he
`Journal of
`Rheumatology
`
`ANNIVERSARY
`
`VOLUME 11‘ NO. 6 (cid:9)
`
`DECEMBER, 1984
`
`Editorials Oxy Radicals, "Peroxide Tone" and Inflammation. Cleland (cid:9)
`The Risk of AS — HLA-B27 Positive Individuals. Khan, van der Linden (cid:9)
`
` 725
` 727
`
`729
`735
`
` 754
`
`Articles
`Modulation of Mitogen-Dependent Lymphocyte Stimulation by flyaluronic Acid. Anastassiades, Robertson
`Oxygen Radical Production by Horse and Pig Neutrophils Induced by a Range of Crystals. Higson, Jones . . .
`Prospective Study of Morphology and Phagocytosis of SF MSU Crystals in Gouty Arthritis.
` 741
`Antommattei, Schumacher, Reginato, Clayburne (cid:9)
`Direct Stimulation of Neutrophil Oxygenation Activity by Serum from Patients with SLE. Via, Allen, Welton 745
`Lymphocyte Subsets and Inflammatory Indices in SF and Blood of Patients with RA.
`Bertouch, Roberts-Thomson, Brooks, Bradley (cid:9)
`A Controlled Two-Center Trial of Parenteral Methotrexate Therapy for Refractory RA.
`Thompson, Watts, Edelman, Esdaile, Russell
` 760
`Gold vs D-Penicillamine Double Blind Study and Followup. Thomas, Rothermich, Philips, Bergen, Hedrick (cid:9) 764
`Radiographic Evaluation of Erosion in RA. Gofton, O'Brien, Hurley, Scheffler ........... . .. . .. . . . .. (cid:9)
`768
`Dose, Plasma Concentration and Response Relationships of D-Penicillamine in Patients with RA.
`Brooks, Miners, Smith, Smith, Fearnley, Birkett......... .. . . (cid:9)
`..... . . . . ... (cid:9)
`...... (cid:9)
`RA: The Effects of Treatment with Dapsone on Hemoglobin. Grindulis, McConkey
`The Renal Excretion of Prostaglandins and Changes in Plasma Renin During Treatment with Either
`Sulindac or Naproxen in Patients with RA and Thiazide Treated Heart Failure.
`Svendsen, Gerstoft, Hansen, Christensen, Lorenzen
`The Lupus Activity Criteria Count (LACC). Urowitz, Gladman, Tozman, Goldsmith._ (cid:9)
`... . ..... . (cid:9)
`AS: A Comparative Study of Patients in an Epidemiological Survey, and Those Admitted to a
`Department of Rheumatology. Gran, Husby
`Computed Tomography of Paraspinal Musculature in AS. Gordon, Sage, Bertouch, Brooks (cid:9)
`The Effect of Juvenile Inflammatory SF on In Vitro Cartilage. Silverman, Smith, Schurman, Miller, III .. (cid:9)
`DISH: A Clinicoradiological Study of the Disease Pattern in Middle Eastern Populations. El Garf, Khater.. (cid:9)
`Muscle Pathology in Primary Fibromyalgia Syndrome: A Light Microscopic, Histochemical and
`Ultrastructural Study. Kalyan-Raman, Kalyan-Raman, Yunus, Masi
`Fibrositis (Fibromyalgia) in RA. Wolfe, Cathey, Kleinheksel (cid:9)
`The Lifetime Economic Costs of RA. Stone..
`
`772
`776
`
`779
`783
`
` 788
` 794
`798
`804
`
` 808
` 814
`819
`
`Case Reports
`Persistent Immunoglobulin Deficiency after
`Prednisolone and Antiepileptic Therapy in a C2
`Deficient Patient with Lupus-Like Syndrome
`Woo, Pereira, Lever (cid:9)
`Coexistent Gout and HOA in Patients with
`Cyanotic Heart Disease.
`Martinez-Lavin, Amigo, CaStillelos, Padilla, Vintimilla 832
`Felty's Syndrome in a Child.
`Rosenberg, Mitchell, Card (cid:9)
`Nodular Regenerative Hyperplasia of the Liver in
`a Patient with Rheumatoid Vasculitis.
`Reynolds, Wanless (cid:9)
`
` 835
`
` 838
`
` 828
`
`Cholestatic Jaundice Induced by Gold Salts Treatment.
`Clinical and Immunological Aspects.
`Schapira, Nahir, Scharf, Pollack (cid:9)
`Occlusive Retinal Vascular Disease in SLE.
`Hall, Buettner, Luthra (cid:9)
`Primary Lymphoma of Bone Presenting as Mono-
`arthritis, Rice, Semble, Ahl, Bohrer, Rothberger (cid:9)
`Clinical Pathological Conference with Discussion
`by Gerald P. Rodnan.
`Gerald P. Rodnan, 1927-1983 (cid:9)
`Letters, Book Reviews, Notices (cid:9)
`Index (cid:9)
`
` 843
`
` 846
`
` 851
`
` 855
` 861
`see page 862
` 873
`Sandoz v. AbbVie
`Sandoz Ex. 1081
`
`Ex. 1081 - Page 1
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`HEALTH SCENCES
`University of Wisconsin
`Madison; Wis. 53706
`-1 !.v)F, Lindp, (cid:9)
`JAN 3 19-8-,3
`
`The
`Journal of
`Rheumatology
`
`EDITOR
`Duncan A. Gordon
`
`BOOK REVIEW EDITOR
`Peter Lee
`
`ASSOCIATE EDITORS
`Dafna D. Gladman
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`
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`
`an international journal
`founded by Metro A. Ogryzlo
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`David A. Bell, LONDON, ON, CANADA
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`Irvin Broder, TORONTO, ON, CANADA
`W. Watson Buchanan, HAMILTON, ON, CANADA
`David E. Caughey, AUCKLAND, NEW ZEALAND
`T. Derek V. Cooke, KINGSTON, ON, CANADA
`George E. Ehrlich, SUMMIT, NJ, USA
`Georges Fallet, GENEVA, SWITZERLAND
`
`Adel G. Fam, TORONTO, ON, CANADA
`Irving H. Fox, ANN ARBOR, MI, USA
`Antonio Fraga, MEXICO CITY, MEXICO
`James F. Fries, STANFORD, CA, USA
`Osvaldo Garcia-Morteo, BUENOS AIRES, ARGENTINA
`J. Philip Gofton, VANCOUVER, BC, CANADA
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`
`Copyright 1984. All rights reserved.
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`Graham R. V. Hughes, LONDON, ENGLAND
`Gene G. Hunder, ROCHESTER, MN, USA
`Edward C. Keystone, TORONTO, ON, CANADA
`Peter E. Lipsky, DALLAS, TX, USA
`Alphonse T. Masi, PEORIA, IL, USA
`Frederick C. McDuffie, ATLANTA, GA, USA
`Henri Menard, SHERBROOKE, PQ, CANADA
`John Mills, BOSTON, MA, USA
`Alastair G. Mowat, HEADINGTON, OXFORD, ENGLAND
`Kenneth D. Muirden, MELBOURNE, AUSTRALIA
`Eimar Munthe, OSLO, NORWAY
`C. Kirk Osterland, MONTREAL, PQ, CANADA
`Kenneth P. H. Pritzker, TORONTO, ON, CANADA
`Donald Resnick, SAN DIEGO, CA, USA
`Anthony S, Russell, EDMONTON, AB, CANADA
`H. Ralph Schumacher, Jr., PHILADELPHIA. PA, USA
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`
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`ISSN 0315-162X
`
`Ex. 1081 - Page 2
`
`

`

`Lahti maletial may be protected by Copyright law (Title IT U.S. ,rdal
`
`A Controlled Two-Centre Trial of Parenteral Methotrexate
`Therapy for Refractory Rheumatoid Arthritis
`ROBERT N. THOMPSON, CRAIG WATTS, JACK EDELMAN, JOHN ESDAILE, and
`ANTHONY S. RUSSELL
`
`Abstract. Forty-eight patients with rheumatoid arthritis refractory to other treatments
`were studied in a placebo controlled trial of methotrexate (MTX) in 2 institutions. Once
`weekly for 6 weeks, the patients were injected with placebo (Group 1), MTX 10 mg
`(Group 2), or MTX 25 mg (Group 3). Then, for the next 6 weeks, Group 1 received
`MTX, either 10 or 25 mg/wk, and Groups 2 and 3 continued their same dose. Adverse
`reactions necessitated change from 25 mg to 10 mg in some patients, but no major side
`effects of MTX were noted. At 6 weeks, the effect of the 2 MTX doses did not differ sig-
`nificantly but patients on MTX had fared significantly better (p < 0.005 - < 0.001)
`than those given placebo. At 12 weeks, all indices showed significant improvement in
`Group 1 and maintenance or enhancement of the improvement in Groups 2 and 3. We
`conclude that weekly low dose MTX therapy is efficacious for refractory rheumatoid ar-
`thritis.(J Rheurnatol 1984; 11:760-763)
`
`Key Indexing Terms:
`METHOTREXATE
`CLINICAL TRIAL
`
`RHEUMATOID ARTHRITIS
`PARENTERAL METHOTREXATE
`PARENTERAL THERAPY
`
`The antimetabolite methotrexate (MTX) binds to
`dihydrofolate reductase, depleting tetrahydrofolate
`and interfering with DNA synthesis'. Its use is well
`established in cancer chemotherapy and, in low doses,
`in the management of psoriasis and psoriatic arthropa-
`thy2-4. Its efficacy in patients with rheumatoid arthritis
`(RA) has been suggested in uncontrolled trials of both
`oral and parenteral therapy5-8, but data from controlled
`studies are lacking.
`At the University of Alberta Hospitals we have been.
`giving MTX parenterally to selected patients with RA,:
`usually in a once weekly dose of 25 mg IM, for more.
`than 5 years, and have been impressed with both its
`efficacy and low withdrawal rate9. To document these
`clinical impressions we conducted a shortterm con-
`trolled trial of weekly IM injections of MTX in patients
`whose RA had become refractory to other treatments.
`Because of the clinical bias inherent in a trial of
`therapy in such a variable condition, our study was
`
`From the Rheumatic Disease Unit, University of Alberta, Edmonton, AB,
`and the Rheumatology Division, Montreal General Hospital, Montreal,
`PQ, Canada.
`Supported by the Medical Services Research Institute of Alberta.
`R.N. Thompson, MB, Bch, MRCP, Research Fellow, University of
`Alberta; C. Watts, MD, FRCP(C), Research Fellow, Montreal General
`Hospital; J. Edelman, MB, BS, FRACP, Research Fellow, University of
`Alberta; J. Esdaile, MD, FRCP(C), Professor of Medicine, Montreal
`General Hospital; A.S. Russell, MA, MB, BCh, FRCP(C), Professor of
`Medicine, University of Alberta.
`Address requests for reprints to Dr. A.S. Russell, 9-112 Clinical Sciences
`Bldg, The University of Alberta, Edmonton, AB, T6G 2G3.
`Submitted Apri119, 1984 revision accepted July 19, 1984.
`
`done independently but with the same experimental
`design in 2 hospitals. The hospitals are nearly 2,000
`miles apart, in demographically different areas, and
`serve populations that are, in the main, ethnically dis-
`similar. Before the study, the investigators met to
`establish criteria and clinical indices. After the study,
`the data from both hospitals were integrated and
`analyzed.
`MATERIALS AND METHODS
`Ambulant outpatients over 18-years-old, attending the rheuma-
`tology clinic at the University of Alberta or the Montreal General
`Hospital, who had definite or classical RA with evidence of active
`disease were considered for study. The following selection criteria
`were applied: (1) The condition had failed to respond to gold or pen-
`icillamine or both; (2) Possession of at least 3 of the following: ? 6
`swollen joints; (cid:9)
`6 tender joints, morning stiffness for (cid:9)
`30 min,
`erythrocyte sedimentation rate (ESR; Wintrobe) (cid:9)
`18 mm/h, and
`active vasculitis; (3) No history of significant leukopenia, throm-
`bocytopenia, abnormal results of liver function tests, or alcoholism.
`Our study was explained to the 48 patients who satisfied these cri-
`teria (Table 1), all of whom gave written consent to the trial. All 48
`were taking nonsteroidal antiinflammatory drugs and 10 were taking
`prednisone. No alterations in medication dosages were permitted,
`and local or intraarticular administration of steroids was prohibited
`during the trial. All of the patients were taking contraceptive pre-
`cautions if appropriate.
`Study design. Our study was approved by the Ethics Committee at
`each institution. It consisted of 2 consecutive 6-week periods. Part 1
`(double blind): the patients were randomly allocated to 3 groups, to
`receive 6 once weekly injections 1M placebo (n = 17); (2) MTX 10
`mg (n = 17); (3) MTX 25 mg (n = 14). At 6 weeks the code was
`broken. Part 2 (single blind): placebo patients were allocated alter-
`nately to 10 or 25 mg MTX weekly; patients on 10 mg/wk continued
`the same dose of MTX; patients on 25 mg/wk who had experienced
`
`760 (cid:9)
`
`The Journal of Rheumatology, 11:6, 1984
`
`Ex. 1081 - Page 3
`
`(cid:9)
`(cid:9)
`

`

`Table 1. (cid:9) Characteristics of the 48 patients who entered the study
`
`No. of patients
`
`Sex (M /F)
`
`MTX
`
`Placebo
`
`10 mg/wk
`
`25 mg/wk
`
`17
`
`7 / 1 0
`
`17
`
`3/14
`
`14
`
`2 / 1 2
`
`Age, yr: mean (range)
`
`55.4 (32 -80)
`
`56.0 (28 -75)
`
`52.0(32 -69)
`
`Duration of disease, yr: mean (range)
`
`11.3 (3 -20)
`
`12.9(1 -31)
`
`17.0 (2 -33)
`
`Patients taking prednisone:-S.10 mg/day
`
`2
`
`Previous disease remittive therapy, no.
`of patients
`gold
`D-penicillamine
`chloroquine
`azathioprine
`plasmapheresis
`auranonn
`
`Rheumatoid factor positive
`
`16
`15
`3
`0
`0
`
`14
`
`2
`
`16
`12
`0
`
`0
`2
`
`II
`
`6
`
`14
`II
`5
`
`0
`
`adverse reactions during the first 6 weeks or in whom these now
`developed had their doses reduced to 10 mg/wk; the others con-
`tinued the 25 mg dose.
`Drugs. MTX was reconstituted in concentrations of 10 and 25 mgI
`ml. The MTX and placebo (folic acid) were made up in solutions of
`the same colour, in identical ampoules, and coded. All patients
`received as their first injection 0.5 ml as a test dose.
`Evaluation. Clinical assessments were made at 0, 3, 6 and 12 weeks
`by RNT or JE (Edmonton) and CW (Montreal). Each patient had
`the same assessor throughout the study. We recorded joint tender-
`ness and swelling (scored on a scale of 0-3)10, pain and the examin-
`ing physician's assessment of general health (scored on visual
`analogue scale, 100 being maximum pain or maximum well being,
`respectively); the reported duration of morning stiffness and of
`fatigue, the measured grip strength, and time taken to walk a
`measured 50 ft on the level. Blood was taken weekly before the
`injection for deterthination of hemoglobin and total leukocyte and
`platelet counts. Liver function tests were performed and ESR deter-
`mined every 3 weeks.
`Statistics. The Wilcoxon signed rank test was used to assess
`intragroup changes (Week 0 vs Week 6, and Week 6 vs Week 12)
`and the Wilcoxon rank sum test to assess the significance of differ-
`ences in intergroup differences. A p value of < 0.01 was considered
`significant; no correction is made in Figure 1 or Table 2 for the
`number of variables tested, but multiplying the p value by 8 (i.e., the
`number of variables assessed for improvement) would have this
`effect. The Fisher exact test was used to determine differences in
`toxicity between the 2 doses of MTX. A x2 with Yates' correction
`was used to assess the differences in Table 3.
`In accordance with previous studieslo we arbitrarily designated a
`50% improvement in a variable as a clinically important response.
`The number of subjects in each of the 3 treatment groups who
`achieved this response is shown for each variable in Table 3.
`
`RESULTS
`Forty-six patients completed Part 1 and 42 of these
`completed Part 2. Withdrawal during Part 1 was
`because of stomatitis after the test dose (12.5 mg) in
`one case and herpes zoster in one. The 4 patients who
`
`Pain
`Score
`
`AM
`Stiffness
`(hours)
`
`Global
`Index
`
`Swollen
`Joints
`Score
`
`Grip
`Strength
`(mmHg)
`
`ESR
`(mm/hr)
`
`35 p<0.001
`
`55 ]
`Joint (cid:9)
`Tenderness
`Score (cid:9)
`15 P<0.002
`35]
`
`----------
`
`15
`150]
`
`100 P<0.005 (cid:9)
`
`2-
`
`25"p<0.001
`
`--T
`
`0 (cid:9)
`
`6
`
`Single Blind
`
`12
`
`3 (cid:9)
`Double Blind (cid:9)
`
`Placebo Controlled (cid:9)
`WEEKS
`Fig. I. Changes (mean ± SE) in scores for pain, morning stiffnes,
`general health (global index), joint tenderness, and joint swelling,
`and for measured grip strength and ESR. Thep values are for differ-
`ences between placebo and MTX at 6 weeks. 0-0) placebo; 0- - -0
`placebo for 6 weeks then MTX for 6 weeks; •—• MTX
`throughout.
`
`withdrew during Part 2 did so for reasons unrelated to
`MTX (herniorraphy, peptic ulcer, fracture, and
`bereavement).
`
`lhompson, et al: MTX therapy in RA
`
`761
`
`Ex. 1081 - Page 4
`
`(cid:9)
`

`

`Table 2. Clinical measurements and ESR at 6 weeks in patients receiving placebo or MTX (mean ± SD)
`
`Clinical or
`Laboratory Variable
`Pain score (0-100 mm, visual analogue scale)
`Duration of morning stiffness (h)
`Global index (0-100 mm, visual analogue scale)
`Joint tenderness score
`Swollen joints score
`Measured grip strength (mm/Hg)
`Time to walk 50' (sec)
`ESR (Wintrobe) mm/h
`* 2 patients withdrawn before 6 wk
`
`Placebo
`(n = 17)
`On Entry
`
`61 -±20
`2.1 ± 1.4
`45±19
`46 ±23
`26 ± I 5
`109 ±7
`13.5±5.3
`40 ±13
`
`6 wk
`65±20
`3.8 ±2.0
`
`38±25
`55 ±29
`35±18
`97 ±7
`14.2 ±4 9
`43 ±13
`
`MTX
`10 or 25 mg/wk
`(n = 31)*
`On Entry
`60 ±18
`2.7 ±I.9
`48 ±20
`36 ±32
`22=1:13
`113 ±8
`13.511:6.0
`35±15
`
`6 wk
`33 ±24
`0.9±1.5
`69 ±23
`25±32
`18:1:15
`126 ±8
`12.6±5.0
`29±14
`
`p
`<0.001
`<0.005
`<0.001
`<0.002
`<0.001
`<0.005
`NS
`<0.001
`
`Table 3. Number qf patients with a clinically important degree of improvement (:,?-50 96)after
`6 weeks' therapy
`
`Variable
`
`Placebo
`
`0
`2
`
`Pain score
`Joint swelling
`Joint tenderness
`Global assessment
`am stiffness
`Fatigue
`Walking time
`Grip strength
`ESR*
`No. in each group
`* ESR decrease by ..?.--'30% included
`t Compared to placebo
`
`2
`3
`0
`0
`0
`17
`
`10 mg
`MTX
`
`8
`5
`6
`10
`10
`4
`0
`1.
`
`17
`
`pt
`
`p <0.01
`p <0.05
`NS
`p <0.01
`p <0.01
`NS
`NS
`NS
`p<0.0I
`
`25 mg
`MTX
`
`5
`
`6
`6
`7
`6
`0
`2
`6
`12
`
`pt
`
`p<0.05
`NS
`p<0.05
`p<0.0I
`p<0.0I
`NS
`NS
`NS
`p <0.005
`
`No side effects of placebo were noted. Toxic effects
`developed in 14 patients receiving MTX, all within 6
`weeks after the first injection. Seven patients com-
`plained of nausea within 24 h after an injection (10 mg
`in 3 and 25 mg in 4), lasting up to 48 h. In 5, the nausea
`was mild and it resolved when the dose was reduced to
`10 mg (n = 2) or antiemetic medication was given; in
`the other 2, severe nausea accompanied by lethargy
`persisted but the patients elected to continue the 25
`mg dose. In 2 patients, a transient increase in serum
`concentrations of liver enzymes, without referable
`symptoms, resolved without change in the MTX dose.
`Mild leukopenia (WBC, > 3.2 x 109/0 developed in
`one patient and thrombocytopenia (platelets, < 100 x
`109/0 in one during receipt of the 25 mg dose that
`resolved after reduction of the dose to 10 mg. One of
`12 female patients on 25 mg/wk developed amenor-
`rhoea. During the 12 week study 4/23 patients
`receiving MTX 10 mg/wk experienced one or more
`side effects compared with 10/25 patients on MTX 25
`mg/wk (p = 0.32 Fischer Exact Test).
`At 6 weeks the MTX treated group showed evi-
`
`dence of significant improvement in scores for pain,
`duration of morning stiffness, joint tenderness, joint
`swelling, fatigue, the observer's assessment of their
`general condition, and in measurements of grip
`strength and ESR (Figure 1, Table 2) but no signifi-
`cant improvement in walking time compared with the
`placebo group. The indices measured at 6 weeks also
`showed a significant improvement over baseline
`values for both MTX groups considered individually
`< 0.05 except for walking time). Patients on a 10
`mg dose fared slightly better than those receiving 25
`mg in almost all indices, although these differences
`were neither clinically nor statistically significant.
`Both groups fared significantly better than placebo in
`most indices, but the power of the intergroup study
`was less than 0.8, and a significant difference between
`the 2 MTX groups could well have been missed. At 12
`weeks, MTX treated patients had maintained or
`enhanced their improvement and patients changed
`from placebo to MTX (either dose) showed evidence
`of significant improvement in the indices studied.
`The number of patients attaining a 50% improve-
`
`762 (cid:9)
`
`The Journal of Rheumatology, 11:6, 1984
`
`Ex. 1081 - Page 5
`
`

`

`went for each variable is listed in Table 3. In this table
`the 2 groups of MTX have been separated, so that
`comparison between the groups and with other drug
`regimes''' can be made more easily.
`
`DISCUSSION
`Both azathioprine and cyclophosphamide can dimin-
`ish disease activity in patients with RA11.'2. Cyc-
`lophosphamide in particular is now rarely used
`because of early side effects and the risk of late neo-
`plasia'3-16. Our results confirmed previous reports of
`uncontrolled trials in which MTX decreased the signs
`and symptoms of inflammation in patients with RA. A
`statistically significant improvement was noted within
`the MTX groups at 6 weeks and appeared to progress
`further during the subsequent single blind part of our
`study. Nevertheless, the proportion of patients with an
`improvement of 50% or greater in each variable at 6
`weeks is comparable with the number seen for gold
`sodium thiomalate or auranofin at 6 months'''. It
`appears to act much more rapidly than other remis-
`sion-inducing agents (e.g., chloroquine, gold salts, pen-
`icillamine, levamisole and azathioprine), and its effect
`wears off more rapidly. It is rarely possible to space
`injections at intervals longer than 3 weeks without
`inducing an immediate flare in disease activity.,
`Whether the progression of erosive changes can be
`altered is not known. Our pilot studies with this drug
`have shown a lower withdrawal rate after a mean of
`2.5-year followup, compared with gold or penicil-
`lamine9. That all of these patients had previously
`relatively resistant disease is testimony to the efficacy
`of MTX as well as, its relative freedom from side effects
`in the shortterm, provided the patients are well
`selected.
`The risk of cirrhosis is the major uncertainty. We
`were heartened by the marked reduction in this side
`effect in patients with psoriasis when a weekly regime
`was used and patients with a heavy alcohol intake were
`excluded". We hope too, by using parenteral therapy,
`to avoid a "first-pass" effect on the liver and thus
`further reduce the risk of cirrhosis, although active
`biliary concentration may vitiate this. No biopsy
`abnormalities were seen in 69 patients with RA who
`received shortterm MTX therapy for RA'8.
`The data obtained in our study did not show any dif-
`ference in efficacy between 10 and 25 mg doses, and
`the 10 mg dose may lessen the risk of adverse reac-
`tions. Nevertheless, we believe that MTX should not
`be widely recommended at present as therapy for RA
`until more is known about the longterm risks of cir-
`rhosis and neoplasia.
`
`ACKNOWLEDGMENT
`The authors thank Drs. J.S. Percy and P. Davis (University of
`Alberta) and Drs. H. Tannenbaum, A. Gutkowski, and P.
`McCracken (Montreal General Hospital), who allowed us to treat
`patients under their care. Miss V. Elias, pharmacist in the University
`of Alberta Hospitals, prepared the test solutions. Dr. M. Grace,
`University of Alberta, performed the statistical analyses. Miss U.F.
`Matthews helped prepare this report.
`
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