1 December 1993
`
`Volume 119
`
`Number 11
`
`of Internal Medicine
`
`P ublished Twice (cid:9)
`
`Published Twice Monthly by the American College of Physicians
`
`a Letters 1148
`Sarcoidosis, Liver
`Transplantation, and
`Cyclosporine
`Association of Cytomegalovirus
`Infection and Penile Ulcer
`Successful Immunosuppressive
`Treatment of High-Titer
`Postpartum Factor VIII Inhibitor
`
`Hepatotoxicity Complicating
`Flutamide Treatment of
`Hirsutism
`When and Whom To Screen
`
`a The Literature of
`Medicine
`1153
`
`CC .e c a
`
`CO C
`
`Cf,
`'U s
`131, "6"
`Ed) 7)
`tt)
`
`c 4 Lu
`
`a ARTICLES
`The Effect of Inhibition of 5-Lipoxygenase by Zileuton in (cid:9)
`Mild-to-Moderate Asthma
`
`Hydroxychloroquine Compared with Placebo in
`Rheumatoid Arthritis: A Randomized Controlled Trial
`
`1059 Israel, Rubin, Kemp,
`Grossman, and others
`
`1067 Clark, Casas, Tugwell,
`Medina, and others
`
`An Outbreak of Gram-negative Bacteremia Traced
`to Contaminated 0-Rings in Reprocessed Dialyzers
`
`1072 Flaherty, Garcia-
`Houchins, and others
`Occurrence of Antibodies to Borrelia burgdorferi in Patients 1079 Kaell, Redecha, Elkon,
`with Nonspirochetal Subacute Bacterial Endocarditis (cid:9)
`Golightly, and others
`
`Coronary Revascularization after Myocardial Infarction in (cid:9)
`the Very Elderly: Outcomes and Long-Term Follow-up
`
`1084 Krumholz, Forman,
`Kuntz, Bairn, and Wei
`
`n BRIEF REPORT
`Interferon-cab: A New Treatment for Polycythemia Vera (cid:9)
`
`1091 Silver
`
`▪ REVIEWS
`Primary Central Nervous System Lymphoma
`
`Efficacy and Cost of Low—Molecular-Weight Heparin
`Compared with Standard Heparin for the Prevention
`of Deep Vein Thrombosis after Total Hip Arthroplasty
`
`▪ NIH CONFERENCE
`Syndromes of Glucocorticoid Resistance
`
`1093 Fine and Mayer
`
`1105 Anderson, O'Brien,
`Levine, Roberts,
`Wells, and Hirsh
`
`1113 Chrousos and others
`
`111 POSITION PAPER
`Generating More Generalists: An Agenda of Renewal for (cid:9)
`Internal Medicine
`
`1125 Federated Council for
`Internal Medicine
`
`n PERSPECTIVE
`The Future of Internal Medicine
`
`a HISTORY OF MEDICINE
`Getting into Medical School in the Good Old Days:
`Good for Whom? The First Nicholas E. Davies Memorial
`Lecture
`
`MI EDITORIALS
`What Is the Future of Internal Medicine?
`
`Hydroxychloroquine Is Safe and Probably Useful in
`Rheumatoid Arthritis
`
`1130 Petersdorf and Goitein
`
`1138 Brieger
`
`1144 Fletcher and Fletcher
`
`1146 Harris
`
`For complete contents, see pages 1-3 and 1-4. For subscription information, see page 1-7. Canadian
`GST ID# 128512159 • AIMEAS 119(11)1059-1154(1993) • US ISSN 0003-4819
`
`Sandoz v. AbbVie
`Sandoz Ex. 1078
`
`Ex. 1078 - Page 1
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`1 December 1993
`
`HEAL (cid:9)
`CES LIBRARY
`University of Wisconsin
`
`Annals of Internal Medicine Table of Contents (cid:9)
`
`NOV 2 9 1993
`
`Volume 119 Number 11 AIMEAS 119(11)1059-1154(1993) US ISSN 0003-4819
`
`Madison,den Drive
`Wi 53105
`
`Articles
`
`The- Effect of Inhibition of 5-Lipoxygenase by (cid:9)
`Zileuton in Mild-to-Moderate Asthma
`E. Israel, P. Rubin, J.P. Kemp, .1. Grossman,
`W Pierson, S. C. Siegel, D. Tinkelman,
`J 1. Murray, W. Busse, A. T. Segal, J. Fish,
`H.B. Kaiser, D. Ledford, S. Wenzel,
`B. Rosenthal, J. Cohn, C Lanni, IL Pearlman,
`p. Karahalios, and J.M. Drazen
`
`1059
`
`Coronary Revascularization after Myocardial (cid:9)
`Infarction in the Very Elderly: Outcomes and
`Long-Term Follow-up.
`H.M. Krumholz, D.E. Forman, R.E. Kuntz,
`I). S. Bairn, and J.Y Wei
`
`1084
`
`A small percentage of very elderly patients with complicated
`acute myocardial infarction, selected by their physicians for
`invasive cardiovascular procedures, can tolerate these
`procedures, avoid serious complications, return to independent
`living, and have excellent probability of survival.
`
`Inhibition of 5-lipoxygenase using zileuton can improve airway
`function in persons with asthma and can decrease symptoms
`and medication use.
`
`Hydroxychloroquine Compared with Placebo in (cid:9)
`Rheumatoid Arthritis: A Randomized Controlled
`Trial
`P. Clark, E. Casas, P. Tugwell, C. Medina,
`C. Gheno, G. Tenorio, and J.A. Orozco
`
`Hydroxychloroquine is moderately effective in early
`rheumatoid arthritis. Side effects were mild, and no patients
`in the hydroxychloroquine group required discontinuation of
`therapy.
`
`Brief Report
`
`1067
`
`Interferon-a2b: A New Treatment for
`Polycythemia Vera
`R. T. Silver
`
`1091
`
`Red cell values can be controlled with recombinant interferon-
`a2b within 6 to 12 months, eliminating the need for
`phlebotomy in patients with polycythemia vera.
`
`Reviews
`
`An Outbreak of Gram-negative Bacteremia
`Traced to Contaminated 0-Rings in Reprocessed
`Dialyzers
`J.P. Flaherty, S. Garcia-Houchins, R. Chudy,
`and P.M. Arnow
`
`Primary Central Nervous System Lymphoma (cid:9)
`H.A. Fine and R.J. Mayer
`
`1072
`
`1093
`
`Lymphoma of the primary central nervous system is probably
`a substantially different disease in persons with and without
`AIDS in regard to patient characteristics, clinical and
`radiographic presentation, and prognosis.
`
`Because dialyzers with removable headers and 0-rings are
`widely used in patients receiving long-term hemodialysis,
`disinfection procedures should include measures to ensure
`adequate disinfection of 0-rings.
`
`Occurrence of Antibodies to Borrelia burgdorferi 1079
`in Patients with Nonspirochetal Subacute
`Bacterial Endocarditis
`A.T. Kaell, P.R. Redecha, K.B. Elkon,
`M.G. Golightly, P.E. Schulman, R.J. Dattwyler,
`D.L. Kaell, R.D. Inman, C.L. Christian, and
`D.J. Volkman
`
`Although a positive serologic test result for B. burgdorferi may
`be a true-positive result, it does not ensure that the clinical
`problem is due to Lyme borreliosis.
`
`Efficacy and Cost of Low—Molecular-Weight (cid:9)
`Heparin Compared with Standard Heparin for the
`Prevention of Deep Vein Thrombosis after Total
`Hip Arthroplasty
`D.R. Anderson, B.J. O'Brien, M.N. Levine,
`R. Roberts, P.S. Wells, and J. Hirsh
`
`1105
`
`Low—molecular-weight heparin is more effective and is at least
`as safe as standard heparin for the prevention of deep vein
`thrombosis after total hip arthroplasty.
`
`(Continued on page 1-4)
`
`Postmaster: Send changes of address to Circulation Manager, Annals of Internal Medicine, Independence Mall West, Sixth Street at Race,
`Philadelphia, PA 19106-1572.
`1993 by the American College of Physicians, Independence Mall West,
`Annals of Internal Medicine is published twice monthly and copyrighted (cid:9)
`Sixth Street at Race, Philadelphia, PA 19106-1572, USA. Basic USA subscription price is $84.00 per year. Second-class postage paid at Philadelphia,
`Pennsylvania, and at additional mailing offices. Canada Post International Publications Mail Sales Agreement #546186. GST ID#128512159.
`
`1 December 1993 • Annals of Internal Medicine • Volume 119 • Number 11 1-3
`
`Ex. 1078 - Page 2
`
`(cid:9)
`(cid:9)
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Itydroxychloroquine Compared with Placebo in
`Rheumatoid Arthritis
`A Randomized Controlled Trial
`
`Patricia Clark, MD; Emilio Casas, MD; Peter Tugwell, MD; Clementina Medina, BSc;
`Coizstanza Gheno, RN; Guadalupe Tenorio, MD; and Jose Antonio Orozco, MSc
`
`• Objective: To assess the efficacy of hydroxychloro-
`quine, 400 mg daily, for rheumatoid arthritis.
`▪ Design: Six-month, double-blind, randomized trial.
`g Setting: Ambulatory referral clinic in a Mexico City,
`Mexico, teaching hospital.
`▪ Patients: A total of 126 patients with early rheuma-
`toid arthritis were randomly assigned to receive hy-
`droxychloroquine, 400 mg/d, or placebo; 121 patients
`completed the study.
`• Results: Hydroxychloroquine showed a clinically
`and statistically significant improvement over placebo
`in joint score (20% greater mean improvement; 10%
`more patients improved by >50%); pain (40% greater
`mean improvement; 19% more patients improved by
`>50%); grip strength (22% greater mean improvement;
`21% more patients improved by >50%); patient global
`assessment (16% more patients stated they had im-
`proved); and physician global assessment (12% more
`patients were judged to have improved). Side effects
`were mild, and no patients in the hydroxychloroquine
`group required discontinuation of therapy. Patient
`compliance with the study medication was high.
`III Conclusion: Hydroxychloroquine is moderately ef-
`fective in early rheumatoid arthritis.
`
`Ann Intern Med. 1993;119:1067-1071.
`
`From Universidad Nacional Autonoma de Mexico and the
`Hospital General de Mexico, Mexico City, Mexico; and Ot-
`tawa General Hospital and the University of Ottawa, Ottawa,
`Canada. For current author addresses, see end of text.
`
`Antimalarial agents have been used to treat some
`rheumatic diseases such as lupus erythematosus since
`the 1800s (1). In 1951, Page (2) first suggested using
`antimalarial agents in patients with other connective
`tissue diseases, describing remission of "associated
`rheumatoid arthritis" in his series of patients. Several
`(13uble-blind, placebo-controlled trials testing antimalar-
`ial drugs in rheumatoid arthritis were conducted in the
`1950s and the early 1960s (3-10). These studies pro-
`duced controversial, widely ranging evidence of effi-
`cacy. In 1989, Rynes (11) noted that the best existing
`published trial of hydroxychloroquine (9) used twice the
`currently recommended daily dose and recommended
`"additional studies of drug effectiveness using the less
`toxic, lower daily doses now prescribed." We felt that
`
`a new trial was therefore needed to provide a more
`accurate estimate of benefit and to allow use of better
`standardized outcomes and minimization of many of the
`potential biases that may have been present in the pre-
`vious studies (12). We conducted a randomized con-
`trolled trial of hydroxychloroquine compared with pla-
`cebo in patients with early rheumatoid arthritis to
`reassess the effectiveness and safety of this drug in
`patients with early, nonaggressive disease.
`
`Methods
`
`Our 24-week, randomized, double-blind, parallel trial com-
`pared hydroxychloroquine, 400 mg/d, with placebo. Hydroxy-
`chloroquine was supplied as 400-mg tablets; placebo tablets
`were identical in shape, taste, and color to the test drug. A
`total of 126 consecutive patients with rheumatoid arthritis
`(American. Rheumatism Association revised criteria, 1987) (13),
`attending the outpatient consultation clinic of the Rheumatol-
`ogy Service, Hospital General de Mexico, from June 1989 to
`August 1991, were enrolled in the study.
`Inclusion criteria included 5 or fewer years since diagnosis
`of disease; age of 18 years or older; onset of rheumatoid
`arthritis after age 16 years; five or more actively inflamed
`joints; and unsuccessful treatment with at least two nonsteroi-
`dal anti-inflammatory drugs or salicylates. Exclusion criteria
`included current or previous treatment with second-line drugs
`or cytotoxic agents; current use of steroids; rheumatoid arthri-
`tis functional class IV; and refusal to give informed consent.
`Disease activity was clinically assessed at study entry and
`every 4 weeks for a period of 24 weeks (7 visits) (14). Patients
`were examined by the same observer throughout the trial, who
`was blinded to the knowledge of whether the study drug or
`placebo was being administered.
`Assessments included a joint score (the sum of joint swelling
`score [58 joints graded on a scale of 0 to 3] and a pain and
`tenderness score [60 joints graded on a scale of 0 to 31) (15).
`The joint score (16) was designated as the primary outcome
`before the start of the study. Patients assessed their joint pain
`using a visual analog scale consisting of a 10-cm horizontal line
`labeled "no pain" at the left side and "maximum imaginable
`pain" at the right side. Grip strength was assessed using, a
`mercury-column sphygmomanometer with a standard grip bag.
`Patients' global assessment of their disease activity was graded
`on a scale of 1 = asymptomatic, 2 = mild, 3 = moderate, 4 =
`severe, and 5 = very severe. Physicians' assessment of global
`efficacy was graded on a scale of 1 = marked improvement,
`2 = moderate improvement, 3 = the same, 4 = moderate
`worsening, and 5 = marked worsening.
`The hematocrit, leukocyte count, platelet count, and rheu-
`matoid factor for each patient were assessed at entry. The
`Wintrobe erythrocyte sedimentation rate was tested every 4
`weeks.
`Every patient was questioned at each visit to determine
`compliance with prescribed nonsteroidal anti-inflammatory
`drugs and test medication. In addition, pill counts of the test
`drug were done.
`An ophthalmic examination, including slit-lamp analysis (17),
`
`01993 American College of Physicians 1067
`
`Ex. 1078 - Page 3
`
`

`

`was done by an ophthalmologist at entry and at the end of the
`study. The Amster grid (18) was provided to every patient with
`instructions for daily use.
`
`Statistical Analysis
`
`The sample size was estimated at 52 per group based on an
`alpha error rate of 0.05; a beta error rate of 0.2; a delta on the
`joint score of 7; and a standard deviation of 12. Statistical
`analysis compared results of treatment on several variables of
`interest. For joint score, grip strength, morning stiffness, pain
`assessment, and the individual differences between the last
`visit and baseline for each patient were computed. These
`"treatment differences" were then used to compare grouped
`drug effects after having adjusted for individual imbalances at
`baseline. Unpaired t-tests and multiple regression analysis
`were used to compare the mean values of the treatment dif-
`ferences for each group. The assumption of normality was
`tested with the Anderson-Darling statistic A2 (19), which has
`been reported as having good power properties. When the
`goodness-of-fit test rejected the hypothesis of normally distrib-
`uted data, the Mann-Whitney nonparametric test was used.
`Chi-square tests were used to compare differences in propor-
`tions and frequencies of the clinical variables (physician and
`patient assessment, functional class, anatomic stage, and phy-
`sician and patient efficacy). The natural logarithm of rheuma-
`toid factor was used to transform the titers to a normal distri-
`bution. The statistical analysis was done using BMDP
`Statistical Software version PC-1987 (BMDP Statistical Soft-
`ware, Inc.; Los Angeles, California).
`
`Results
`
`A total of 126 patients fulfilled the entry criteria and
`were admitted to the study, and 101 (80.2%) completed
`the trial. Twenty-five patients dropped out (19.8%), 14
`of the 61 (23.0%) on placebo and 11 of the 65 (16.9%)
`on hydroxychloroquine. The reasons for withdrawal
`from the study were as follows: Two patients moved, 1
`patient became pregnant during the study, 1 patient
`developed severe anemia, 1 patient had severe depres-
`sion, 5 patients did not return because of economic
`problems, and 15 did not return for unknown reasons.
`Twenty of these patients were included in the intent-to-
`treat analysis. Five patients did not return for the sec-
`ond visit and thus had no variables available to analyze,
`even for the intent-to-treat analysis. The final, analysis
`was based on 121 patients, using the last assessment
`available. Compliance with taking the study tablets was
`excellent: Only 95 out of 20 160 tablets were not taken
`based on pill counts and patient questionnaires.
`The two groups did not differ significantly in demo-
`graphic characteristics, duration of disease, or labora-
`tory test results (Table 1). Table 2 shows the mean
`changes (with CIs) in the continuous clinical variables
`(joint score, pain [visual analog scale], and grip
`strength) between the beginning and end of the trial. All
`three variables were statistically significant. The pri-
`mary end point—joint score—showed a clinical and sta-
`tistical significant improvement favoring the hydroxy-
`chloroquine group. The hydroxychloroquine group had
`a mean reduction of 18.5 active joints compared with
`11.9 in the placebo group at the end of the study, giving
`a difference between groups of 6.6 active joints favoring
`the hydroxychloroquine group (P = 0.03). Patient and
`physician global assessment also offered the following
`information: patient (hydroxychloroquine: improved,
`64%; no change, 28%; worse, 8%; placebo: improved,
`
`45%; no change, 34%; worse, 22%); and physician (hy-
`droxychloroquine: improved, 89%; no change, 5%;
`worse, 6%; placebo: improved, 73%; no change, 19%;
`worse, 7%). Global assessment scores were also statis-
`tically different at the 0.05 level, favoring the hydroxy-
`chloroquine group. Figure 1 shows the monthly data for
`the 101 patients who continued to be followed at these
`time points. No changes were noted in the number of
`nonsteroidal anti-inflammatory agents and aspirin anal-
`gesics consumed. The erythrocyte sedimentation rate
`and the natural logarithm of the rheumatoid factor
`showed no differences between the two groups.
`Side effects occurred in 56 patients (46%), 28 in the
`active group and 28 in the placebo group. All side
`effects were minor except in 1 patient who had severe
`anemia and had to be withdrawn from the study; this
`patient was on placebo. Of these 56 patients, 32 had
`one side effect; 19 patients, two different side effects;
`and only 5 patients, three or more side effects. A total
`of 91 reactions were recorded (Table 3). No ocular
`toxicity was detected.
`
`Discussion
`
`This study was designed to test as homogeneous a
`group as possible with mild disease unresponsive to
`nonsteroidal therapy, the group for which the textbooks
`recommend it (i1). This was satisfactorily accomplished
`as evidenced by 80% of patients being functional class
`1; 40%, being rheumatoid factor positive; and 93%,
`having five or fewer radiographic erosions. A clinically
`and statistically significant benefit was observed in val-
`idated clinical outcomes known to be responsive to
`change in clinical trials of rheumatoid arthritis (20).
`Many previous controlled (3-10, 12) and uncontrolled
`(21-24) trials of hydroxychloroquine have been con
`ducted, with differing results. Controversy exists con-
`cerning the benefits of hydroxychloroquine compared
`with other second-line agents. Some authors have sug-
`gested (25-27) that the degree of response seen with
`currently recommended doses of hydroxychloroquine is
`
`Table 1. Characteristics at Entry for Patients Complet-
`ing Trial by Treatment Group*
`
`Characteristics
`
`Hydroxy- (cid:9)
`chloroquine
`
`Placebo
`
`Patients, n
`Male/female, nIn
`Age (mean), y
`Duration of disease (mean), ma
`Functional class, %
`1
`2
`3
`Rheumatoid factor >1:40, %
`Joint score (mean)
`Pain (mean), mm
`Erythrocyte sedimentation rate
`(mean), mm/h
`Radiographic erosions, %
`0 to 1
`2 to 5
`>5
`
`65
`4/61
`39
`30
`
`80
`16
`4
`48
`25.8
`46.3
`35.7
`
`68
`26
`6
`
`* All differences are not significant at P = 0.05.
`
`65
`6/55
`36
`27.9
`
`82
`14
`2
`49
`22.9
`40.G
`37.5
`
`80
`18
`2
`
`1068 1 December 1993 • Annals of Internal Medicine • Volume 119 • Number 11
`
`Ex. 1078 - 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)
`(cid:9)
`(cid:9)
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`Table 2. Mean Changes in Clinical Variables between Beginning and End of Trial
`
`Change
`
`Joint
`Score
`
`Hydroxychloroquine
`Grip
`Pain
`Strength
`
`mm
`
`mm Hg
`
`Erythrocyte
`Sedimenta-
`tion Rate
`mm/h
`
`Joint
`Score
`
`Placebo
`Pain
`
`Grip
`Strength
`
`mm
`
`mm Hg
`
`Erythrocyte
`Sedimenta-
`tion Rate
`mmlh
`
`o week
`24 weeks
`Mean change
`95% CI
`Mean
`improve-
`ment, %
`Patients with
`>25%
`improve-
`ment, %
`Patients with
`>50%
`improve-
`ment, %
`P value*
`
`40.6
`35.7
`37.5
`106.1
`22.9
`100.4
`46.3
`25.8
`33.2
`34.1
`30.1
`116.8
`11.0
`132.3
`20.5
`7.35
`-4.3
`-6.5
`+103
`-11.9
`-5.6
`+31.9
`-25.8
`-18.5
`-15.1 to -21.8 -18.7 to -32.9 28.5 to 35.2 -2.2 to -8.9 -8.6 to -15.2 -14.8 to 1.8 -1.2 to 22.6 -L2 to -7.4
`
`72
`
`80
`
`56
`
`66
`
`32
`
`47
`
`16
`
`35
`
`71
`0.03
`
`50
`<0.001
`
`40
`0.01
`
`18
`>0.2
`
`52
`
`71
`
`61
`
`16
`
`51
`
`31
`
`10
`
`29
`
`19
`
`11
`
`25
`
`5
`
`P value comparing use of hydroxychloroquine and placebo.
`
`similar to that seen with gold (both intramuscular and
`oral), D-penicillamine, and azathioprine. On the other
`hand, a 2-year, double-blind study conducted at the
`Mayo Clinic (28), comparing hydroxychloroquine and
`D-penicillamine, showed that D-penicillamine was supe-
`rior to hydroxychloroquine at 6 months. 'The controlled
`trials have had methodologic flaws such as the use of a
`heterogeneous rheumatoid study sample in terms of dis-
`ease severity and activity and inclusion criteria (3-5,
`7-8, 12). Some trials used hydroxychloroquine (7-9)
`and others used chloroquine (3-6, 10); different doses
`were tested or doses were not standardized (7-9); or
`baseline differences existed between active and control
`groups (3, 4, 6, 7, 12). Some studies were not blinded
`(6, 7, 9); the sample size in some was small (4, 5); and
`the end points were not standardized.
`These problems have led many clinicians not to use
`hydroxychloroquine. A survey in the United States in
`1987 showed that only 16 of 91 rheumatologists (18%)
`and 4 of 63 internists (6%) selected hydroxychloroquine
`as their first choice of a second-line agent in patients
`who failed to respond to nonsteroidal anti-inflammatory
`agents (29). Pullar (30), in reviewing the choice of sec-
`ond-line therapy in the United Kingdom, stated; "Most
`British Rheumatologists would probably agree that so-
`dium aurothiomalate is the most effective of the stan-
`dard agents, with sulfasalazine and penicillamine similar
`to each other and next in ranking order and with anti-
`malarials the least effective." Brooks and colleagues
`(31) surveyed Australian rheumatologists in 1984 and
`1989 and found that antimalarial agents were used "of-
`ten" by 54% in 1984 and by 60% in 1989 in comparison
`with gold being used "often" by 94% in 1984 and by
`89% in 1989. The recent meta-analyses by Felson and
`colleagues (25) based on both comparative and placebo-
`controlled studies of both hydroxychloroquine and chlo-
`roquine suggest that antimalarial drugs are more effec-
`tive than are azathioprine and auranofin. Our study
`increases the precision of the Felson meta-analysis es-
`
`timate and may provide useful evidence on the efficacy
`of currently recommended doses of interest to rheuma-
`tologists and internists considering whether to prescribe
`it.
`The side effects caused by hydroxychloroquine were
`minor and transient, occurring in 28 patients in the
`hydroxychloroquine group and in 28 in the placebo
`group; there were no cases in the active group in which
`the therapy had to be discontinued (see Table 3). Nau-
`sea and epigastric pain were the most frequent and were
`found in 30.2% in the active group and 17.5% on the
`placebo group (P = 0.11); these gastrointestinal com-
`plaints have been reported so far to be the most fre-
`quent reactions and mimic those of nonsteroidal anti-
`inflammatory drugs (32). Headache was also present in
`12.7% in the active group compared with no headache
`in the control group (P = 0.004). The toxicity profile in
`our study did not differ from those of other studies (10,
`12). As expected, no cases of ocular abnormalities oc-
`curred. This type of toxicity, as is well documented, is
`low and has not, to our knowledge, been;reported with
`the doses we used during this length of observation.
`The place of hydroxychloroquine in the sequence of
`slow-acting agents is in early mild disease. The study by
`Davis and colleagues (12) showed that patients with
`very mild disease (synovitis limited to the hands and
`feet, and erythrocyte sedimentation rate <30 mm/h)
`who would normally receive only a nonsteroidal anti-
`inflammatory agent, showed benefit from hydroxychlo-
`roquine. In contrast, our study shows that patients who,
`despite a trial of nonsteroidal anti-inflammatory drugs,
`have widespread synovitis of longer duration, higher
`sedimentation rates, arid a greater degree of disability,
`show clinical benefits.
`Hydroxychloroquine is less toxic than any of the
`other second-line agents (33). Lower toxicity (27) has
`been confirmed in a study using life-table analysis that
`compared hydroxychloroquine to intramuscular gold
`and D-penicillamine.
`
`1 December 1993 • Annals of Internal Medicine • Volume 119 • Number 11 1069
`
`Ex. 1078 - Page 5
`
`

`

`Active Joint Score
`
`Table 3. Side Effects
`
`Side Effect
`
`Hydroxychloroquine Placebo
`(n = 58)
`(n = 63) (cid:9)
`n (%)
`
`_______ +, Placebo
`
`HydroxychloroquIne
`
`4 (cid:9)
`
`8 (cid:9)
`
`12
`Weeks
`
`18
`
`20
`
`24
`
`Patient Assessment of Pain (VAS)
`
`- (cid:9)
`
`Placebo
`
`Hydroxychlorogulne
`
`4
`
`8
`
`12 (cid:9)
`Weeks
`
`18 (cid:9)
`
`20
`
`24
`
`Grip Strength
`
`Hydroxychlorogulne
`
`-I- - - - ---
`Placebo
`
`Nausea or epigastric pain
`Skin rash
`Headache
`Dizziness
`Intestinal cramps
`Hair loss
`Pruritus
`Diarrhea
`Insomnia
`Tinnitus
`Constipation
`Blurred vision
`Hyperpigmentation of skin
`Paresthesia
`Rectorrhagia
`Ageusia
`Anorexia
`Anemia
`Ocular soreness
`
`19 (30)
`2 (3)
`8 (13)
`3 (5)
`1 (2)
`2 (3)
`2 (3)
`2 (3)
`2 (3)
`3 (5)
`1 (2)
`2 (3)
`1 (2)
`1 (2).
`1 (2)
`0 (0)
`1 (2)
`0 (0)
`1 (2)
`
`11 (17)
`6 (9)
`0 (0)
`4 (6)
`4 (6)
`3 (5)
`2 (3)
`2 (3)
`2 (3)
`0 (0)
`1 (2)
`0 (0)
`1 (2)
`1 (2)
`0 (0)
`1 (2)
`0 (0)
`1 (2)
`0 (0)
`
`A related finding is the clinical and statistical im-
`provement of both the placebo as well as the hydroxy-
`chloroquine group during the course of the study. For
`the joint score, our primary variable, the improvement
`in the placebo group of 11.0 joints (P = 0.001) was
`much higher than in most other reported studies of
`slow-acting agents. This finding has been noted in
`other studies of patients with early disease (25); our
`patients were in an early stage of rheumatoid arthritis,
`with a mean duration of disease. of 30 months for the
`hydroxychloroquine group and 27,9 months for the pla-
`cebo group. Because improvement is associated with
`the'-natural history of the disease, it is not surprising in
`view of the relatively short duration of disease in this
`trial compared with patients studied in many of the
`reported trials of slow-acting agents. Even with this
`large placebo effect, however, our results are statisti-
`cally significant in favor of the hydroxychloroquine
`group.
`Our study showed that hydroxychloroquine has mod-
`est but useful benefit in patients with early rheumatoid
`arthritis who would benefit from its relatively low tox-
`icity. It was superior to placebo during a period of 6
`months and offered benefit as the first choice of a sec-
`ond-line agent in patients with early rheumatoid arthritis
`who did not respond to therapy with appropriate non-
`steroidal anti-inflammatory drugs.
`
`Acknowledgments: The authors thank Dr. Alfonse T. Masi for his useful
`suggestions and Ms. Diane Gagnon for preparation of the manuscript.
`
`Grant Support: In part by Sanofi-Winthrop. Company, Mexico City,
`Mexico.
`
`Requests for Reprints: Patricia Clark, MD, MSc, Faculty of Medicine,
`Universidad Nacional Autonoma de Mexico and Hospital General +3e
`Mexico, Unidad de Epidemiologia Clinica, Dr. Balmis, 148 Col. Doc-
`tores, C.P. 06726, Mexico.
`
`Current Author Addresses: Dr. Clark: Faculty of Medicine, Universidad
`Nacional Autonoma de Mexico and Hospital General de Mexico,
`Unidad de Epidemiologia Clinica, Dr. Balmis, 148 Col. Doctores, C.P.
`06726, Mexico.
`Drs. Casas and Tenorio and Ms. Medina, Ms. Gheno, and Mr. Orozco:
`Hospital General de Mexico, Mexico City, Mexico.
`
`28
`24
`22
`20
`18
`18
`14
`12
`10
`a
`8 (cid:9)
`0
`
`Number of Joints
`
`E
`E
`
`50 -
`
`45
`
`40 -
`
`36
`
`30
`
`26
`
`20
`
`
`16 (cid:9)
`0 (cid:9)
`
`136
`
`130
`
`126
`
`120
`
`115
`
`110
`
`106
`
`100 (cid:9)
`0 (cid:9)
`
`
`
`4 (cid:9)
`
`8 (cid:9)
`
`18 (cid:9)
`
`20 (cid:9)
`
`24
`
`12
`Weeks
`Figure 1. Raw mean scores for joint scores, patient assessment of
`pain, and grip strength variables for each visit and each treat-
`ment group. VAS = visual analog scale.
`
`The treatment effect of hydroxychloroquine on joint
`score takes some weeks to separate out from the im-
`provement seen in the placebo group; some authors
`have reported that the maximal benefit may not be
`observed for a year (see Figure 1) (27). Because at 6
`months in our study, the lines (shown in Figure 1)
`between placebo and hydroxychloroquine were continu-
`ing to diverge, it is possible that this benefit will con-
`tinue to increase. In contrast, the benefit in pain relief
`was substantially different between groups beginning
`with the second visit (Figure 1).
`
`1070 1 December 1993 • Annals of Internal Medicine • Volume 119 • Number 11
`
`Ex. 1078 - Page 6
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`Dr. Tugwell: Department of Medicine, University of Ottawa, Ontario,
`Canada K1H 8L6.
`
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