9)
`
`Variable
`
`Initial values and changes at 24 weeks
`
`Treatments
`
`Initial value (SI)) Changc at 24 weeks (95 % CI.)
`
`Significance o/•
`change (p-i)
`
`Significance of
`difference (p -z)
`
`Functional capacity
`(grade)
`
`Morning stiffness
`(min)
`
`Patient assessment
`(analogue score)
`
`Patient assessment
`(grade, 4 point scale)
`
`Joint score
`
`Grip strength
`(mmHg)
`
`Haemoglobin
`
`ESR (mm/h)
`
`Placebo
`1.25 AZ
`2.5 AZ
`
`Placebo
`1.25 AZ
`2.5 AZ
`
`Placebo
`1.25 AZ
`2.5 AZ
`
`Placebo
`1.25 AZ
`2.5 AZ
`
`Placebo
`1.25 AZ
`2.5 AZ
`
`Placebo
`1•25 AZ
`2.5 AZ
`
`Placebo
`1.25 AZ
`2.5 AZ
`
`Placebo
`1.25 AZ
`2.5 AZ
`
`1.73 (0.75)
`1.64 (0.86)
`1.13 (0.52)
`
`57.5 (25,73).
`65.0 (22,82)*
`45.0 (7,66)•
`
`51.4 (16.4)
`56.9 (11.4)
`44.8 (19.1)
`
`3.15 (1.07)
`3.36 (0.93)
`2.73(1.10)
`
`6.85 (1.85)
`7.25 (2.84)
`7.23 (2.68)
`
`119 (63.1)
`124 (57.7)
`116 (39.6)
`
`11.6 (1.55)
`12.1 (1.35)
`12.7 (1.63)
`
`60.0 (21.6)
`62.3 (30.7)
`49.5 (24.6)
`
`-0.10 (0.26, -0.46)
`0.69)
`--0.31 (0.07, (cid:9)
`-0.34 (0.08, (cid:9) -0.76)
`
`-1.2 ( --29,19)*
`-45 (-78, (cid:9)
`-31)*
`-27 (-60, -8)•
`
`-13.65 (-2.60, - 24 • 69)
`-25.39 (-13.81, -36.97)
`-38.74 (--25.79, (cid:9) -51.691
`
`1.23)
`---0.72 (--0.19, (cid:9)
`-1.28)
`- 0.77 ( (cid:9) 0.26, (cid:9)
`-2.18 (-1.56, -2.80)
`
`-2.03 (--0.29, -3.77)
`-2.81 (0.98, -4.64)
`-4.32 (-2.79, -6.36)
`
`-2.2 (11.56, -15.92)
`12.9 (27.36, -1.47)
`31.6 (47.69,15.45)
`
`0.24 (0.81, -0.33)
`-0.45 (0.22, -1.12)
`-0.15 (0.52, -0.82)
`
`-4.7 (6.78, -16.18)
`-11.8 (1.68, -25.24)
`-8.1 (5.38, -21.54)
`
`NS
`NS
`NS
`
`NS
`0.05
`0.05
`
`0.05
`0.01
`0.001
`
`0.05
`0.05
`0.001
`
`0.05
`0.02
`0.01
`
`NS
`NS
`0.01
`
`NS
`NS
`NS
`
`NS
`NS
`NS
`
`•Median and midquartile range. CL (cid:9)
`
`confidence limits. NS = not significant.
`
`NS
`
`0.05
`
`0.05
`
`}If 0.01
`
`f
`
`NS
`
`r 0.01
`
`NS
`
`NS
`
`J
`
`Si
`r(
`
`si
`p
`
`tl
`si
`
`g
`
`a
`
`g
`b
`
`it
`
`2
`
`2
`2
`
`This material wascopie-d
`atthe NLM and may be
`
`Ex. 1072 - Page 5
`
`

`

`Azathioprine in rheumatoid arthritis 357
`
`• Placebo
`• 1.25 AZ
`• 2.5 AZ
`
`Morning (cid:9)
`stiffness (cid:9)
`(min) (cid:9)
`
`0
`-20
`-40
`-60
`0
`
`Patient
`assessment -1
`(4point)
`
`-20
`
`10
`Patient
`0
`assessment -10
`(analog) (cid:9)
`-20
`-30
`
`Joint score
`
`0
`-2
`-4
`-6
`
`30
`Grip strength 20
`(mmHg) (cid:9)
`
`40
`0
`-10
`
`;is of
`LTeat.
`Laion
`than
`;ntry,
`Was
`se of
`iahce
`hot
`effect
`npo.
`their
`oiled
`lined
`D the
`
`dn115-
`eATIY
`The
`ciAn's
`ables.
`
`Were
`13 to
`;rows
`of
`
`disease, age, and sex distribution, nor was there any
`significant difference between the groups with
`respect to the initial clinical or laboratory assess-
`ments except functional capacity, which was
`significantly better in the 2.5 AZ group than in the
`placebo group.
`Table I shows the starting values for all the
`variables studied and the overall changes without
`taking compliance into account. Fig. I illustrates
`the monthly changes in those variables showing
`significant treatment effects.
`
`Joint score. Changes here were found to be
`significantly dependent on the initial values. All
`treatment groups (including placebo) improved
`significantly during the trial, but the 2.5 AZ group
`had improved more than placebo at 8 and 20 weeks
`and was also better than I.25 AZ at 20 weeks. Early
`superiority of 1.25 AZ over placebo at 4 and 8
`weeks was not apparent later in the trial.
`
`Patient assessment (visual analogue). All treatment
`groups improved significantly during the trial but
`2.5 AZ significantly more so than placebo at 12
`and 24 weeks.
`
`Patient assessment (4-point scale). All treatment
`groups improved significantly during the trial, and
`by the end 2.5 AZ was considerably better than
`1.25 AZ and placebo.
`
`P < 0.01
`
`IP< 0.05
`
`P< 0.01
`
`0 4 8 10 16 20 24
`WEEKS
`Fig. 1 Sequential changes from the initial values for
`5 variables. Placebo:41, 1.25 AZ: 0, 2.5 AZ: MI
`
`e
`(p<)
`
`Morning stifthess. Both 2.5 AZ and 1.25 AZ
`improved significantly during the trial and were
`better than placebo by 24 weeks.
`
`Grip strength. 2.5 AZ was significantly better than
`placebo at 24 weeks.
`Fig. I illustrates the pattern of change in these
`variables over the 6 months. In general all improved
`
`Table 2 Patients withdrawn from the trial
`
`Treatment group
`
`Time of witheirmval
`in weeks
`
`Reason tie withdrawal
`
`2.5 AZ
`
`2.5 AZ
`
`2.5 AZ
`
`2 (cid:9) AZ
`2.5 AZ
`
`2.5 AZ
`2.5 AZ
`
`1•25 AZ
`
`1.25 AZ
`1.25 AZ
`1.25 AZ
`
`Placebo
`
`F
`
`F
`
`M
`M
`
`M
`M
`
`F
`
`M
`M
`M
`
`F
`
`Placebo
`
`M
`.f)extropropoxyphene IIII and paracetamol.
`
`2
`
`3
`
`3
`8
`
`I
`12
`
`3
`
`4
`6
`15
`
`4
`
`6
`
`Vomiting, rash
`
`Generally unwell
`
`Nausea, headache, itching, sore tongue
`
`Rash, leucopenia
`Anaemia? bleeding
`
`Vomiting
`headache, vomiting
`
`Vomiting, giddiness
`
`Left ventricular failure
`Weakness
`Treatment failure
`
`Rash
`
`Headache
`
`Other drugs
`
`Ibuprofen
`Distalgesic*
`Indomethacin
`Ketoprofen
`Indomethacin
`Paracetomol
`Fenoprofen
`Aspirin
`Aspirin
`Indomethacin
`Indomethacin
`Aspirin
`Indomethacin
`Aspirin
`Indomethacin
`Indomethacin
`Ketoprofen
`Naproxen
`Indomethacin
`Naproxen
`Distalgesic
`Ibuprofen
`
`This material was copied
`
`Ex. 1072 - Page 6
`
`(cid:9)
`

`

`me
`eft
`wh
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`
`358 (cid:9) Woodland, Chaput de Saintonge, Evans, Sharman, Currey
`
`gradually over the period of the study, and, except
`for grip strength, the placebo group improved
`significantly too. However, there was throughout a
`clear trend for the high dose to be more effective
`than the half dose, which in turn was more effective
`than placebo.
`Functional capacity, haemoglobin, and erythro-
`cyte sedimentation rate showed no treatment effect,
`although, as with the clinical parameters, changes
`were dependent on the initial values.
`
`Withdrawals. There were 7 withdrawals (47%)
`from 2.5 AZ, 4 (29%) from 1.25 AZ, and 2 (15%)
`from placebo. This difference in number of patients
`withdrawn did not reach statistical significance.
`Nine out of 14 men were withdrawn compared
`with 4 out of 28 women, but there was a tendency
`for there to be more males in the high-dose group.
`None of these differences reached significance. The
`reasons for withdrawal are shown in Table 2.
`Generally withdrawals tended to occur early in
`the trial, and only 1 patient (1.25 AZ group) was
`withdrawn because of lack of effectiveness. Dis-
`criminant analysis showed that of the entry variables
`male sex and mild symptoms (on the visual analogue
`scale) correlated best with dropout.
`
`Compliance. The effect of noncompliance did not
`significantly alter the results.
`
`Analgesic consumption. There were no consistent
`differences between the groups. In particular the
`improvement in the 2.5 AZ group could not be
`accounted for by greater analgesic consumption.
`
`PHYSICIANS' ASSESSMENT
`At the end of the trial the physicians were presented
`with a set of figures giving initial and final values for
`each variable for all patients. The physicians were
`then asked to grade (`blind) the response of each
`patient. Patients judged to have improved sig-
`nificantly contained more 2.5 AZ patients than
`either of the other treatments. Discriminant analysis
`suggested that patients who did well had a high
`initial joint score, received 2.5 AZ, and at 4 weeks
`had little morning stiffness and good functional
`capacity. However, early improvements in morning
`stiffness and functional capacity were not such good
`predictors of the final outcome as judged by the
`trial physicians.
`
`Discussion
`
`These results need to be interpreted with caution
`because of the small numbers of patients in each
`
`treatment group and because of the relatively high
`withdrawal rate. Withdrawal of patients may affect
`the result of the trial in a number of ways. It could
`be argued that patients receiving little benefit from
`the trial medication may be more likely to complain
`of unwanted effects and hence be withdrawn. This
`would bias the result in favour of patients who have
`responded well. We do not feel this factor played a
`significant part in this trial, as the majority of the
`dropouts occurred within the first 3 months before
`the patient had been led to expect any noticeable
`improvement. Withdrawals because of ineffective-
`ness could produce a similar bias; we had only
`patient—in the 1.25 AZ group—withdrawn for thin
`reason.
`A notable aspect of these results is the improve-
`ment seen in the placebo group. The fact that this
`reached statistical significance for a number of
`variables is a reminder that the sheet anchor of
`testing the effectiveness of 'slow-acting' drugs in
`rheumatoid arthritis remains the double-blind com-
`parison with placebo, demanding though the
`ethical and logistic aspects of this are.
`These results confirm again that azathioprine in
`a daily dosage of 2.5 mg/kg is an effective slow..
`acting drug in rheumatoid arthritis. The relatively
`small numbers in the treatment groups do not per-
`mit one to draw precise conclusions about the
`effectiveness of 1.25 mg/kg daily compared with
`full doses and with placebo, but the general trend of
`the results leave no doubt that the half dosage group
`fell somewhere between the other 2. It is tempting to
`interpret the lower dropout rate in the half-dosage
`group as pointing to a reduction in short-term
`effects compared with full dosage. In fact, this
`difference might well have occurred by chance.
`We believe that azathioprine continues to have
`place in the treatment of certain cases of severe
`rheumatoid arthritis. It is relatively easy to manage,
`and short-term toxicity is troublesome rather that-.
`dangerous.' It is the probable, slight risk of malig-
`nancy" which places it after penicillamine and gole_'
`in the choice of slow-acting drugs. Although the
`mechanism of this oncogenesis is unknown and the
`relationship of risk to dosage unproved, it is never-
`theless mainly this consideration which makes 17
`obligatory to employ the minimum effective dosage
`The message from this study is that, if one is te
`achieve the—admittedly modest—effect of azathio-
`prine in full, then it is probably necessary to star:
`with a daily dose of about 2.5 mg/kg.
`How long should full doses be continued? This
`study again shows that improvement in a sloe..
`acting drug continues for at least 6 months. On this
`evidence it would seem reasonable to regard t.
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Ex. 1072 - Page 7
`
`(cid:9)
`

`

`months on full doses as an adequate test of the
`effectiveness of the drug in an individual patient,
`while for those who both tolerate the drug and
`improve on it continuing full doses for a total of I
`year probably achieves maximum effectiveness.
`After 12 months there is a strong case for pro-
`gressively reducing the dose to the minimum which
`will maintain this effect. Improvement may be
`maintained over a number of years on small daily
`doses, with the patient relapsing if the drug is
`finally withdrawn altogether." The striking parallel
`with the situation when azathioprine is used to
`prevent rejection of renal transplants12 perhaps
`points to the effectiveness of the drug depending on
`a similar mechanism in these 2 conditions.
`
`References
`
`Currey H L F, Harris J, Mason R M, et al. Comparison of
`azathioprine, cyclophosphamide, and gold in treatment of
`rheumatoid arthritis. Br Med J 1974; iii: 764-6.
`.2 Currey H L F. Immunosuppressive drugs in rheumatoid
`arthritis-toxicity. In: Fallet G H, Fischer T L. Selected
`Therapeutic „Symposium, Geneva. Munich: Urban and
`Schwarzenberger, 1973: 98-104.
`
`Azathioprine in rheumatoid arthritis 359
`
`Kinlen L J, Sheil A G R, Peto J, Doll R. Collaborative
`United Kingdom-Australasian study of cancer in patients
`treated with immunosuppressive drugs. Br Med J 1979;
`ii: 1461-6.
`4 Mason M, Currey H L F, Barnes C G, Dunne J F,
`Hazelman B L, Strickland I D. Azathioprine in rheumatoid
`arthritis. Br 'Vied J1969; 1: 420-2.
`Goebel K M, Janzen R, Joseph K, Borngen U. Disparity
`between clinical and immune responses in a controlled
`trial of azathioprine in rheumatoid arthritis. Ear J Clin
`Pharmaeol 1976; 9: 405-10.
`Phials R S. Azathioprine in the treatment of chronic
`polyarthritis: long-term results and adverse effects in 25
`patients. Rheumatology 1976; 3: 140-4.
`7 Cade R, Stein G, Pickering M, Schlein E, Spooner G. Low
`dose, long-term treatment of rheumatoid arthritis with
`azathioprine. Southern Med J1976; 69: 388-92.
`8 Dwosh I L, Stein H B, Urowitz M B, Smythe H A,
`Hunter T, Ogryzlo M A. Azathioprine in early rheumatoid
`arthritis. Arthritis Rheum 1977; 20: 685-91.
`9 Taves D R. Minimisation: a new method of assigning to
`treatment and control groups. Clio Pharmacol Ther 1974;
`15: 443-53.
`10 Joyce C R B. Patient co-operation and the sensitivity of
`clinical trials. J Clown Dis 1962; 15: 1025-56.
`11 De Silva M, Hazleman B L. Long-term azathioprine in
`rheumatoid arthritis—a double-blind study. Paper
`presented to the Heberden Society, London, 6 June 1980.
`12 Hamburger J, Crosnier J, Dormont J, Bach J-F. Prepara-
`tion and care of the patient. Azathioprine. Renal Trans-
`plantation, Theory and Practice. Baltimore: Williams and
`Wilkins, 1972: 151.
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`this material was copied
`at th e NUA and may be
`Subject LIS Copyright Laws
`
`Ex. 1072 - Page 8
`
`