INDEX
`
`Page
`
`81
`
`97
`
`P. van der Meer: Rheumatoid Arthritis and the Cervical Spine
`G. DiPasquale, V. L. Beach & B. G. Steinetz: Evans Blue Dye
`
`Transport Across the Granuloma Pouch Wall (cid:9)
`E. Zachariae & H. Z a c h a r i a e: The Histamine Content of Human
`
`Synovial Membrane (cid:9)
`L. Danielsen: Immuno-Electrophoretic Analysis of Serum Proteins in Pso-
`
`riasis and Psoriatic Arthritis (cid:9)
`J. Stepan, 0. Vojtigek & E. Paluska: On the Problems of the
`Total Iron-Binding Capacity of Serum (TIBC) in Patients with Articular 119
`Disease
`
`J. L. K alliom a k,i & P. A. Lauren: Development of Temporal Arteritis
`in a Patient with Rheumatoid Arthritis during Treatment with Indomethacin 131
`J. I u e I & J. Kr y g e r: Local Cutaneous Atrophy Following Corticosteroid
` 137
`Injection
`M. BHckdahl & 0. Strandber g: The treatment of Nodose Tendinitis
`
`in the Rheumatoid Hand (cid:9)
`
`107
`
`112
`
`145
`
`true hydrocortisone solution
`for effective, percutaneous treatment
`
`Malmo 9 .
`
`l't1\
`
`IIREADING
`ROOM
`ACTA RHEUMATOLOGICA
`SCANDINAVICA
`
`REDACTORES
`
`J. J. DE BLIICOURT K.
`Groningen
`
`BROCHNER-MORTENSEN
`Kobenhavn
`
`V. FORBECH
`Oslo
`
`V. LAINE
`Heinola
`B. OLHAGEN
`Stockholm
`
`C. HOLTEN
`Aarhus
`W. L'ORANGE
`Oslo
`
`FR. SUNDELIN
`Nynashamn
`
`EDITOR
`G. EDsTRom
`
`SV. CLEMMESEN
`Kobenhavn
`
`E. JONSSON
`Stockholm
`P. VAN DER MEER
`Rotterdam
`
`M. VIRKKUNEN
`Helsinki
`
`REDIGENDA CURAVI
`
`0. LoVGREN
`Stockholm
`
`NATIONAL LIBRARY OF MAIGINE
`
`RECD, NOV 22 1965
`ITC
`VOL-ISSUE
`INDEXER
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`COLLABORANT
`IN DANIA: G. Asboe-Hansen, E. Bruun, 0. Boje, T. Geill, Ch. Hamburger,
`H. Jacobsen, K. Kalbak, K. 0. Moller, E. Snorrason, 0. Sylvest, G. Teilum.
`IN FENNIA: E. Adlercreutz, K. A. J. Jarvinen, P. Peltola, P. Soisalo, L. E. Totterman.
`IN NEDERLANDIA: B. J. ter Bals, J. J. Bode, G. van Dam, W. H. D. der Haas,
`J. J. Siemelink.
`IN NORVEGIA: H. Hegna, E. Kass, 0. Mellbye, 0. Sydnes.
`IN SUECIA: K. Berglund, A. Bjure, F. Bohman, L. Brahme, C. Ekelund, P.O. Gedda,
`B. Ingelmark, 0. Lovgren, K. E. Thulin, St. Thune, St. Winblad.
`
`Vol XI (cid:9)
`
`1965 (cid:9)
`
`FASC 3
`
`STEINSVIKS BOKFORLAG AB • STOCKHOLM
`
`itfEri."
`
`r it: 0
`
`Ex. 1068 - Page 1
`
`(cid:9)
`(cid:9)
`

`

`NOTICE TO CONTRIBUTORS
`
`The ACTA RHEUMATOLOGICA SCANDINAVICA
`publishes papers on rheumatology.
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`
`All papers offered should be written in English, French or German. Above tbt
`a.
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`the work in question has been carried out. In cases where several authors have coll b,
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`
`Authors are expected to follow the usual practice of reading one proof of their own
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`articles. Corrections in proof involving alterations of the manuscript should be restrict'
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`Manuscripts from Scandinavian and Dutch authors should be addressed to the edi-
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`(See also 3rd page of cover).
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`Acta Rheumatologica Scandinavica appears annually with one volume of four
`fascicles. Annual subscription rate in Scandinavia (Denmark, Finland, Iceland, Nor-
`way and Sweden): Swed. Kr. 50:00, abroad US $ 12.00.
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`Butazolidin®
`Geigy
`vid kroruska reumatiska ledsjukdomar
`
`J. R. Geigy A.G., Basel (Schweiz)
`Representant i Sverige for farmacevtiska specialiteter:
`AB Hassle, Box 691, Goteborg 6
`
`Ex. 1068 - Page 2
`
`

`

`"1--)
`CONTAINS INIZ'
`
`-A
`IVNG
`°°14(.A.CTA RHEUMATOLOGICA
`SCANDINAVICA
`
`I j
`
`REDACTORES
`
`J. J. DE BLECOURT K.
`Groningen
`V. FORBECH
`Oslo
`V. LAINE
`Heinola
`B. OLHAGEN
`Stockholm
`
`BROCHNER-MORTENSEN
`Kobenhavn
`C. HOLTEN
`Aarhus
`W. L'ORANGE
`Oslo
`FR. SUNDELIN
`Nynashamn
`
`SV. CLEMMESEN
`Kobenhavn
`E. JONSSON
`Stockholm
`P. VAN DER MEER
`Rotterdam
`M. VIRKKUNEN
`Helsinki
`
`EDITOR
`G. EDSTRoM
`
`REDIGENDA CURAVI
`0. LaVGREN
`Stockholm
`
`MTION. MARX 01: MEDICINE
`/V•5- "
`RECD. FEB 16 I566
`7) (cid:9)
`JIG
`VOL-ISSUE
`INDEXER
`
`COLLABORANT
`IN DANIA : G. Asboe-Hansen, E. Bruun, 0. Boje, T. Geill, Ch. Hamburger,
`H. Jacobsen, K. Kalbak, K. 0. Moller, E. Snorrason, 0. Sylvest, G. Teilum.
`IN FENNIA : E. Adlercreutz, K. A. J. Jarvinen, P. Peltola, P. Soisalo, L. E. Totterman.
`IN NEDERLANDIA: B. J. ter Bals, J. J. Bode, G. van Dam, W. H. D. der Haas,
`J. J. Siemelink.
`IN NORVEGIA : H. Hegna, E. Kass, 0. Mellbye, 0. Sydnes.
`IN SUECIA : K. Berglund, A. Bjure, F. Bohman, L. Brahme, C. Ekelund, P.O. Gedda,
`B. Ingelmark, 0. Lovgren, K. E. Thulin, St. Thune, St. Winblad.
`Vol XI
`1965 (cid:9)
`
`FASC 4
`
`STEINSVIKS BOKFORLAG AB • STOCKHOLM
`
`INDEX
`
`Page
`
`R. S h a t i n: The Epidemiology of Rheumatoid Arthritis and Human Ecology
`J o h. F o s s g r e e n: Druckmessungen in der Achillessehne des Menschen
`Bendt Kirchheine r: Vitamin C Deficiency and Connective Tissue II .. 177
`
`161
`169
`
`B. Kir chheiner & A. Mar ckmann: Vitamin C Deficiency and
`.....
`..
`Connetive Tissue III ......................................
`Odd K ogst a d: Baker's Cyst .....................................
`........... (cid:9)
`Erik Kass: Indomethacin in Ankylosing Spondylitis .........
`C h r. Mo ens & J. Br octeu r: Treatment of Rheumatoid Arthritis with
`Immunosuppressive Drugs I ........................................
`J. Br oct e u r & Ch r. Moen s: Treatment of Rheumatoid Arthritis with 221
`..
`Immunosuppressive Drugs II .....................................
`.
`M. Hvatu rn: A Blood Cell Column Technique for Purification of Rheu
`matoidFactor ................................................... 231
`
`185
`194
`205
`
`212 I
`
`true hydrocortisone solution
`for effective, percutaneous treatment
`
`Malmo 9
`
`Ex. 1068 - Page 3
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`?1oens, Chr. & Brocteur, J.: Acta Rheum. Scand., 11, 212-220, 1961.
`
`From the Centre Medico Social de Bruxelles, Brussels, Belgium
`
`TREATMENT OF RHEUMATOID ARTHRITIS WITH
`IMMUNOSUPPRESSIVE DRUGS
`
`I. Clinical Study
`
`By
`
`CHRISTIAN MOENS and J. BROCTEUR
`
`6-Mercaptopurine and its derivatives depress antibody formation in
`several different species of animals (see review by Hitchings and Elion
`1963). These drugs are being widely used to prolong the survival time
`of grafted organs. Caine (1960) showed that 6-Mercaptopurine increased
`the survival time of kidney transplants in dogs and this is attributed to
`an immunosuppressive action of the drug. B.W. 57-322, a derivative
`of 6-Mercaptopurine, designed to have a better therapeutic index than the
`parent drug, proved also to be more effective in depressing antibody
`formation in mice. This led Caine to study its effect in the survival of
`kidney grafts in dogs. He concluded that B.W. 57-322, now called
`azathioprine (Imuran) was at least as effective in this respect as 6-Mer-
`captopurine and easier to control with regard to bone marrow depression.
`In an attempt to prolong even further the life of kidneys grafted into
`dogs, Caine and Murray (1961), Alexandre and Murray (1962), Caine,
`Alexandre and Murray (1962) and Alexandre, Murray, Dammin and
`Nolan (1963) studied the effects of Imuran in combination with a
`variety of cytotoxic agents, e.g. actinomycin C, actinomycin D, nitrogen
`mustard, "X" irradiation, cyclophosphamide, azaserine and methotrex-
`ate. The best mean survival time was obtained with a combination of
`Imuran and actinomycin C. Addition of most of the other drugs to these
`two increased toxicity to bone marrow without prolonging the survival
`
`TREATMENT OF R.A. WITH IMMUNOSUPPRESSIVE DRUGS I 213
`
`time of the graft. It is to be assumed that, in the dog at least, this com-
`bination of Imuran and actinomycin C has the greatest immunosuppres-
`sive action of all the combinations of drugs tested.
`
`Studies in Man
`Analogous work in man has been the subject of several recent reviews
`(Goodwin 1962, Leading article, Lancet 1963, Hitchings & Elion 1963).
`In brief, the findings in dogs, quoted above, have been confirmed in man
`and combinations of Imuran, actinomycin C and prednisone are widely
`used to control graft rejection. Some workers combine the use of these
`drugs with "X" irradiation of the whole body, or those parts of it believed
`to be concerned with the production of immunity against the graft, e. g.
`spleen, thymus, or the lymph glands which drain the area to receive the
`grafted kidney. Therapy is based on the assumption that the normal
`immune response to grafted tissue must be suppressed and that antibody
`formation must be inhibited.
`
`Imnzunosuppressive Drugs and Auto-immune Disease
`The discovery of cortisone provided the first immunosuppressive drug
`to be widely used in the treatment of auto-immune disease. The use of 6-
`Mercaptopurine and its derivatives for this purpose was a natural se-
`quence. The subject has recently been reviewed (Hitchings & Elion 1963).
`The work was pioneered by Dameshek and Schwartz (1960, 1962)
`who treated successfully several cases of auto-immune hemolytic anemia
`and lupus erythematosus with 6-Mercaptopurine and thioguanine. There
`have been many reports from other workers of the successful treatment
`of various auto-immune diseases with these drugs (Rundles, Laszlo, Ito-
`ga, Hobson & Garrison 1961, Merrill 1962, Eisen, Demis & Crosby
`1962, Weiss, Demis, Elgart, Brown & Crosby 1963, Richmond, Wood-
`ruff, Cumming & Donald 1963, Page, Condie & Good 1962, Brand-
`riss 1963, Mackay & Wood 1963, Mackay, Weiden & Ungar 1964).
`
`The Effect of Imuran and Actinomycin C in Rheumatoid Arthritis and
`Lupus Erythematosus
`After consulting one of the original workers in the field of kidney
`grafting (Alexandre, personal communication), it was decided to try the
`effect of Imuran and actinomycin C in patients whose condition was de-
`teriorating rapidly, in spite of classic orthodox therapy.
`
`Ex. 1068 - Page 4
`
`

`

`214 (cid:9)
`
`CHRISTIAN MOENS & J. BROCTEUR
`
`OF R.A. WITH IMMUNOSUPPRESSIVE DRUGS I
`
`215
`
`=_- Steroids.
`
`N
`
`N
`N
`
`N
`N
`
`\ O
`N
`
`*
`
`co N
`
`co
`
`r-1
`
`O
`
`0 V" \
`
`‘r,
`
`I O (cid:9)
`
`N-
`
`' • (cid:9)
`
`\
`
`,n
`
`ON CD
`
`C'S
`
`In CO
`
`\ (cid:9)
`
`\
`
`•et. (cid:9)
`
`ON
`
`C)
`\ N
`
`trl
`..714
`
`tf
`1-1
`
`\
`
`N
`N
`O
`en
`
`N
`en
`
`N
`
`N
`
`N
`
`,r‘
`
`•
`
`C1
`
`0 N 1-4
`
`v•N
`
`trN
`
`N N
`N
`
`e-i
`
` ,
`
`N
`
`C \
`N
`
`co
`
`N
`N
`
`N
`
`N
`N
`
`CO (cid:9)
`
`eel
`
`\O
`
`Both on ethical grounds and because work on kidney grafting' in
`ct
`dogs and in man, had suggested either an additive or a synergistic effe
`between steroids and Imuran, it was decided that patients already beings
`treated with steroids should be maintained on them. Actinomycin C
`reserved for those patients who failed to respond to steroids and/or Imu-
`At
`ran. These studies were intended to be of a preliminary nature only.
`this stage, a fully controlled clinical test would have been unethical.
`However, each patient served as his own control and it is reasonable to
`conclude that after a long period of deterioration any marked change
`particularly in such things as the erythrocyte sedimentation rate, is due t°
`treatment. In all cases, clinical change and the patient's own assessment
`ce
`
`of his condition were noted, although every rheumatologist of experien
`when
`knows that these can be unreliable guides. Great care was taken
`explaining to the patients that a new type of treatment was proposed, that
`they might feel worse and the treatment have to be stopped. They were
`
`lt
`given no cause for optimism and it is probable that the improvement
`they felt under treatment would not have been produced by a placebo. It
`
`is highly probable that changes in the erythrocyte sedimentation rate and
`in the inflammatory index (see Smyth, Johnson & Clark 1959) are due
`to treatment and that when these were linked with relief of the patients
`symptoms a true therapeutic effect was being achieved.
`How long such an effect lasts, which combination of drugs is mos.. f ef-
`fective, what type of case, if any, should be treated, will require much
`more work and it is not the intention of thispaper to speculate along
`these lines. The intention is to record some facts which provide some 'Ira
`11
`on the mode of action of these drugs. In brief, even when the ESR
`and the inflammatory index showed marked improvement and the clin
`cal response was most satisfactory, there was no significant change in tuot
`electrophoretic estimation of serum proteins, the globulins did n _
`tests under5
`change, nor was there any alteration in the immunological
`taken and reported fully by Brocteur and Moens 1965. These finding
`suggest that the immunosuppressive action of these drugs is not due to ,
`reduction in circulating antibodies. (cid:9)
`
`N
`
`ti
`
`*
`
`\
`
`N
`
`0 CO
`CO
`
`N
`
`co
`N
`
`CO
`
`N
`
`0
`7/4
`
`Co
`N
`
`CO I N (cid:9)
`
`1-4 VfN (cid:9)
`e-1 4-1 (cid:9)
`
`s7f• (cid:9)
`
`•
`•
`
`(.4
`cl-‘
`e-1 ®
`
`IVY
`
`Ocq ON
`s;t'
`
`®
`
`O
`
`O
`
`ON
`
`..:11
`
`en
`..;r1
`
`*
`
`N
`
`O
`
`O
`
`vn CO
`(...1
`
`en N
`N N
`
`c0
`
`1-1 '714 0
`N
`N `I" 1 0
`N
`
`▪ Ir. 0
`LIN
`
`GN
`\
`
`r-1
`
`Co 0
`
`tn
`
`Co
`®N
`
`O
`
`O.\ \ N
`
`11. Mrs. B. 0.
`
`The Investigation
`Eleven patients with rheumatoid arthritis and two with lupus etYthe,:
`matosus were selected for treatment. All had failed to respond to classic
`011,
`therapy, including salicylates, gold salts, antimalarials and steroids.
`Patients 1 and 4 were on daily prednisone and this treatment was con
`
`1St
`
`ti
`
`cs
`• .< c4
`
`vi
`N
`
`P4 (cid:9)
`
`g (cid:9)
`
`c‘ (cid:9)
`
`M (cid:9)
`
`,A
`
`4
`
`Ex. 1068 - Page 5
`
`

`

`216 (cid:9)
`
`CHRISTIAN MOENS & J. BROCTEUR (cid:9)
`
`TREATMENT OF R.A. WITH IMMUNOSUPPRESSIVE DRUGS I
`
`217
`
`tinued for the reasons stated above (see table). Patients 2 and 3 were re-
`ceiving a weekly injection of 40 mg. of 6-methyl-deltahydrocortisone and
`this was continued, for ethical reasons, throughout the investigation. All
`patients were treated with Imuran 2.5 mg./kg. daily by mouth. Patients
`1, 2, 5, 6 and 7 received actinomycin C 6 micrograms per kilogram intra-
`venously at the times indicated in the table.
`Twice weekly the erythrocyte sedimentation rate (ESR) (Wester-
`gren) and the inflammatory index were recorded on the first and second
`lines respectively of the table. The latter is based on sensitivity, pain,
`swelling and heat of the joints and the presence of intra-articular fluid
`(see Smyth, Johnson & Clark 1959). The times when blood was taken
`for antibody determinations are shown in the table by black dots. Leuco-
`cyte counts were carried out twice weekly.
`
`RESULTS
`
`In five patients No. 2, 8, 9, 10 and 11 treatment was stopped. The
`drugs used are very potent and for ethical reasons patients were with-
`drawn from the investigation immediately they had obvious side-effects.
`In four patients treatment was stopped because of gastric pain and in one
`because of leucopenia. The pain stopped and the leucocytes returned to
`normal once this had been done. Unfortunately, patients 8 and 10, the
`only ones with lupus erythematosus, were among those withdrawn. As no
`data on the effect of the drugs were obtained from patient No. 8, this
`patient was excluded from the investigation.
`Treatment caused a marked fall in the ESR in 9 out of 12 patients and
`a reduction in the inflammatory index in 8 out of 12.
`With such small numbers and considerable variation in the type of
`case, it is not possible to assess which was the most effective combination
`of drugs. It is too early to consider the therapeutic value of treatment
`other than to claim a short-term benefit which varied between patients.
`The important fact which emerges from this study is that in no patient,
`however well they responded, was there a significant change in the anti-
`Gms., the anti-A and the anti-J3 isoagglutinins or in the RA test. These
`results and their significance are discussed by Brocteur and Moens (1965).
`It is noteworthy that when, after 17 weeks' treatment, patient No. 1
`relapsed, actinomycin C caused clinical improvement, a fall in the inflam-
`matory index but no change in the ESR. It is hard to believe that a change
`
`in the inflammatory index can be due to a placebo effect in a patient who
`had responded well once, but this possibility cannot be excluded. It re-
`mains to be seen how long improvement is maintained in the other pa-
`tients.
`
`DISCUSSION
`
`These findings are consistent with those obtained in patients with auto-
`immune disease treated with these drugs by other workers. The good re-
`sults in patients 1, 2, 3 and 4 are in keeping with the suggestion of
`Mackay, Weiden and Ungar (1964) that Imuran and steroids have a syn-
`ergistic effect in lupoid hepatitis. They are in keeping also with the
`findings quoted above of a similar effect in renal transplantation in dogs
`and in man. But our data cast some doubt as to whether the effect in
`man of Imuran and actinomycin C is strictly "immunosuppressive" in
`the sense of impairing the formation of circulating antibody.
`Much of the data on these drugs has been obtained in the study of
`their effects on graft rejection. But as the analogy between graft rejec-
`tion and the delayed allergic response of the tuberculin type is very close
`and as 6-Mercaptopurine and Imuran are known to depress this type of
`reaction (Hoyer & Condie 1962), there is no need to look for an effect
`of these drugs on antibody formation in order to explain the benefit de-
`rived from drug therapy. The beneficial effect of cortisone on graft sur-
`vival in man can be explained on the same basis for cortisone depresses
`the delayed allergic response but does not depress antibody formation
`(Long 1960). Its mode of action is probably different from that of
`Imuran and it is therefore reasonable that they would exert an additive or
`synergistic effect.
`Richmond, Woodruff, Cumming and Donald (1963) carried out
`what is believed to be the first study of the effect of Imuran and actino-
`mycin C on an auto-immune disease. They treated a patient suffering
`from a very severe auto-immune hemolytic anemia and thrombocytope-
`nia. This patient received steroids, Imuran, actinomycin C and, in addi-
`tion, "X" irradiation to the thymus and, as a result, the Coombs test fluc-
`tuated and, eventually, after the patient had gone into a complete remis-
`sion and recovered fully, became negative. But their charts suggest that
`this may have been a consequence of curing the disease and not the cause
`of it.
`
`Ex. 1068 - Page 6
`
`

`

`218 (cid:9)
`
`CHRISTIAN MOENS & J. BROCTEUR
`
`TREATMENT OF R.A. WITH IMMUNOSUPPRESSIVE DRUGS I 219
`
`Our finding that Imuran and actinomycin C did not influence antibody
`titers can be readily explained in terms of Long's hypotheses (1960). He
`divided animals into cortisone-resistant and cortisone-sensitive species.
`The first group consists of man, monkey and guinea-pig, the second
`group, rat, mouse and rabbit. The first group is readily sensitised to bac-
`terial allergens and produces the classic tuberculin-type delayed allergic
`reaction; the latter group does not. The first group cannot synthesise
`ascorbic acid; the latter group can. The first group maintains body weight,
`gamma globulin and antibody levels in the blood when treated with
`large doses of cortisone (50 mg.Jkg.); the latter group shows a reduction
`in all these with as little as 5 mg./kg.
`Long and his colleagues showed that cortisone caused a fall in gluta-
`thione associated with decreased sensitivity to tuberculin and also that in-
`jected glutathione abolished this anti-inflammatory action of cortisone
`(1958, 1960).
`The analogy between these findings and the effects obtained with 6-
`Mercaptopurine and Imuran are remarkably close. 6-Mercaptopurine and
`Imuran depress antibody levels in rabbits and mice (cortisone-sensitive
`species) but have no such effect in guinea-pigs and according to our find-
`ings Imuran and actinomycin C have no effect on globulins or antibodies
`in man (cortisone-resistant species). Moreover, glutathione prevents the
`ability of Imuran to depress antibody formation in mice (Personal com-
`munication, Hitchings and Elion).
`It is suggested that the beneficial effect of Imuran and actinomycin C
`in rheumatoid arthritis is due to an anti-inflammatory effect rather than
`to an immunosuppressive effect and that it may be a depression of a de-
`layed allergic response. The point is important. To depress antibody is
`to decrease resistance to infection; to depress inflammation need not be
`associated with this risk.
`
`SUMMARY
`
`1. Eleven patients with rheumatoid arthritis and two with lupus ery-
`thematosus who failed to respond to classic conservative therapy were
`treated with Imuran and actinomycin C.
`2. Two patients with lupus erythematosus and three with rheuma-
`toid arthritis were withdrawn from the trial because of side-effects.
`3. Treatment caused a marked fall in the erythrocyte sedimentation
`
`rate in nine out of twelve patients and a reduction in the inflammatory
`index in eight out of twelve patients.
`4. In all patients antibodies and globulins remained unchanged.
`5. It is suggested that these drugs exerted an anti-inflammatory rather
`than an immunosuppressive effect.
`6. The possible mode of action is considered.
`
`RtSUMr.
`
`1. Onze patients atteints de polyarthrite et deux de lupus erythemateux
`ayant manqué de reagir a la therapie conservatrice classique ont ete traites
`avec de l'Imuran et de l'Actinomycine C.
`2. Deux patients atteints de lupus erythemateux et trois de polyarthrite
`furent retires des epreuves a cause de l'apparition d'effets secondaires.
`3. Le traitement causa une chute de la vitesse de la sedimentation du
`sang dans neuf de douze cas et une reduction de l'index inflammatoire
`dans huit de douze cas.
`4. Chez tous les patients les anticorps et globulines resterent inchanges.
`5. Les auteurs supposent que ces drogues exercent plutot un effet anti-
`inflammatoire qu'une action immunosuppressive.
`6. Le mode d'action possible est pris en consideration.
`
`ZUSAMMENFASSUNG
`
`1. Elf Patienten mit chronischer Gelenkentzundung und zwei mit
`Lupus erythematodes, die auf klassische konservative Therapie nicht
`ansprachen, wurden mit Imuran und Actinomycin C behandelt.
`2. Zwei Patienten mit Lupus erythematodes und drei mit chronischer
`Gelenkentzundung wurden wegen des Auftretens von Nebenwirkungen
`von den Versuchen ausgeschlossen.
`3. Die Behandlung bewirkte eine deutliche Abnahme der Blutsenkungs-
`geschwindigkeit bei neon von zwolf Patienten und eine Reduktion im
`Entziindungsindex bei acht von zwolf Patienten.
`4. Bei alien Patienten traten keine Veriinderungen im Verhalten der
`Antikorper und Globuline auf.
`5. Es wird auf die Moglichkeit hingewiesen, dass diese Drogen eher
`eine antientzandliche als eine immunosuppressive Wirkung ausiiben.
`6. Die vermutliche Wirkungsweise wird in Betracht gezogen.
`
`Ex. 1068 - Page 7
`
`

`

`220 (cid:9)
`
`CHRISTIAN MOENS & J. BROCTEUR
`
`Acknowledgements
`
`Brocteur, J. & Moens, Chr.: Acta Rheum. Scand., 11, 221-230, 1965.
`
`We are grateful to Dr. Guy Alexandre and to Dr. David Long for
`advice, to the Wellcome Foundation for the Imuran and to the Bayer
`Company for the actinomycin C used in these studies.
`
`From le Service de Transfusion Sanguine (Dir. Prof. P. Moureau)
`Universite de Liege, Belgium
`
`REFERENCES
`
`Alexandre, G. P. & Murray, J. E.: Surg. Forum, 13, 64, 1962.
`— Murray, J. E., Dammin, G. J. & Nolan B.: Transplantation, 1, 432, 1963.
`IV,: Preliminary experience with administration of 6-thioguanine in
`Brandriss, (cid:9)
`chronic hepatitis. In Clinical Staff Conference at National Institutes of Health
`— Current studies on the effect of antimetabolites in nephrosis, other non-
`neoplastic diseases, and experimental animals. Ann. intern. Med., 59, 398, 1963.
`Brocteur, J. & Moens, C.: Acta Rheum. Scand., 11, 221, 1965.
`Caine, R. Y.: Lancet, i, 417, 1960.
`— & Murray, I. E.: Surg. Forum, 12, 118, 1961.
`— Alexandre, G. P. & Murray, J. E.: Ann. N. Y. Acad. Sci., 99, 743, 1962.
`Danzeshek, TV. & Schwartz, R.: Tr. Assoc. Am. Physicians, 73, 113, 1960.
`
`Eisen, B., Dennis, D. J. & Crosby, IV. H.: J. Amer. Med. Assoc., 179, 789, 1962.
`Gerwing, J. & Long, D. A.: Biochem. J., 70, 652, 1958.
`Goodwin, TV, E.: The present status of renal transplantation (Dec. 1962) in Year
`Book of Urology 1962-1963, ed. by W.W. Scott.
`Hitchings, G, H. & Elion, G. (cid:9)
`Pharmacol Rev., 15, 365, 1963.
`Royer, I. R. & Condie, R. Al,: Fed. Proc., 21, 277, 1962.
`Leading article. Renal transplantation. Lancet, i, 69, 1963.
`Long, D. A.: Antibiotica et Chemotherapia, 7, 29, 1960.
`Mackay, I. R. & TVood, I. J.: Gastroenterology, 45, 4, 1963.
`— Treiden, S. & Ungar, B,: Lancet, i, 899, 1964.
`Merrill, J. P.: Blood, 20, 119, 1962.
`Page, A. R., Condie, R. M. & Good, R. A.: Blood, 20, 118, 1962.
`Richmond, J., 1Voodru f, M, F. A., Cumming, R. A. & Donald, K. TV.: Lancet, ii,
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`Rundles, R. 1V„ Laszlo, J,, Itoga, G., Hobson, J. B. & Garrison, F. E.: Cancer Che-
`mother. Rep., 14, 99, 1961.
`Schwartz, R. & Dameshek, IV.: Blood, 19, 483, 1962.
`Smyth, C. J,, Johnson, R. L. & Clark, G. M.: Postgrad. Med., 25, 315, 1959.
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`Med., 268, 753, 1963.
`
`TREATMENT OF RHEUMATOID ARTHRITIS WITH
`IMMUNOSUPPRESSIVE DRUGS.
`
`II. Immunological Study
`
`By
`
`J. BROCTEUR and CHR. MOENS
`
`INTRODUCTION
`
`Schwartz et al. (1958) have shown that the administration of 6-Mer-
`captopurine depresses the primary immune response in the rabbit. This
`inhibition of antibody formation is less apparent when secondary antigen
`stimulation occurs (Schwartz et al. 1959) but depression can also be ob-
`tained if the product is administered in higher doses (Laplante et al.
`1962).
`As a result of these observations, 6-Mercaptopurine and some of its
`derivatives such as 'Imuran' (B. W. 57-322 — azathioprine) have
`been used to prolong the life of homografts and in the treatment of a
`number of auto-immune diseases.
`In a previous paper (Moens & Brocteur 1965), we gave the clinical
`results of this type of treatment in patients suffering from chronic rheu-
`matoid arthritis.
`In the present paper we report tile results of blood tests that were made
`in some of these patients.
`
`MATERIAL AND METHODS
`
`Various blood tests were carried out on six of the thirteen patients treat-
`ed with 'Imuran' (Moens & Brocteur 1965). These patients were all suf-
`
`Ex. 1068 - Page 8
`
`