`
`Rheumatology
`
`Fourth Edition
`
`Volume 1
`
`WILLIAM N. KELLEY, M.D.
`Chief Executive Officer
`
`University of Pennsylvania Medical Center
`Executive Vice President and Robert G. Dunlop
`Professor of Medicine and Biochemistry and Biophysics
`University of Pennsylvania
`Dean, University of Pennsylvania School of Medicine
`Philadelphia, Pennsylvania
`
`EDWARD D. HARRIS, Jr., M.D.
`Arthur L. Bloomfield Professor and Chairman
`
`Department of Medicine
`Stanford University School of Medicine
`Stanford, California
`
`SHAUN RUDDY, M.D.
`Elam Toone Professor of Internal Medicine,
`Immunology, and Microbiology
`Chairman
`
`Division of Rheumatology, Allergy, and Immunology
`Department of Internal Medicine
`Medical College of Virginia
`Virginia Commonwealth University
`Richmond, Virginia
`
`CLEMENT B. SLEDGE, M.D.
`
`John B. and Buckminster Brown Professor of Orthopedic Surgery
`Harvard Medical School
`Chairman
`
`Department of Orthopedic Surgery
`Brigham and Women’s Hospital
`Boston, Massachusetts
`
`W.B. SAUNDERS COMPANY
`Harcourt Brace Jovanovlcl, Inc.
`Philadelphia
`London
`Toronto Montreal
`
`Sydney
`
`Tokyo
`
`Page 1 of 14
`
`.
`
`ANTARES Exhibit 1018
`
`ANTARES Exhibit 1018
`
`Page 1 of 14
`
`
`
`W.B. SAUNDERS COMPANY
`Harcourt Brace lovanovich, Inc.
`The Curtis Center
`independence Square West
`Philadelphia, Pennsylvania 19106
`
`Library of Congress Cataloging-in-Publication Data
`
`Textbook of rhcumatology I William N. Kelley .
`4th ed.
`
`.
`
`. [ct al.].—
`
`p.
`
`cm.
`
`for Library of Congress
`
`Includes bibliographical references and indexes.
`
`ISBN 0—7216—3157—6 (set)
`
`1. Rheumatology.
`I. Kelley, William N ., 1939-
`2. Rheumatic Diseases.
`[DNLM:
`1. Arthritis.
`WE 544 T355 1993]
`RC927.T49 1993
`
`616.7'23—dc20
`
`DNLM/DLC
`
`TEXTBOOK OF RHEUMATOLOGY, Fourth Edition
`
`ISBN
`
`0—7216—3155—X
`Volume I
`0-7216-3156-8
`Volume ll
`Two Volume Set 0-7216-3157-6
`
`Copyright © 1993, 1989, 1985, 1981 by W.B. Saunders Company.
`I
`
`All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any
`means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval
`system, without permission in writing from the publisher.
`
`'
`
`Printed in the United States of America.
`
`Last digit is the print number:
`
`9
`
`8
`
`7
`
`6
`
`5
`
`4
`
`3
`
`2
`
`1
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`Page 2 of 14
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`Page 2 of 14
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`
`
`
`Chapter 47
`
`Methotrexate
`
`Michael E. Weinblatt
`
`tions without the need for reduction by the enzyme
`dihydrofolate reductase. Folinic acid (leucovorin) is
`used to "rescue” normal cells from the toxicity in-
`duced by methotrexate. Folinic acid is used as a
`”rescue” agent in cancer chemotherapy and as a
`treatment for acute methotrexate overdose and he-
`
`matologic toxicity.
`Folates in the blood have a single terminal glu-
`tamate structure. Most intracellular folates are me-
`
`tabolized to a polyglutamated compound. These po-
`lyglutamates have longer cellular retention and are
`more efficient cofactors than the monoglutamate
`compound. Similar to the folate cofactors, metho-
`trexate also is metabolized from a monoglutamate to
`a polyglutarnated derivative. Methotrexate polyglu-
`tamates have stronger cellular retention,
`remain
`within the cell in the absence of extracellular drugs,
`and are more potent than the monoglutamate struc-
`ture.‘ The synthesis of the methotrexate polyg1uta-
`mates increases with the duration of therapy. The
`polyglutamated derivatives predominate in hepatic
`tissue, which may be a factor in toxicity. The concen-
`tration of hepatic methotrexate polyglutamates de-
`creases after folinic acid therapy.’
`The mechanism of action of low-dose methotrex-
`ate in rheumatoid arthritis is not known. Whether
`
`its therapeutic effect is due to its antifolate activity,
`immunomodulating properties, immunosuppressive
`properties, or anti-inflammatory effects is under
`Stu y. It is most likely that a combination of these
`factors accounts for its therapeutic profile in rheu-
`matoid arthritis. High-dose methotrexate at doses
`used for cancer therapy has immunosuppressive
`properties including suppression of antibody forma-
`tion and suppression of primary and secondary im-
`mune response? In rheumatoid arthritis, however, a
`profound immunosuppressive effect has not been
`documented with low-dose methotrexate. Neither a
`
`global suppression of T cell function nor changes in
`T cell subsets were re orted in short-term studies in
`
`rheumatoid arthritis. ' 5 After 2 years of therapy,
`however, a si nificant increase in the percentage of
`T3 and T4 celfs and an increase in thymidine incor-
`poration responses to selected mitogens and anti ens
`were noted.‘ These changes may have reflecte
`the
`reduction in prednisone dose and overall improve-
`ment in disease activity that occurred after 2 years of
`drug administration rather than a selective effect of
`the drug.
`The effect of methotrexate on in vivo gamma M
`immunoglobulin (IgM) rheumatoid factor production
`767
`
`Methotrexate has become an established treat-
`
`for rheumatoid arthritis. Low-dose weekly
`ment
`methotrexate was approved by the United States
`Food and Drug Administration in 1988 as a therapy
`for active rheumatoid arthritis. There is also signifi-
`cant interest in low-dose methotrexate as a therapy
`for a variety of other autoimmune,
`inflammatory,
`and rheumatologic conditions.
`
`CHEMICAL STRUCTURE
`
`Methotrexate is an antimetabolite and is a struc-
`
`tural analogue of folic acid. The structure of folic acid
`(pteroylglutamic acid) consists of three elements: a
`multiring pteridine group linked to a para—aminoben-
`zoic acid that is connected to a terminal glutamic acid
`residue (Fig. 47-1). Methotrexate differs from folic
`acid in that an amino group substitutes for a hydroxyl
`group in position 4 of the pteridine portion of the
`molecule and by the addition of a methyl group in
`position 10 of the 4 amino-benzoic acid structure
`(see Fig. 47-1).
`
`BIOCHEMICAL PHARMACOLOGY
`
`Dietary folic acid is reduced enzymatically by
`the enzyme dihydrofolate reductase to both dihydro—
`folate and tetrahydrofolate, which are metabolically
`active reduced folates. These reduced folates are
`
`essential in the conversion of homocysteine to me-
`thionine, in the metabolism of histidine, in the syn-
`thesis of purines, and in the biosynthesis of thymi-
`dylate, which is
`required for DNA synthesis.
`Methotrexate, an antimetabolite, binds and inacti-
`' vates the enzyme dihydrofolate reductase, resulting
`in the depletion of metabolically active intracellular
`folates with subsequent inhibition of the synthesis of
`thymidylate and inosinic acid (Fig. 47-2). Addition-
`ally, methotrexate affects protein synthesis by pre-
`venting the conversion of glycine to serine and ho-
`' mocysteine to methionine. Methotrexate exerm its
`maximum inhibitory effect on cells that are actively
`undergoing DNA synthesis, particularly those cells
`in the S phase of the cell cycle. Cells undergoing
`rapid cellular turnover such as in the epidermis and
`gastrointestinal tract are the most susceptible to the
`effects of the drug. Folinic acid (leucovorin), a fully
`reduced metabolically active folate coenzyme, func-
`
`
`
`Page 3 of 14
`
`Page 3 of 14
`
`
`
`768
`
`Clinical Pharmacology in Rheumatic Diseases - 47
`
`PIIHO
`
`Ir: Iuu¢turo__\
`
`23:“
`"'”W". ‘
`en,
`on
`"” °N"_¢"
`"0
`coau
`L? Pluoi: Acid 4 \— Glvllnic‘,
`A: a c
`
`rouc ACID
`
`(luvoylglulumc ac-d)
`
`"a"\r/N
`\
`c o,»
`on \ I
`/
`C "3
`N
`c H:
`” "2 " c o N ,‘ _c ,,
`"
`C 02,,
`
`‘ " ‘ " ° ’ ' ‘ " ’ "
`
`I’-’ig‘urc 47-1. Structure of folic ac_id, amino}:-
`tenn, methotrexate, and leucovonn.
`
`I Y"
`_\I
`up‘,
`
`cap»
`\
`cu,cn’
`;Lw
`/” CONN—CN
`cu
`co!“
`
`MEYMOIIIEXAYE
`
`llmethoplcv-n)
`
`so
`
`u
`
`zflfinx
`
`II\
`”
`
`0
`
`N
`I
`N
`c”°N
`
`cu
`3cu
`CONN‘CN
`1
`2
`co “
`
`co,"
`
`LEUCOVOIIN
`'(Folin‘u¢ lend)
`
`
`
`.
`I
`N -FORMVL F“;
`
`¢—j——_.—5N$¢_;('§MyL_;u‘G.h)_n.
`
`(LEUCOVOFINI K I
`
`N*"°-IGMETMENYI.-FH,(Gnu..)
`
`Figure 47-2. Mechanism of action of methottex—
`ate. MTX, Methot-rexate; DHFR, dihydrofolale re-
`ductase; TS, thymidylate synthctase; FH,, tema-
`hydrofolate; FH, dihydrofolate; Glu, giutamyl;
`dTMP, thymidylate; dUMP, dioxyuridylate. Bro-
`ten lines indicate enzyme inhibition. (From 10-
`‘vet, 1., Cowan, K. H., Curt, G. A., Clendeninn,
`N. 1., and Chabner, B. A.: The pharmacology and
`clinical use of methotrexate. N. Engl. J. Med.
`309:1095, 1983. Reprinted by permission of the
`New England Ioumal of Medicine.)
`
`._
`N METHYHH‘
`
`N"‘°-ao-ME'mYLEr£-fluGIu..l
`
`Mamomu
`E
`SYNTHUASE
`
`FH.0GIu..l
`
`MTX
`
`Page 4 of 14
`
`
`
`Page 4 of 14
`
`
`
`
`
`
`
`as measured by agglutination assays has been vari-
`able.‘ 5' 7 A suppression of IgA rheumatoid factor and
`IgM rheumatoid factor as measured by an enzyme-
`Iinked immunosorbent assay (ELISA), however, was
`observed in vivo in patients enrolled in multicenter
`trials of methotrexate.‘ A suppression of in vitro
`rheumatoid factor production has also been ob-
`served? Inhibition of selected interleukin-1 (IL-1)
`activity has been reported in vitro, but the in vivo
`data are inconclusive.“’ Methotrexate exerts an anti-
`
`proliferative effect on peripheral blood mononuclear
`cells in vitro," inhibits in vitro vascular epithelial cell
`proliferation and in vivo neovascularization, and may
`affect adenosine release. ”« 13'
`
`An anti-inflammatory effect with methotrexate
`has been suggested by its rapid onset of action and
`the flare after drug discontinuation. In an air sac
`model of inflammation, pretreatment of mice with
`low-dose methotrexate inhibited neutrophil migra-
`tion that was induced by both C5a and leukotriene
`B," In vivo chemotaxis after stimulation with C53
`and leukotriene B, was blod<ed in psoriasis patients
`after methotrexate administration.” ‘5 Suppression of
`leukotriene B4 ex vivo was observed with methotrex-
`ate in rheumatoid arthritis patients.“
`Low-dose methotrexate inhibited adjuvant in-
`duced and streptococcal cell wall induced arthritis."
`In adjuvant arthritis, methotrexate inhibited macro-
`phage activation, inhibited neutrophil migration, and
`prevented the induction of an IL-2 deficiency in
`animals.”
`
`PHKRMACOKINETICS
`
`Methotrexate at low doses can be administered
`
`by either an oral or parenteral route. The bioavail-
`ability of low-dose oral methotrexate is relatively
`high, but there is individual patient variability. In 41
`rheumatoid patients who received 10 mg per ml of
`oral methotrexate, a mean bioavailability of 0.7 with
`a range of 0.4 to 1.0 was reported.” Patients not
`responding on oral methotrexate should be given a
`trial of parenteral methotrexate to ensure complete
`bioavailability.
`Intramuscular
`and subcutaneous
`methotrexate are rapidly absorbed;
`the maximum
`serum concentration is attained within 2 hours of
`
`injection. The pharmacokinetics of subcutaneous
`methotrexate is the same as intramuscular metho-
`trexate in rheumatoid arthritis.” Mcthotrcxate dif-
`
`fuses into synovial fluid at concentrations equal to
`serum levels.“
`
`Methotrexate distributes throughout the body,
`with higher concentrations found in intestinal epi-
`thelium and hepatic cells. Methotrexate is only 50 to
`60 percent bound to plasma proteins. An increase in
`free methotrexate owing to its displacement from
`albumin by more highly protein bound drugs such
`as aspirin, nonsteroidal anti—inflammatory drugs, and
`sulfonamides can occur. This displacement appears
`to be of limited clinical significance with low meth-
`
`Michael E. Weinblatt - Methotrexate
`
`769
`
`otrexate doses because the increase in free metho-
`
`trexate may only be modest. Mcthotrcxate may
`undergo hepatic metabolism by the enzyme aldehyde
`oxidase
`to 7—hydroxymethotrexate. Excretion of
`methotrexate and its metabolites is by the kidney by
`both glomerular filtration and proximal tubular se-
`cretion. Organic acids such as phenylbutazone, pen-
`icillin,
`sulfonamides,
`salicylates, and probenecid
`competitively inhibit tubular secretion, which may
`affect methotrexate clearance. The plasma half-life of
`methotrexate is less than 10 hours but increases in
`
`the presence of renal insufficiency. The toxic effect
`of methotrexate on normal tissue is generally related
`to the duration of exposure rather than the peak
`level of the drug.
`Several kinetic studies have failed to note a
`
`significant interaction between low-dose methotrex-
`ate and a variety of nonsteroidal anti-inflammatory
`drugs.‘°- 2‘ With high doses of methotrexate, coad-
`ministration of nonsteroidal anti-inflammatory drugs
`or aspirin may be toxic and must be avoided. Drugs
`that affect renal function, such as probenecid, or
`drugs with antifolate activity, such as trimetho-
`prim/sulfamethoxazole, should be used with great
`caution owing to an increased risk for toxicity.
`
`RHEUMATOID TART}-IIRITIS
`
`Because aminopterin was a potent inhibitor of
`connective tissue proliferation, Gubner et al.” in 1951
`administered this drug to six patients with rheuma-
`toid arthritis. A rapid improvement in the arthritis
`symptoms occurred in five of the six patients, but
`exacerbations followed drug discontinuation. In 1972,
`Hoffmeister’-’ reported the beneficial effect of low-
`dose intramuscular methotrexate in 29 patients. Hoff-
`meister expanded his series to include 78 patients
`with a treatment follow-up as long as 15 years."
`Forty-five patients (58 percent) had a "marked" im-
`provement, including 28 patients who were judged
`to be- in ”complete remission.” Seven patients dis-
`continued therapy owing to adverse reactions,
`in-
`cluding elevation in liver blood tests, stomatitis,
`headadies, nausea, or increasing fatigue.
`In another open study, 67 patients received low-
`dose oral weekly methotrexate for a treatment period
`that ranged from 3 months to 10 years.” A ”one-
`step” response was noted in 33 (49 percent) and a
`"two-step” response was noted in 18 (27 percent) of
`the patients. Thirty-four patients discontinued ther-
`apy, including 11 because of nausea or gastrointes-
`tinal intolerance.
`
`There was significant improvement in a 21—pa-
`tient open study of 38 weeks’ duration. The metho-
`trexate dose ranged from 7.5 to 25.0 mg per week.“
`Eleven (52 percent) of the patients had an ”unequiv—
`ocal” response, five (24 percent) had an ”equivocal”
`response, and two patients were unresponsive to
`therapy. Three patients discontinued methotrexate:
`two because of noncompliance and fear of toxicity
`
`
`
`Page 5 of 14
`
`Page 5 of 14
`
`
`
`Figure 47-3. Mean change in se-
`lected clinical variables by treat-
`ment (placebo vs. methotrexate)
`at 6, 12, and 18 weeks of therapy.
`(From Williams, H. 1., Willkens,
`R. F., Samuelson, C. 0., Jr., et
`al.: Comparison of low-dose oral
`pulse methotrexate and placebo
`in the treatment of rheumatoid
`arthritis: A controlled clinical
`trial. Arthritis Rheum. 28:276,
`1985. Reprinted from Arthritis
`and Rheumatism Journal, copy-
`right 1985. Used by pemiission
`of the American College of Rheu-
`matology.)
`
`770
`
`Clinical Pharmacology in Rheumatic Diseases - 47
`
`°
`-5
`-|o
`
`
`
` 0
`
`"5
`-20
`
`-25
`
`o -PLACEBO
`0 -METHOTREXATE
`
`
`
`Painful!
`Tender
`Joint
`Score
`
`----- -.o__-----—-o- ----- "°
`
`0
`
`0
`
`and one because of a hypersensitivity reaction that
`included fever and hepatitis. In a follow-up of these
`18 patients, there was sustained clinical response
`after a mean of 42. months of treatment.” Three
`
`two
`patients withdrew from this long-term study:
`because of gastrointestinal toxicity and one because
`of a planned pregnancy.
`In another study, intravenous methotrexate at a
`dose as high as 50 mg per week was effective in 11
`of 14 patients, with improvement occurring within 4
`weeks of drug initiation.“ Twelve of these 14 pa-
`tients, however, developed toxicity, primarily nausea
`and stomatitis, that led to drug discontinuation in
`three patients.
`The positive results from these uncontrolled
`studies led to four placebo-controlled trials in patients
`who had failed prior second-line therapies, including
`gold salts. In an 18-week randomized multioenter
`study, 189 patients received either oral methotrexate
`(7.5 mg to 15.0 mg per week) or placebo.’ 'l‘here was
`a significant improvement in all clinical variables (Fig.
`47-3) as well as the erythrocyte sedimentation rate
`in the methotrexate group. Thirty patients on meth-
`otrexate withdrew owing to adverse reactions that
`included elevated liver blood tests in 18, stomatitis
`in five, gastrointestinal
`toxicity in three, pancyto-
`penia in two, and leukopenia in two. All the adverse
`reactions resolved with drug discontinuation.
`A significant improvement in efficacy parameters
`was also reported in a 35—patient, 24-week, double-
`blind crossover trial of low-dose weekly methotrexate
`versus placebo.‘ An improvement in clinical param-
`eters began within 3 weeks after methotrexate initi-
`ation.
`Individual patient response defined as a
`greater than 50 percent improvement in the joint
`pain or tenderness index or joint swelling index
`occurred in 54 percent and 34 percent of the metho-
`
`trexate patients (Fig. 47-4). During the crossover
`period, an increase in disease activity occurred within
`3 weeks after methotrexate discontinuation. One
`
`patient withdrew owing to drug toxicity that caused
`severe diarrhea that resolved with drug discontin-
`uation.
`
`Two other randomized trials, including a 6-week
`parallel study” and a 24-week crossover study,5
`noted similar improvement with methotrexate ther-
`apy. A meta-analysis of the four randomized trials
`noted a significant improvement with methotrexate
`in all parameters except the 50-foot walk time.” There
`was a 46 percent reduction in the duration of morning
`stiffness, a 27 percent reduction in the number of
`painful joints, and a 26 percent reduction in the
`number of swollen joints in the methotrexate-treated
`patients.
`Two short-term crossover studies" 5 and two
`
`longer—term studies” *2 reported a flare of arthritis
`activity following methotrexate discontinuation. In
`one study, ten patients who had previously received
`36 months of methotrexate were now randomized to
`
`receive placebo or methotrexate.“ A flare of arthritis
`activity occurred in all the patients randomized to
`the placebo group. This flare occurred within 4 weeks
`of discontinuing methotrexate.
`There have been several studies comparing
`methotrexate with other second-line therapies.
`In
`patients with advanced disease who had received
`prior therapy with either gold salts or D-peniciIla-
`mine, methotrexate was compared with azathioprine.
`Forty—two patients entered a 24-week randomized
`trial of methotrexate versus azathioprine, and both
`treatment groups improved on therapy.” There was
`no significant difference between the response in the
`two groups. In a 53—patient study, both treatment
`groups improved and there was no difference be-
`
`Page 6 of 14
`
`Page 6 of 14
`
`
`
`
`
`Michael E. Weinblatt - Methotrexate
`
`771
`
`RESPONSE ON THERAPY
`
`Methotrexata
`
`100
`
`8
`
`Percent.
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Improved p< .01
`
`
`p< .01
`
`I
`
`L:-.'._g
`Marked
`lniyrovcrmvrt
`
`.
`Moderate or
`Marked
`Impioumont
`
`
`
`n—\u-wuawwww
`
`
`
`
`
`iv-1-wu:—ai--I'-‘'--'‘-'‘V'‘'‘‘'‘‘’''''''''‘'
`
`Pain/Tondunui
`
`Swelling
`
`Plgire 47-4. Individual patient response in a 35-patient, 24-week crossover trial. Marked improvement in the joint pain/tendemess
`and swelling index defined as a decrease of 50 percent or more in their value; moderate improvement defined as a decrease of 30 to
`49 percent in these indexes. Improvement in physician and patient assessments represented at least a 2-point change in a 5-point
`scale.
`
`tween groups in the clinical response.“ Fifty percent
`of the patients withdrew from the study owing to
`either toxicity or a lack of drug efficacy. Owing to
`the small study populations, a type II statistical error
`likely occurred, so conclusion from these trials about
`relative drug efficacy is not possible.
`Gold therapy, both parenteral and oral, has been
`compared with methotrexate. These studies enrolled
`patients with earlier and milder disease in contrast
`to all the other studies of methotrexate. In studies of ’
`
`35 and 40 patients who had never received other
`second-line therapies,
`intramuscular gold therapy
`and methotrexate induced similar improvements in
`disease activity, but gold salts were more toxic.35' 3°
`In a 9-month, 282-patient trial comparing methotrex-
`ate with auranofin,
`there was an improvement in
`disease parameters with both drugs.” Methotrexate
`was superior to auranofin in improving disease activ-
`ity parameters and individual patient response (Fig.
`47-5). Auranofin was also more toxic than metho-
`trexate in this study.
`There have been several long-term studies of
`methotrexate in rheumatoid arthritis. Twenty-nine
`patients were treated in an open study of methotrex-
`ate for a mean of 29 months.“ There was a significant
`improvement, with the maximum beneficial effect
`being achieved by month 6. This beneficial response
`was maintained through the study period. There was
`also a significant reduction in prednisone dose. The
`
`r
`maximum dose of methotrexate was 25.0 mg
`week. Two patients withdrew owing to toxicity t at
`included pneumonitis and gastrointestinal toxicity.
`There was a sustained clinical improvement after 54
`months of therapy in the 25 patients who remained
`in the study.” The mean dose of methotrexate in-
`creased from 12.4 to 14.6 mg per week. Adverse
`events were frequent but were generally mild.
`Similar efficacy results were seen in another
`long-term prospective study. Twenty—six patients
`who completed a 24-week crossover trial‘ enrolled in
`an open study of methotrexate.‘ in this study, the
`maximum dose of oral methotrexate was 15.0 mg per
`week. Sixteen patients received 36 months of ther-
`apy. There was a significant improvement in disease
`activity, with the maximum beneficial effect being
`seen by 6 months (Fig. 47-6). The prednisone dose
`was significantly reduced. Adverse events were fre-
`quent but were generally mild. Only one patient
`withdrew owing to a lack of efficacy.
`Intramuscular methotrexate at a dose of 5.0 to
`
`25.0 mg per week was administered to 128 patients.‘°
`Forty-nine patients received 3 years of therapy. The
`clinical variables improved with treatment. Forty-
`three patients withdrew from the study, including
`23 because of toxicity and 15 because of a lack of
`drug efficacy.
`A total of 123 patients who had successfully
`completed a 9-month randomized trial comparing
`
`7 of 14
`
`Page 7 of 14
`
`
`
`
`
`772
`
`Clinical Pharmacology in Rheumatic Diseases - 47
`
`
`
`.
`
`.
`
`as
`
`no
`
`7o
`
`so
`
`50
`
`40
`..
`
`20
`
`3
`
`5 E
`
`§
`
`Figure 47-5. Individual patient
`response, methotrexate versus
`auranofin study. Percentage of
`patients with marked improve-
`ment in four clinical measures of
`rheumatoid arthritis activity, by
`treatment group. Solid column
`indicates methotrexate group;
`shaded column indicates auran-
`ofin group. The significance of
`differences between groups was
`calculated by the Mantel-Haen
`szel chi-square text. (") indicates
`P < 0.01; " P = 003. (From
`Weinblatt, M., et a1.: Low-dose
`methotrexate compared with au-
`ranofin in adult rheumatoid ar-
`thritis. A 36-week, double—blind
`trial. Arthritis Rheum. 33:330,
`1990. Reprinted from Arthritis
`and Rheumatism Journal, copy-
`right, 1992. Used by permission
`of the American College of Rheu-
`matology.)
`
`Painful/tender
`joint index’
`
`Joint swelling
`index‘
`
`Physician
`gtobal assessment‘ '
`
`Patient
`otobal assessment‘
`
`methotrexate with auranofin” enrolled in a long-
`term open study of oral methotrexate.“ The maxi-
`mum dose of methotrexate in this study was 20.0 mg
`per week. Thirty-two patients received at least 36
`months of therapy. The standard parameters of rheu-
`matoid arthritis activity significantly improved. The
`mean number of painful joints and swollen joints
`decreased by 80 percent. There was no significant
`difference between the improvement seen at month
`6 and that seen at month 36. A significant reduction
`in prednisone dose was achieved. Adverse events
`occurred frequently but were generally mild. Twenty-
`seven patients (22 percent) withdrew, including four
`(3 percent) because of a lack of efficacy and six (5
`percent) because of clinical and laboratory adverse
`experiences. The overall probability of remaining on
`therapy for 48 months was projected at 72 percent.
`Several retrospective studies reported that a sig-
`nificant percentage of patients initiating methotrexate
`could be maintained on long-terrn therapy.
`In a
`review of 124 patients treated with methotrexate, 60
`patients (48 percent) continued to receive methotrex-
`ate for 2 years with a sustained clinical benefit."
`Adverse drug reactions were the major reason for
`patient withdrawal. In a study of 152 rheumatoid
`patients, the probability of continuing methotrexate
`at 1 year was 71 percent and at 6 years was projected
`at 49 percent.“ The major reason for withdrawal was
`drug toxicity. Of 230 patients enrolled in ongoing
`long-term pros ective studies of methotrexate, 174
`(75 percent) sti 1 remain on methotrexate.“ Fifty-one
`patients (23 percent) have received more than 4 years
`of treatment. It was projected that 63 percent of the
`patients would remain on drug therapy for at least 6
`years.
`The effects of methotrexate on radiographic
`
`changes are variable. A halting of radiographic pro-
`gression has not yet been demonstrated. One study
`reported a healing of erosions within the first 29
`months of methotrexate therapy?“ however, after a
`mean of 54 months of therapy, new erosions were
`noted.” In another study, after a mean of 28 months
`of treatment worsening of the radiographs was noted
`in six of 14 alients.‘ An improvement in the number
`and size 0 the erosions was seen in five of the 14
`
`patients, but a marked narrowing of the joint space
`was observed in these five patients. Three of these
`five patients had the most "substantial” clinical re-
`sponse on methotrexate. In a study of 18 patients
`who experienced significant improvement on meth-
`otrexate, radiographic progression continued despite
`30 months of treatment.‘-" In the two patients who
`achieved a clinical remission, there was no evidence
`of radiographic progression. Two other studies sug-
`gested slowing of radiologic progression in a subset
`of patients.” Methodologic differences, lack of an
`appropriate control group, and a limited treatment
`duration hinder interpretation of all of these studies.
`Methotrexate has been used in combination with
`
`several other second-line therapies. A randomized
`trial of methotrexate in combination with auranofin
`
`noted no difference in either efficacy or toxicity with
`the combination compared with solo therapy.” An
`improvement without greater toxicity was noted with
`the combination of methotrexate and intramuscular
`
`gold,“ methotrexate and sulfasalazine,” and metho-
`trexate and azathioprine.-”° Several of these combi-
`nations are being studied in randomized trials.
`
`OTHER DISEASES
`
`After the initial report” of the beneficial effects
`of aminopterin in_psoriasis and psoriatic arthritis,
`
`Page 8 of 14
`
`Page 8 of 14
`
`
`
`Michael E. Weinblatt - Methotrexate
`
`773
`
`Open studies in glucocorticoid-resistant poly-
`myalgia rheumatica and giant cell arteritis,“ systemic
`lupus erythematosus,“ and cutaneous vasculitis of
`rheumatoid arthritis“ all reported improvement with
`low-dose methotrexate. Preliminary open studies
`suggested
`some
`effect with methotrexate
`in
`scleroderrna.57- 5” Efficacy with methotrexate was re-
`ported in juvenile rheumatoid arthritis.” 5° A prelim-
`inary analysis of an international study of methotrex-
`ate in juvenile rheumatoid arthritis noted that
`methotrexate at a dose of 10 mg per ml per week
`was more effective than placebo.“ Methotrexate at
`doses of 30 to 50 mg per week was also effective in
`glucocorticoid—resistant polymyositis and dermato-
`myositis.“
`Open studies in sarcoidosis,“ sclerosing cholan-
`gitis,“ primary biliary cirrhosis,“ and inflammatory
`bowel disease“ all suggested efficacy with low-dose
`methotrexate. Short-term randomized trials“ ‘*5 and
`
`a longer-term study“ reported efficacy with low-dose
`methotrexate in glucocorticoid-dependent asthma.
`Studies of methotrexate are continuing in these dis-
`eases as well as in multiple sclerosis, uveitis, and
`recent-onset diabetes.
`
`DOSE AND DRUG ADMINISTRATION
`
`Methotrexate is given only on a weekly basis
`because more frequent administration is associated
`with a greater incidence of acute and chronic toxicity.
`Methotrexate is administered either orally or by par-
`enteral injection. Oral methotrexate can be taken as
`one dose, or it can be cycled over a 24-hour period.
`The initial dose of methotrexate is generally 7.5 mg
`per week, but a lower dose may be used in patients
`for whom toxicity is a particular concern. If a positive
`response has not been noted within 4 to 8 weeks
`after methotrexate initiation and there has been no
`
`toxicity, the dose may be increased. Even though the
`optimal dose in rheumatoid arthritis is unknown,
`most studies used doses of 7.5 to 20.0 mg per week.
`In the randomized trial comparing auranofin with
`methotrexate, 43 percent of the methotrexate patients
`increased their methotrexate dose from 7.5 to 15.0
`
`mg per week for greater efficacy.” A dose response
`study suggested a linear dose response between
`placebo at 5 mg per ml and at 10 mg per ml.” Once
`a satisfactory clinical response occurs, the dose of
`methotrexate may be slowly reduced. Some patients
`may require higher doses over time to maintain a
`beneficial response. Doses above 20 mg per week
`should be administered parenterally owing to de-
`creased oral bioavailability at
`these higher doses.
`Doses above 30 mg per week have been associated
`with greater toxicity. One study of 10 patients, how-
`ever, reported efficacy and tolerability with intrave-
`nous therapy at an initial dose of 40 mg per ml and
`a final dose of 26 mg per ml." A pilot study of five
`patients with refractory disease reported efficacy and
`good tolerability with high-dose intravenous metho-
`
`NUMBER OF PAINFLI. JOINTS
`
`20
`
`40
`
`‘lo
`CHANGE
`Faou
`snssune so
`
`80
`
`100
`VISIT (months)
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`NUMBER OF SWOLLEN JOINTS
`
`100
`VISIT (months)
`
`6
`
`12 .
`
`‘ll
`
`24
`
`30
`
`36
`
`Figure 47-6. Long-term response in patients receiving methotrex-
`ate. Mean percentage of change from baseline (A) and number of
`painful joints and number of swollen joints (B). Number of patients
`at each visit was as follows: 12 months, 19 patients; 24 months,
`18 patients; 36 months, 16 patients. (From Weinblatt, M. E., et
`al.: Long-term prospective trial of low-dose methotrexate in rheu-
`matoid arthritis. Arthritis Rheum. 311167, 1988. Re rinted from
`Arthritis and Rheumatism Journal, copyright 1992.
`sed by per-
`mission of the American College of Rheumatology.)
`
`extensive studies withmethotrexate in psoriasis were
`performed. An important risk factor for toxicity was
`the frequency of methotrexate dosing. Weekly ad-
`ministration was less toxic than daily administration
`of the drug. An oral regimen based on skin kinetics
`was developed in which methotrexate was adrninis-
`tered at 12-hour intervals for three doses once a
`
`week.“ This regimen produced less toxicity than
`daily therapy and was as effective and no more toxic
`than weekly parenteral therapy.
`Methotrexate is also effective for psoriatic arthri-
`tis and Reiter’s syndrome at doses of 7.5 to 30.0 mg
`per week. In a review of 21 patients with Reiter’s
`syndrome, there was improvement in the mucocu-
`taneous disease in 90 percent and an improvement
`in the arthritis in 75 percent of patients.” Three
`patients discontinued therapy owing to toxicity that
`included stomatitis, anemia, and abnormal
`liver
`blood tests.
`
`the leukocyte count irn—
`In Felty’s syndrome,
`proved with low-dose methotrexate.” The leuko-
`penia, however, returned with drug discontinuation.
`
`{Page 9 of 14
`
`Page 9 of 14
`
`
`
`774
`
`Clinical Pharmacology in Rheumatic Diseases - 47
`
`trexate (500 mg per in’) and leucovorin (50 mg per
`1112) administered biweekly for 8 weeks.” The clinical
`response lasted 6 to 14 weeks after the infusions
`were completed. Further studies with high-dose ther-
`apy are in progress.
`A depletion in the serum folate concentration
`and an alteration in a folate-dependent enzyme sys-
`tem (the C,
`index) developed with methotrexate
`therapy.” Supplemental folic acid at a dose of 1 mg
`per day did not reduce the efficacy of methotrexate
`in a 24-week, placebo-controlled trial." There was a
`suggestion of less toxicity in the folic acid—treated
`group. Folinic acid (leucovorin) administered mid-
`way between methotrexate doses did not influence
`either the efficacy or the toxicity of methotrexate in
`a 13—patient randomized trial.” In another study,
`seven patients received folinic acid (15 mg) starting
`4 to 6 hours after the methotrexate dose for 3 con-
`secutive days.7° Each patient received a total of 45
`mg per week of folinic acid for 4 weeks. Nausea that
`was present before the study resolved on folinic acid
`therapy. A flare of arthritis, however, occurred on
`folinic acid thera y and resolved with folinic acid
`discontinuation. Iiblinic acid at a dose that was equal
`to the methotrexate dose (5 to 15 mg) was adminis-
`tered 4