ALTH
`
`•-qi. • (cid:9)
`
`o
`
`RA RY (cid:9)
`
`19:7b
`
`Scan &Ravi „tern
`, (cid:9)
`is. 53706
`• Journal of
`Rheumatology
`
`Formerly published as
`
`Acta Rheumatologica Scandinavica
`
`Chief Editor
`Veikko Laine
`
`Managing Editor
`011e Loygren
`
`Editorial Board
`Denmark: Hans Graudal
`Finland: Otto Wegelius
`Iceland: Jon Thorsteinsson
`Norway: Erik Kass
`Sweden: Borje Olhagen
`
`Vol. 5 No. 1 1976
`
`Sandoz v. AbbVie
`Sandoz Ex. 1085
`
`The Almqvist Et Wiksell Periodical Company, Stockholm, Sweden
`
`Ex. 1085 - Page 1
`
`

`

`Scandinavian Journal of Rheumatology
`(formerly Acta Rheumatologica Scandinavica)
`
`Published by the Scandinavian Society of Rheumatologists
`
`Chief Editor
`Veikko Laine, M.D.
`SF-181 20 Heinola 12
`Finland
`
`Managing Editor
`011e Lovgren, M.D.
`S:t Eriks Sjukhus
`P.O. Box 12600
`S-112 82 Stockholm, Sweden
`
`Advertising
`Medicinska Annonsexpeditionen AB
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`
`Subscription and Distribution
`The Almqvist & Wiksell Periodical
`Company
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`S-101 20 Stockholm 1, Sweden
`
`Printers
`Almqvist & Wiksell
`Tryckeri AB
`S-751 81 Uppsala, Sweden
`
`The Scandinavian Journal of
`Rheumatology
`publishes papers on
`— clinical aspects of rheumatic dis-
`orders including therapy, prophylaxis
`and surgical treatment
`— laboratory investigations, including
`mainly biochemistry, immunology,
`microbiology, pathology, patho-
`physiology
`— radiological investigations
`— epidemiological and social aspects
`of rheumatic disorders.
`The journal is intended mainly for the
`publication of articles from Denmark,
`Finland, Iceland, Norway and Sweden,
`but articles from other countries may
`also be accepted.
`Expeditious handling will be accorded
`to important, brief preliminary reports
`and to short communications not ex-
`ceeding 2 printed pages inclusive of one
`table and one figure.
`Papers are open for discussion or
`comment in brief Letters to the Editor.
`All papers or letters will be published
`in English.
`
`Subscriptions
`The Scandinavian Journal of
`Rheumatology is published four times
`a year, each issue consisting of approx.
`48 pages. Four issues constitute one
`volume.
`Price per volume: Sw. kr. 125 postage
`included.
`Supplements free.
`
`(0 1976 The Scandinavian Society of Rheumatologists
`
`Ex. 1085 - Page 2
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Scand J Rheumatology 5: 216-220, 1976
`
`IMMUNOTHERAPY WITH LEVAMISOLE IN
`RHEUMATIC DISEASES
`
`M. Rosenthal. U. Trabert and W. Willer
`
`From the University of Basel, Rhemnatological University Clinic, Felix Platter-Spital,
`Basel, Switzerland
`
`t(
`
`ABSTRACT. The immuno-modulatory effect of
`Levamisole' in the treatment of rheumatic diseases was
`studied in an open trial. Nine patients with rheumatoid
`arthritis (RA), 13 with ankylosing spondylitis (AS) and one
`with Reiter's syndrome (RS) were treated initially with 150
`mg Levamisole daily for 4 weeks, then intermittently 3 days
`a week. Significant clinical improvement was observed in 7
`out of 9 patients with RA, in 4 out of 13 patients with AS,
`and in the one patient with RS, An increased skin sensitivity
`to a panel of antigens was noted in 3 out of 9 RA patients
`and in 6 out of 13 AS patients. A fall in rheumatoid factor
`titre was observed in 2 out of 5 patients with seropositive
`RA. No development of other auto-antibodies was observed.
`No significant changes in the absolute lymphocyte counts
`either of the total counts or of the T, B, and null cell counts,
`were noted. Drug-related adverse reactions were seen in 13
`patients, mostly allergic skin rash which required a short
`interruption in therapy. Severe leucopenia was observed in
`2 patients, whereupon therapy was definitely withdrawn.
`Levamisole seems to have a definite beneficial effect on RA
`and a possible effect on AS and RS. Severe adverse reac-
`tions, mostly on the haemopoietic system, demonstrated
`some potential hazardous complications of the drug and
`required physical and laboratory examinations at short in-
`tervals.
`
`an impairment of cellular immune response might
`be involved in the pathogenesis of rheumatoid
`arthritis (RA) and ankylosing spondylitis (AS) (2, 5,
`7, 18, 29, 32), Such observations might explain the
`beneficial effect of an immuno-suppressive therapy
`in rheumatic diseases. However, the rationale for
`an immuno-stimulation and immuno-modulation
`was revealed, since it became apparent that cellular
`immune mechanisms do involve helper as well as
`suppressor cell populations (17, 15). First attempts (
`to introduce immuno-stimulation in rheumatoid dis-
`eases were made. with BCG Vaccination (30) and
`transfer factor therapy (12, 16). Some preliminary
`work (3, 33) suggested that the drug might be bene-
`ficial in RA. Other authors warn that the drug might
`be lacking in therapeutic effect (11).
`In order to study the clinical and immunological
`effect of Levamisole we conducted a long-Term
`open study by treating 23 patients with either RA,
`AS, or Reiter's syndrome (RS).
`
`(
`
`Levamisole, an anti-helminthic drug, was recently
`introduced as an immuno-stimulatory agent (6, 21,
`22, 24, 25). Extensive clinical and laboratory
`studies revealed that the drug influences preferen-
`tially the cellular immune response (9, 10, 35, 36).
`Anergic patients with Hodgkin's disease and
`other malignancies were the first to be treated (4, 8,
`34), followed by patients with skin diseases mostly
`of viral origin (13, 14, 19, 20, 31) and sarcoidosis
`(27).
`Firm evidence has accumulated suggesting that
`
`' Levamisole (2,3,5,6 tetrahydro-6-phenyl imidazo (2,
`I-b) thiazole hydrochloride) was kindly supplied by Jans-
`sen Pharmaceutica, Beerse, Belgium.
`
`MATERIALS AND METHODS
`Subject studies. Nine patients with classical rheumatoid
`arthritis as defined by the ARA criteria (26), 13 patients
`with ankylosing spondylitis and one patient with Reiter's
`syndrome were included in the study (Table I). All pa-4
`tients showed an active disease state upon entering the
`study and received no other medication except non-
`steroidal anti-inflammatory drugs. None of the patients
`received either gold, D-penicillamine, synthetic anti-
`malaria drugs or immuno-suppressive agents clurilig the
`study or shortly before.
`Levamisole was administered per orally 50 mg three
`times daily during the first 4 weeks, thereafter continued
`as a maintenance therapy of 150 mg daily for 3 days a
`week. All patients were examined at 2-week intervals.
`The clinical examination of the patients with RA in-
`cluded joint score, grip strength, and walking time. The
`
`Scand J Rheumatology 5
`
`Ex. 1085 - Page 3
`
`

`

`Immunotherapy with Levamisole in rheumatic diseases (cid:9)
`
`2l7
`
`Diag- (cid:9)
`nosis
`
`Age
`(y.) (cid:9)
`
`Sex
`
`Dis. stage
`(Stein-
`brocker)
`
`Dis.
`duration
`(y.)
`
`Dis.
`activity
`
`Rheumat. factor
`(SSCA-test)
`
`Neg.
`1: 1 024
`Neg.
`Neg.
`Neg.
`1:256
`1: 2 048
`I: (cid:9) 16
`1:512
`
`HL-A B 27
`
`3
`10
`2
`6
`15
`3
`4
`1
`3
`
`13
`11
`8
`7
`8
`10
`5
`7
`7
`
`0.5
`0.5
`6
`1.5
`
`+++
`+++
`
`++
`+++
`++
`++
`++
`+++
`
`+++
`
`++
`++
`+ -I- +
`+ +
`++
`
`+++
`++
`+++
`+++
`++
`+++
`
`III
`
`11-111
`III
`
`11
`
`III
`
`I-11"
`11"
`III"
`
`IV"
`11"
`IV"
`IV"
`In"
`II"
`
`III"
`
`M
`F
`F
`F
`F
`M
`F
`F
`F
`
`KKKKK
`
`KK4K
`
`RA
`RA
`RA
`RA
`RA
`RA
`RA
`RA
`RA
`
`AS
`AS
`AS
`AS
`AS
`AS
`AS
`AS
`AS
`AS
`AS
`AS
`AS
`RS
`
`41
`62
`68
`70
`62
`36
`67
`51
`60
`
`35
`32
`28
`29
`29
`48
`25
`27
`31
`39
`50
`21
`42
`33
`
`Table I
`
`Patients
`
`I. L. A.
`2. B. A.
`3. S. E.
`4. V. S.
`5. K. R.
`6. G. V.
`7. S. A.
`8. S. E.
`9, G. A.
`
`0. G. J.
`I. S. W.
`2. R. H.
`3. B. B.
`4. F. P.
`5. G. L.
`6. L. A.
`7. K. U.
`8. G. M.
`9. L. J.
`20. S. K.
`21. R. S.
`22. N. C.
`23. Z. W.
`
`a AS stage: I=iliosacral joint involvement, II= l+syndesmophytes and reduced range of spinal motion, III=1 +multiple
`calcified spine ligaments, IV=I+practically rigid spine, V= I+ bony ankylosis of the spine,
`
`patients were questioned about their general feeling, dura-
`tion of morning stiffness, pain level and intake of medica-
`ments for the relief of symptoms. The patients with AS
`and RS were examined for spine suppleness and involve-
`ment of peripheral joints and other organ manifestations.
`They were questioned about pain duration at night and in
`all patients adverse reactions were noted.
`Laboratory examinations included erythrocyte sedi-
`mentation rate (ESR), red and white blood counts with
`differentials, determinations of lymphocyte subpopula-
`tions in peripheral blood, utilizing a combined method
`(23) allowing the simultaneous determination of T, B, and
`null cells. Electrolytes, urea, creatinine, uric acid levels,
`liver, muscle and bone enzymes as well as urine were
`checked regularly. Rheumatoid factor titres were meas-
`ured in the serum at 2-week intervals, utilizing the
`I sensitized sheep red cell agglutination (Waaler-Rose) and
`
`r‘
`
`Latex Fixation Test. Antinuclear antibodies, antibodies
`against other cellular elements and anti-DNA-antibodies
`were also determined. Skin tests against a panel of .5
`antigens (Tuberculin, Candida albicans, SK/SD, Tricho-
`phitin and Coccidiodin) were performed at the begin-
`ning of the study, and 2 and 4 weeks as well as 6 months
`thereafter.
`
`RESULTS
`
`Clinical evaluation of Levamisole
`(Table 11)
`
`Rheumatoid arthritis. 7 out of 9 patients with RA
`showed a subjective and objective improvement af-
`ter a mean observation time of 9 weeks. An objec-
`
`Table II. Clinical effect of Levamisole
`
`Diagnosis
`
`Rheumatoid arthritis (RA)
`Ankylosing spondylitis (AS)
`Reiter's syndrome (RS)
`
`No. of
`patients
`
`9
`13
`1
`
`Observation
`time
`(weeks)
`
`9 (6-18)
`22 (8-32)
`22
`
`Subject
`improv.
`
`Objective
`improv.
`
`7
`7
`
`7
`4
`1
`
`Scand J Rheumatology 5
`
`Ex. 1085 - Page 4
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`218 (cid:9) M. Rosenthal et al.
`
`Table III. Immunological effect of Levamisole
`
`Increased
`skin sen-
`sitivity°
`
`Fall in
`RF titre"
`
`Develop-
`ment of
`autoanti-
`bodies
`
`3/9
`
`2/5
`
`0/9
`
`6/13
`
`0/1
`
`—
`
`—
`
`0/13
`
`0/1
`
`Absolute lymphocyte counts
`
`Changer
`
`Total
`
`T-lymph. B-lymph. 0-lymph.
`
`I
`
`I
`
`=
`
`2/8
`1/8
`5/8
`2/8
`5/8
`1/8
`I/I
`
`2/8
`2/8
`4/8
`2/8
`4/8
`2/8
`I/I
`
`5/8
`1/8
`2/8
`2/8
`2/8
`4/8
`I/l
`
`3/8
`3/8
`2/8
`0/8
`5/8
`3/8
`1/1
`
`Diagnosis
`
`Rheumatoid
`arthritis (RA)
`
`Ankylosing
`spondylitis (AS)
`
`Reiter's
`syndrome (RS)
`
`" At least for one antigen a definite positive skin reaction of a tenfold antigen dilution as being negative at the beginning
`of the study.
`b Fall in rheumatoid factor titre measured by SSCA or LFT of at lest 2 titre dilutions.
`" Change of at least 20% of the absolute cell count.
`
`tive clinical improvement was evidenced by a re-
`duction in joint score, fall in ESR, improved walk-
`ing time and/or substantial cut in intake of anti-
`inflammatory drugs.
`Ankylosing spondylitis. Following a mean obser-
`vation time of 22 weeks a subjective clinical im-
`provement was reported in 7 out of 13 patients,
`though objectively only 4 patients showed an im-
`provement as measured by the fall in ESR, in-
`creased range of motion of the spine and/or a sub-
`stantial cut in intake of anti-inflammatory drugs.
`The only patient with Reitees syndrome with
`extensive peripheral joint involvement was free of
`symptoms after 3 weeks of therapy. Since then he
`has remained symptom-free despite the fact that
`drug intake had to be stopped due to an adverse
`reaction which occurred after 3 weeks.
`
`Immunological evaluation of Levamisole
`(Table III)
`Immunological parameters were: skin tests with 5
`antigens, the demonstration of autoantibodies and
`determinations of total lymphocyte counts as well
`as absolute T, B, and null cell counts. It can be seen
`that increased skin sensitivity following Levamisole
`administration was observed in only 3 out of 9 pa-
`tients with RA, and in 6 out of 13 patients with AS.
`No change in skin tests was noted in the patient
`with RS.
`A fall in titre of rheumatoid factor of at least two
`titres was noted in only 2 out of 5 seropositive RA
`patients. It is worth noting that none of the patients
`included in the study showed a development of
`other auto-antibodies during Levamisole therapy•
`The absolute lymphocyte counts determined in 8
`
`Table IV
`
`Adverse reaction
`
`Urticarious rash
`
`Leucopenia/agranulocytosis
`
`Gastrointestinal discomfort
`(nausea, stomach pain)
`Fatigue
`Headache
`
`Scand Rheuniatology 5
`
`Adverse reactions
`
`Cases
`
`Drug
`related
`
`Severity
`
`Policy
`(Levamisole
`therapy)
`
`7
`
`2
`
`3
`
`4
`1
`
`7
`
`1
`
`Mild
`Moderate
`Severe
`f < I 000/mm3
`>1 000/mm"
`f Mild
`Moderate
`Mild
`Mild
`
`3
`
`3
`1
`1
`
`1
`4
`
`f Temporarily
`t interrupted
`
`f Definitely
`interrupted
`
`Continued
`
`Continued
`Continued
`
`Ex. 1085 - Page 5
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`Immunotherapy with Levamisole in rheumatic diseases
`
`219
`
`patients with RA, 8 patients with AS and 1 patient
`With RS did not show any specific trend. The
`number of patients in each group is too small to
`allow of a valid statistical analysis of the changes.
`
`Adverse reactions (Table IV)
`Adverse reactions were seen in 17 cases, of which
`13 could be ascribed to the drug. The adverse reac-
`tions observed were urticarious rash, leucopenia,
`gastro-intestinal discomfort, fatigue and headaches.
`liLevamisole administration had to be discontinued
`completely in 2 patients with leucopenia, while a
`temporary withdrawal of the drug was necessary in
`7 cases of urticarious rash. In some of these patients
`a readministration with increasing doses was toler-
`ated without any recurrence of the rash. In both
`cases with leucopenia, examination of the hone
`marrow revealed a "promyelocyte marrow". By
`utilizing the sera of these 2 patients, a positive
`leukocyte agglutination test could be performed in
`the presence of Levamisole. In both patients a
`spontaneous and complete recovery of the leuko-
`cyte count was seen within a few days.
`
`DISCUSSION
`
`Immuno-stimulation provides a new approach to
`the treatment of rheumatic diseases. It is of consid-
`erable interest that besides the introduction of BCG
`vaccination and the leukocyte product, transfer
`factor, a defined chemical agent could restore
`lymphocyte function both in vitro and in vivo. Sev-
`eral authors have reported on the clinical use of this
`drug in oncology and dermatology. Preliminary re-
`ports on Levamisole administration in RA were
`controversial. In the open clinical study reported
`here, we observed that a clinical improvement can
`be expected in some cases of RA but in fewer cases
`of AS. The clinical improvement is accompanied by
`immunological changes as measured by delayed
`e type skin sensitivity and auto-antibody determina-
`' lions only in a few cases. The total lymphocyte
`counts and the absolute counts of the different sub-
`populations showed no significant changes. The
`lack of overwhelming changes in the immunological
`parameters raises the question as to the extent to
`which clinical improvement is really due to the
`drug. On the other hand the validity of the im-
`munological parameters used to characterize a pos-
`sible immuno-stimulatory effect of this drug could
`also be questioned. We consider the conducting of a
`
`double-blind long-term study on a large patient
`series as very essential in order to exclude the pos-
`sibility of spontaneous remission. Furthermore,
`only the introduction of pathologic-anatomical as
`well as immunological studies of the involved
`synovia and other tissues will allow a critical
`judgement of this therapy. The effect of Levamisole
`in experimental arthritis models is another tool for
`use in the assessment of the efficacy of this drug.
`Such studies are now in progress in our
`laboratories.
`The gastro-intestinal side effects as well as the
`fatigue are mild and in most of the cases do not
`require interruption of therapy. However, the al-
`lergic adverse reactions as manifested in urticarious
`rash and leucopenia, which were seen in several
`cases, are of considerable interest. They may be
`due not only to conventional drug hypersensitivity
`but may also represent an immuno-stimulatory
`activity of this drug. As yet, it cannot be excluded
`that a low dose Levamisole regime might cause less
`severe adverse reactions but still give a substantial
`therapeutic effect. This might well be the case, in
`view of the low incidence of side effects reported by
`other authors (1).
`The observations reported here should encourage
`other workers to study this drug in respect to its
`immuno-modulatory effect, not only in rheumatic
`diseases but also in other auto-immune states, bear-
`ing in mind the potential hazardous adverse reac-
`tions.
`
`ACKNOWLEDGEMENT
`This work was supported by the Swiss National Fonds,
`Credit No. 3.0830.73.
`
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`Scand J Rheumatolugy 5
`
`Ex. 1085 - Page 6
`
`

`

`220 (cid:9) M. Rosenthal et al.
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`27. Rosenthal, M., Trabert, U., Muller, W., Muller, S. &
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`28. Schuermans. Y.: Levamisole in rheumatoid arthritis.
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`29. Stastny, P., Rosenthal, M., Andreis, M. & Ziff, M.:
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`33. Trabert, U., Rosenthal, M., Muller, W., Milner, S. &
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`restoration of cutaneous delayed hypersensitivity in
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`
`Submitted for publication October 21, /975
`
`fl
`
`0
`
`M. Rosenthal
`University of Basel
`Rheumatological University Clinic
`Felix Platter-Spital
`Basel
`Switzerland
`
`Sand J Rheumatology 5
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`Ex. 1085 - Page 7
`
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