Textbook of
`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 Int ernal Medicine,
`Immun ology, and Microbiology
`Chairman
`Division of Rheumatology , Allergy , and Immunology
`Department of Int ernal 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 Jo,a•orldl,
`Inc.
`Philadelphia London Toronto Montreal Sydney Tokyo
`
`Page 1 of 14
`
`KOIOS Exhibit 1018
`
`

`
`W.B. SAUNDERS COMPANY
`Harcourt Brace Jovanovich, Inc.
`The Curtis Center
`Independence Square West
`Philadelphia, Pennsylvania 19106
`
`cm .
`
`Library of Congr ess Cataloging-in-Publi cation Data
`[et al.J.-
`Textbook of rh eumatology I William N. Kelley ...
`4th ed.
`p.
`Includes bibliographical references and indexes.
`ISBN 0-7216-3157-6 (set)
`I. Kelley, William N., 1939-
`1. Rheumato logy.
`l. Arthr itis .
`2. Rhe umatic Diseases .
`[DNLM: ·
`WE 544 T355 1993]
`
`RC927.T491993
`
`616.7'23-dc20
`
`DNLM/DLC
`for Library of Congress
`
`92-48331
`CIP
`
`TEXTBOOK OF RHE9Mf. TOLOG Y, Fourth Edition
`
`ISBN
`
`0-7216-315~X
`Volume l
`Volume II
`0-7216-3156-8
`Two Volume Set 0-7216-3157-o
`
`Copyright© 1993, 1989, 1985, 1981 by W.B. Saunders Company.
`
`All rights reserved . No part of this publication may be reprod uced 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
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`8
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`7
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`6
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`5
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`4
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`3
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`2
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`Page 2 of 14
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`KOIOS Exhibit 1018
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`

`
`Chapter 47
`Methotrexate
`
`Michael E. Weinblatt
`
`Methotrexate has become an establish ed treat(cid:173)
`ment for rheumatoid arthrit is. Low-dose weekly
`methotrexate was approved by the United States
`Food and Drug Administration in 1988 as a therapy
`for active rheum atoid arth ritis. There is also signifi(cid:173)
`cant interest in low-dose methotrexate as a therapy
`for a variety of other autoimm une, inflammatory,
`and rheuma tologic conditions.
`
`CHEMICAL STRUCTURE
`
`Methotrexate is an antimetabolite and is a struc(cid:173)
`tural analogue of folic acid. The structure of folic acid
`(pteroylglutamic acid) consists of three elements: a
`multiring pterid ine group linked to a para-aminoben (cid:173)
`zoic acid that is connected to a termina l glutamic acid
`residue (Fig. 47-1). Methotrexate differs from folic
`acid in that an amino group subs titutes 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 enzymatical ly by
`the enzym e dihydrofolate reductase to both dihydr o(cid:173)
`folate and tetrahydrofolate, which are metabolically
`active reduced folates. These redu ced folates are
`essential in the conversion of homocysteine to me(cid:173)
`thionine, in the metabolism of histidine, in th e syn(cid:173)
`thesis of purines, and in the biosynthesis of thymi·
`dylate, which
`is required
`for DNA synthe sis.
`Methot rexate, an antimetabolite, binds and inacti-
`. vates th e enzyme dihydrofola te reductase, resulti ng
`in the depletion of metabolically active intracellular
`folates with subse quent inhibition of the syn thesis of
`thymidyla te and inosinic acid (Fig. 47- 2). Addition(cid:173)
`ally, methotrexate affects protein synthesis by pre(cid:173)
`venting the conversion of glycine to serine and ho·
`mocysteine to met hionine. Methotrexate exerts its
`maximum inhibitory effect on cells that are actively
`und ergoing DNA synthesis, particularly those cells
`.in the S phase of the cell cycle. Cells und ergoing
`rapi~ cellula r tu rnover such as in the epidermis and
`gastrointestina l tract are the most susceptible to the
`effects of the dru g. Folinic acid (leucovorin), a fully
`reduced metabolically active folate coenzyme, func-
`
`tions without the need for reduction by the enzyme
`dihydrofolate reduc tase. Folinic acid (leucovor in) is
`used to "re scue" norma l cells from the toxicity in(cid:173)
`duced by methotrexate. Folinic acid is used as a
`"rescue" agent in cancer chemo therapy and as a
`treatment for acute methotrexate overdose and he(cid:173)
`matologic toxicity.
`Folates in the blood have a single terminal glu(cid:173)
`tamate str ucture. Most intracellular folates are me(cid:173)
`tabolized to a polyglutamated compound . These po(cid:173)
`lyglutamates have longer cellular retention and are
`more efficient cofactors than
`the monoglutamate
`compound . Similar to the folate cofactors, metho(cid:173)
`trexate also is metaboliz ed from a monoglutamate to
`a polyglut amated derivative. Methotrexate polyglu(cid:173)
`tamates have stronger cellular ret ention, remain
`within the cell in the absence of extracellular drugs,
`and are more potent than the monoglutamate struc(cid:173)
`ture.1 The synthesis of the methotrexate polygluta·
`mates increases with the duration of therapy. The
`polyglutamated derivat ives predom inate in hepatic
`tissue, which may be a factor in toxicity. The concen(cid:173)
`tration of hepatic methotrexate polyglutamates de(cid:173)
`creases after folinic acid therapy. 2
`The mechanism of action of low-dose methotrex(cid:173)
`ate in rheumatoid arthritis is not known. Whether
`its therapeu tic effect is due to its an:tifolate activity,
`immunomodulati ng prope rties, immunosuppressive
`pr oper ties, or anti-inflamma tory effects is under
`study. It is most likely that a combination of these
`factors accounts for its therapeutic profile in rheu(cid:173)
`matoid arthritis. High- dose methotrexa te at doses
`used for cancer therapy has immunosuppressive
`properties includi ng supp ressiQn of antibody forma (cid:173)
`tion and suppression of primary and secondary im(cid:173)
`mune response. 3 [n rheumatoid arthritis, however, a
`profound immunos uppress ive effect has not been
`documented with low-dose meth otrexate. Neithe r a
`global suppr ession of T cell function nor chang es in
`T ceU subsets were rep orted in short -term studies in
`rheumatoid arthritis. · 5 After 2 years of therapy,
`however, a significant increase in the percentage of
`T3 and T4 cells and an increase in thy midin e incor(cid:173)
`poration responses to selected mitogens and antigens
`were noted . 6 These changes may have reflected the
`reductio n in pred nisone dose and overall improve (cid:173)
`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) rh eum atoid factor production
`767
`
`Page 3 of 14
`
`KOIOS Exhibit 1018
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`

`
`768
`
`Clinical Pharmacology in Rheumatic Diseases • 47
`
`F OL I C ACID
`
`, , 1ero
`
`y l9lv
`
`lam i c
`
`• c.. d)
`
`.l MI NO P TE AIN
`
`Figure 47- 1. Structure of folic acid, aminop(cid:173)
`terin, methotrexa te, and leucovorin.
`
`ME T HO TA EXATE
`
`( A ,n e- thoptt-r.n)
`
`L EUC OV ORI N
`· fFolin
`i c a cid)
`
`N1-l'ORMYL·FH4
`tl.EUCOVORINI
`
`PURINE
`'°·fOAMYL ·FHJG"-'nl-
`l •------N
`~ SYNTHESIS
`
`N' "'°·1o.METtEN YL·FH4 (Glu,J
`
`· :
`
`Figure 17-2. Mechanism of action of methotrex(cid:173)
`ate. MDC, Methotrexate; DHFR, dihydrofo late re(cid:173)
`ductase; TS, thymidylate synthetase; FH,, tertra(cid:173)
`hydrofolate; FH, dihydrofolate; Glu, glutamyl;
`dTMP, thymidylate; dUMP, dioxyuridyla te. Bro(cid:173)
`ken lines indicate enzyme inhibition. (From )o(cid:173)
`live!, J., Cowan, K. H ., Curt, G. A ., Clendeninn,
`N. J., 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 Journal of Medicine.)
`
`N'-METHYL .f t1
`4
`
`t
`
`:
`
`·-· -(--\_;~··!
`SYNTHETASE FH.tGl"°I ~ !
`
`tf '°
`
`'
`
`',
`
`,,
`
`1-- ----
`
`,/
`
`/
`MTX -
`
`J(Glu.)
`
`:
`I
`I
`I
`I
`I
`I
`,
`MTX(Glu.)• -
`
`dTMP:
`I
`I
`I
`I
`I
`I
`- _ J
`
`-
`
`Page 4 of 14
`
`KOIOS Exhibit 1018
`
`

`
`1 ' .
`
`.
`.
`
`:r,
`,\
`
`as measured by agglutination assays has been vari(cid:173)
`able.4· 5• 7 A suppression of lgA rheumatoid factor and
`IgM rheumatoid factor as measured by an enzyme (cid:173)
`linked immunosorbent assay (ELISA), however, was
`observed in vivo in patients enrolled in multicenter
`trials of methotrexat e.8 A suppression of in vitro
`rheumatoid factor production has also been ob(cid:173)
`served. 9 Inhibition of selected interleukin-1 (IL-1)
`activity has been rep orted in vitro, but the in vivo
`data are inconclusive. 10 Methotrexate exerts an anti(cid:173)
`proliferative effect on peripheral blood monon uclear
`cells in vitro, 11 inhibits in vitro vascular epithelial cell
`proliferation and in vivo neovascu larization, and may
`affect adenosine release. 12. 1:z.
`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(cid:173)
`tion that was induced by both C5a and leukotriene
`84 • u In vivo chemotaxis after stimulation with CSa
`and leukotriene B4 was blocked in psoriasis patients
`after methotrexate administration. 14• 15 Suppression of
`leukotriene B4 ex vivo was observed with methotrex(cid:173)
`ate in rheumatoid arthrjtis patients .16
`Low-dose methotrexate inhibited adjuvant in(cid:173)
`duced and streptococcal cell wall induced arthritis . 17
`In adjuvant arthritis, methotrexate inhibited macro(cid:173)
`phage activation, inhibited neutrophil migration, and
`prevented
`the induction of an IL-2 deficiency in
`animals. 17
`
`PHARMACOKINETICS
`
`Methotrexate at low doses can · be administered
`by either an oral or parenteral route . The bioavail(cid:173)
`ability of low-dose oral methotrexate is relatively
`high, but there is individual patient variability. In 41
`rheumatoid patient s who received 10 mg per m2 of
`oral methotrexate, a mean bioavailability of 0.7 with
`a range of 0.4 to. 1.0 was reported. 18 Patients not
`responding on oral methotrexate should be given a
`trial of parenteral methotre xate to ensure complete
`bioavailability.
`Intram uscular and
`subcutaneous
`methotrexate are rapidly absorbed; the maximum
`serum concentration is _attained within 2 hours of
`injection. The pharmacokin etics of subcutaneous
`methotrexate is the same as intramuscular metho(cid:173)
`trexate in rheumatoid arthritis. 19 Methotrexate dif(cid:173)
`fuses into synovial fluid at concentrations equa l to
`serum levels. 18
`Methotrexate distributes throughout the body,
`with higher concentrations found in intestinal epi(cid:173)
`thelium and hepatic c-ells. 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, non steroidal 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 dos es because the increase in free rnetho(cid:173)
`trexate may only be modest. Met hotrexate may
`undergo hepatic metabolism by the enzyme aldehyde
`oxidase
`to 7-hydroxymethot rexate. Excretion of
`methotrexat e and its metabolites is by the kidney by
`both glomerular filtration and proximal tubular se(cid:173)
`cretion. Organic acids such as phenylbutazone, pen (cid:173)
`icillin, sulfonamides, salicylates, and proben ecid
`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(cid:173)
`ate and a variety of nonsteroidal anti-inflammatory
`drug s. 20, 21 With high doses of methotrexate, coad(cid:173)
`ministra tion of nonsteroidal anti-inflammatory drugs
`or aspirin may be toxic and must be avoided . Drugs
`that affect renal func tion, such as probenecid, or
`drugs with antifolate activity, such as trimetho(cid:173)
`prim/sulfamethoxazole, should be used with great
`caution owing to an increased risk for toxicity.
`
`RHEUMATOID ARTHRITIS
`
`. Because aminopterin was a potent inhibitor of
`connective tissue proliferation, Gubner et al. 22 in 1951
`administered this drug to six patients with rheuma(cid:173)
`toid arthritis . A rapid improv ement in the arthritis
`symptoms occurred in five of the six pati ents, but
`exacerbations followed drug discontinuation. In 1972,
`Hoffmeister23 reported the bene ficial effect of low(cid:173)
`dose intramuscular methotrexate in 29 patients. Hoff(cid:173)
`meister expanded his series to include 78 patients
`with a treatment follow-up as long as 15 years . 24
`Forty-five patients (58 percent) had a ' 'marked" im(cid:173)
`provement, including 28 patients :who were judged
`to be· in "complete remission." Seven patients dis(cid:173)
`continued therapy owing to adverse reactions, in(cid:173)
`cluding elevation in liver blood tes ts, stomatitis,
`headache s, nausea, or increasing fatigue.
`In another open study, 67 patients received low(cid:173)
`dose oral weekly methotrexate for a treatment period
`that ranged from 3 months to 10 years. 25 A "one(cid:173)
`step" respon se 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 (cid:173)
`apy, including 11 because of naus ea or gastrointes(cid:173)
`tinal intolerance.
`There was significant improvement in a 21-pa(cid:173)
`tient open study of 38 weeks' duration. The metho(cid:173)
`trexate dose ranged from 7.5 to 25.0 mg per week. 26
`Eleven (52 percent) of the patients had an "unequiv (cid:173)
`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
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`KOIOS Exhibit 1018
`
`

`
`Numberof Ors····--o----·--·-<>--·-·---~
`
`0
`Poinful/ - 5
`Tender · 10
`Joint
`Score
`
`- 15
`-20
`· 25..,_--~
`
`.. '0-
`
`- - - - -- - o... -- ----
`
`- -o
`
`-
`
`--~
`
`--
`
`~
`
`: =
`Score ::~~-,·
`
`Figur e 47--3. Mean change in se(cid:173)
`lected clinical variables by treat ·
`ment (placebo vs. methotrexate)
`at 6, 12, and 18 weeks of therapy.
`(From Williams, H. J., Will.kens,
`R. F., Samuelson, C. 0 ., Jr., e t
`al.: Comparison of low-dose oral
`pulse me tho trexate and plac ebo
`in the treatmen t of rheumatoid
`clinical
`arthritis : A controlled
`trial. Arthritis Rheum. 28:276,
`1985. Reprin ted from Arthritis
`and Rheuma tism Journal, copy(cid:173)
`righ t 1985. Used by permission
`of the American College of Rheu(cid:173)
`ma tology .)
`
`770
`
`Clinical Pharma cology in Rheumatic Diseases • 47
`
`o -PLACEBO
`• - METHOTREXATE
`
`
`
`Poinful/
`Tender
`Joints
`
`• 5
`
`-10
`-15~ ---r-
`
`-
`
`-
`
`-,- -
`
`-~
`
`.:c··-----~---------o----------0
`
`Swollen
`Jo,nt
`
`~!o1
`Joints
`
`-10
`_
`15
`-20 -
`
`0
`-.2
`
`-. 4
`Physic ian
`Assessmtnt -. 6
`-.8
`
`--
`
`-,- --
`
`---r-
`
`-
`
`--.
`
`-20~~~---
`
`~---r--
`
`-
`
`--.
`
`· · -----
`
`--~---·-···<>-·------~
`
`0
`-.2
`
`..........
`--o..- .. _ ... _ __ - o- - -- - -- --o
`
`-1:0-
`
`-
`
`-
`
`-,- --
`6
`WEEKS
`
`-,-----,
`12
`
`18
`
`- .4
`Poticnt
`Assessment - .G
`
`-.6
`
`-1.0--
`
`--.-
`
`-
`
`----,
`
`6
`
`WEEKS
`
`--
`12
`
`--
`
`18
`
`and one because of a hyper sensitivity reactiQn that
`included fever and hepati tis. In a follow-up of these
`18 patients, there was sustained clinical response
`after a mean of 42. months of treatmen t.27 Three
`patient s withdrew from this long-term study: two
`because of gastrointestinal toxicity and one because
`of a planned pregnancy.
`In another study, intravenous rnethotrexate at a
`dose. as high as 50 mg per week was effective in 11
`of J4 patients, with improvement occurring within 4
`weeks of drug initiation. :ia Twelve of these 14 pa(cid:173)
`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 muJticenter
`study, 189 patients received eithe r oral methotrexate
`(7.5 mg to 15.0 mg per week) or placebo.7 There was
`a significant impr ovement in all clinical variables (Fig.
`47- 3) as well as the erythrocyte sedimentation rate
`in the methotrexate group. Thirty patients on meth(cid:173)
`otrexate withdrew owing to adverse reactions that
`included elevated liver blood tests in 18, stomatitis
`in five, gastrointestina l toxicity in three, pancyto(cid:173)
`penia in two, and leukopenia in two. All the adverse
`reactions resolved with drug discontinuation.
`A significant improvement in efficacy parameters
`was also report ed in a 35-patient, 24-week, double(cid:173)
`blind crossover trial of low-dose weekly methotrexate
`versus placebo.4 An improvement in clinical param·
`eters began within 3 weeks after methotrexate initi(cid:173)
`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 methotrexat e discontinuation. One
`patient withdrew owing to drug toxicity that caused
`severe diarrhea that resolved with drug discontin(cid:173)
`uation.
`Two other randomized trials, includ ing a 6-week
`parallel study-29 and a 24-week crossover study,5
`noted similar improvement with methotrexate ther(cid:173)
`apy. A meta-analysis of the four randomized trials
`noted a significan t improvement · with methotrexate
`in all parameters except the SO;foot walk time. 30 The re
`was a 46 percent reduction in the durati on 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 studies4• 5 and two
`longer-term studies 31•
`32 reported a flare of arthritis
`activity following methotrexate discontinuation. In
`one study, ten patients who had prev iously received
`36 month s of methotrexa te were now randomized to
`receive placebo or methotrexate. 31 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 stud ies comparing
`methotrexate with other second-line therapies. In
`pat.ients with advanced disease wh o had received
`prior therapy with either gold salts or D-penicilla(cid:173)
`mine, methotrexate was compared with azath ioprine .
`Forty-two patients entered a 24-week randomized
`trial of methotrexate versus azathioprine, and both
`treatment groups improved on therapy. 33 There was
`no significant difference betw een 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
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`

`
`Michael E. Weinblatt • Methotrexate
`
`771
`
`RESPONSE ON THERAPY
`
`Ill Methotrexate
`O Placebo
`
`p<
`
`.01
`
`.. p < .001
`
`P< .OS
`
`p< .05
`
`p<
`
`.0 1
`
`p<
`
`.01
`
`-
`
`Mar Iced
`Improvement
`
`Moderate or
`Matk ed
`lmp,ovemant
`
`M>tked
`Improvement
`
`Moderate or
`Marked
`lmprovem9nt
`
`Physician
`Auenmen t
`
`Patient
`Assessment
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Pat"'1' ender-no,
`Figure 47-4. Individual patient response in a 35-patient, 24-week crossover trial. Marl<ed improvement in the joint pain/tenderness
`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. 34 Fifty percent maximum dose of methotrexate was 25.0 mg per
`of the patien ts withdrew from the study owing to week. Two patients withdrew owing to toxicity that
`either toxicity or a lack of drug efficacy. Owing to
`included pneumonitis and gastrointestina l toxicity.
`the small study populations, a type II statistical error There was a sustained clinical improvement after 54
`likely occurred, so conclusion from these trials about months of therapy in the 25 patients who remained
`relative drug efficacy is not possible.
`in the study. 39 The mean dose of methotrexate in-
`Gold therapy, both parenteral and oral, has been
`creased from 12.4 to 14.6 mg per week . Adverse
`compared with methotrexate. These studies emolled
`events were frequent but were generally mild.
`patients with earlier and milder disease in contrast
`Similar efficacy results were seen in another
`to all the other studies of methotrexate . In studies of · long-term prospective study. Twenty-six patients
`35 and 40 patients who had never received other who completed a 24-week crossover trial' enr olled in
`second-line therapies, intramuscular gold therap y an open study of methotrexate. 6 In this study, the
`and methotrexate induced similar improvements in maximum dose of oral methotrexate was 15.0 mg per
`disease activity, but gold salts were more toxic.35
`36 week. Sixteen patients received 36 months of ther(cid:173)
`•
`In a 9-month, 282-patient trial comparing methotrex-
`apy. There was a significant improvement in disease
`ate with auranofin, there was an improvement in
`activity, with the maximum beneficial effect being
`disease parameters with both drugs. 37 Methotrexate
`seen by 6 months (Fig. 47-6). The prednisone dose
`was superior to auranofin in improving disease activ- was significantly reduced. Adverse events were fre(cid:173)
`ity parameters and individua l patient response (Fig. quent but were generally mild . Only one patient
`47-5). Auranofin was also more toxic than metho- withd rew owing to a lack of efficacy.
`trexate in this study.
`Intramus cular methotrex ate at a dose of 5.0 to
`There have been several long-term studies of 25.0 mg per week was administered to 128 patients. 40
`methotrexate in rheumatoid arthritis. Twenty-nine Forty-nine patients received 3 years of therapy. The
`patients were treated in an open study of methotrex-
`clinical variables improved with treatment. Forty(cid:173)
`ate for a mean of 29 months. 38 There was a significant
`three patients withdrew from the study , including
`improvement, with the maximum beneficial effect 23 because of toxicity and 15 because of a lack of
`being achieved by month 6. This beneficial response
`drug efficacy.
`was maintained through the study period. There was
`A total of 123 patients who had successfully
`also a significant reduction in predni sone dose. The
`completed a 9-month randomized
`trial comparing
`
`' ' \
`l
`
`l
`\
`3
`
`t
`
`Page 7 of 14
`
`KOIOS Exhibit 1018
`
`

`
`-------
`
`-~--~-- -~ -
`
`--
`
`-
`
`772
`
`Oinical Pharmacology in Rheumatic Diseases • 47
`
`80
`
`70
`
`IIO
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`j
`!
`
`0 i
`
`Painful/tender
`joint index•
`
`Joint swelling
`index•
`
`Physician
`globa l a~sment
`
`Patie nt
`• • globe! asS8S!Sfflent"
`
`Figure 47- 5. Individual patient
`response, methotrexa te versus
`auran .ofin study. Percentage of
`patien ts with marked improve·
`ment in four clinical measures of
`rheumatoid arthritis activity, by
`treatment group . Solid column
`indicates methotrexate group;
`shaded column indicates auran(cid:173)
`ofin group . The significance of
`differences between groups was
`calculated by the Mantel -Haen (cid:173)
`szel chi-square text. (") indicates
`P < 0.01; ... P = 0.03. (From
`Weinblatt, M., et al.: Low-dose
`methotr exate compared with au(cid:173)
`ranofin in adult rheumatoid ar(cid:173)
`thritis. A 36-week, double-blind
`trial. Arthritis Rheum. 33:330,
`1990. Reprinted
`from Arthri tis
`and Rheumatism Joumal, copy·
`right, 1992. Used by permission
`of the American College of Rheu(cid:173)
`matology.)
`
`methotrexate with auran ofin37 enrolled in a long(cid:173)
`term open study of oral methot rexate.41 The maxi(cid:173)
`mum dose of methotrexate in this study was 20.0 mg
`per week. Thirty-two patients received at least 36
`months of therapy. The standa rd parameters of rheu (cid:173)
`matoid arthritis activity significantly improved . The
`mean numbe r 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(cid:173)
`seven patie nts (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 retro spective studies reported that a sig(cid:173)
`ruficant percentage of patie nts initiating methotrexate
`could be maintained on long-term therapy. In a
`review of 124 patients treated with methotrexate, 60
`patients (48 percent) continued to receive methotre x(cid:173)
`ate for 2 years with a sustained clinical benefit. 42
`Adverse drug reactions were the major reason for
`pa~ent withdrawal. In a study of 152 rheuma toid
`patients , the probability of continuing methotrexate
`at 1 year was 71 percent and at 6 years was projected
`at 49 percent. 43 The major reason for withdrawal was
`drug toxicity. Of 230 patients enrolled in ongo ing
`long-term prospective studies of methotrexa te 174
`(75 percent) still remain on methotrexate. 44 Fifty-one
`patients (23 percen t) 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 methotr exate on radiographic
`
`changes are variable. A halting of radiogr aphic pro(cid:173)
`gression has not yet been demons trated. One study
`reported a healing of erosions within the fiist 29
`months of methotrexate therapy;38 however, after a
`mean of 54 months of therapy, new erosions were
`noted. 39 In another study, after a mean of 28 months
`of treatment worsening of the radiographs was noted
`in six of 14fat ient:s.6 An improvement in the num ber
`and size o 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 "substan tial" clinical re(cid:173)
`sponse on metho trexate. In a study of 18 patients
`who experienced significant improvement on meth(cid:173)
`otrexate, radiographic progres sion continued despite
`30 months of treatment. 45 In the two patients who
`achieved a clinical .remission, there was no evidence
`of radiogra phic progression. Two other studie s sug(cid:173)
`gested slowin8 of radiologic progression in a subset
`of patien ts.40
`• Methodologic differences, lack of an
`appropriate control grou p, and a limited trea tment
`du ration hinde r interp retation of all of these stud ies.
`Methotr exate has been used in combination with
`s~veral other second -line therap ies. A random ized
`trial of methotr exate in combination with auranofin
`noted no difference in either efficacy or toxicity with
`the combination compared with solo therapy .47 An
`improvement without greater toxicity was noted with
`the combination of methotrexate and intramu scular
`gold, 48 methotrexate and sulfasalazine, 49 and metho·
`trexate and azathioprine. 50 Several of these combi·
`nations are being studied in randomized trials.
`
`OTHER DISEASES
`After the initial report 22 of the beneficial effects
`of aminopterin in_ psoriasis and psoriatic arthritis,
`
`Page 8 of 14
`
`KOIOS Exhibit 1018
`
`

`
`NUMBER OF PAINFUL JOINTS
`
`A o
`
`20
`
`40
`%
`CHANGE
`FROM
`BASELINE 60
`
`80
`
`100+- ~---.-~~
`~·slT (months)
`6
`
`...- ~
`12
`
`....... ~~...-~----~~-
`24
`18
`
`30
`
`36
`
`NUMBER OF SWOLLEN JOINTS
`
`B o
`
`20
`
`40
`
`...
`CHANGE
`FROM
`BASELINE 60
`
`80
`
`....... ~~ ....
`100+-~--,.~~....-~-.~~...-~
`VISIT (months)
`30
`18
`12
`.
`36
`6
`Figure 47-6. Long-t enn response in patients re<:eivin g 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 pati en ts. (From Weinblatt, M. E., et
`in rh~u(cid:173)
`al.: Long-term prospective trial of low-dose methotrexate
`matoid arthritis . Arthritis Rheu m . 31:167, 1988. Reprinted from
`Arthritis an d Rheumatism Journal, copyright 1992. Used by per(cid:173)
`mission of the American College of Rheumatology .)
`
`extensive studies with-methotrexate in psoriasis were
`performed. An important risk factor for toxicity was
`the frequency of methotrexate dosing. Weekly ad(cid:173)
`ministration was less toxic than daily administration
`of the drug. An oral regimen based on skin kinetics
`was developed in which methotrexate was adminis(cid:173)
`tered at 12-hour intervals for three doses once a
`week. 51 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 arthr i(cid:173)
`tis and Reiter's syndrome at doses of 7.5 to 30.0 mg
`per week. fn a review of 21 patients with Reiter's
`syndrome, th ere was improvement in the mucocu(cid:173)
`taneous disease in 90 percent and an improvement
`in the arthritis in 75 percent of patients. 52 Three
`patients discontinued therapy owing to toxicity that
`included stomatitis, anem ia, and abnormal
`liver
`blood tests.
`In Felty's syndrome,
`the leukocyte count im(cid:173)
`proved with low-dose methotrexate. 53 The leuko(cid:173)
`penia, however , returned with drug discontinua tion.
`
`Michael E. Weinblatt • Methotrexate
`
`773
`
`in glucocorticoid-resistant poly(cid:173)
`Open studies
`myalgia rheu matica and giant cell arteritis, 54 systemic
`lupus erythematosus, 55 and cutaneous vasculitis of
`rheumatoid arthri tis56 all repor ted improvement with
`low-dose methotrexate. Preliminary open studies
`suggested
`some
`effect with methotrexate
`in
`scleroderma.57
`• 58 Efficacy with methotrexate was re(cid:173)
`ported in juvenile rheumatoid arthritis. 59• 60 A prelim(cid:173)
`inary analysis of an international study of methotrex(cid:173)
`ate
`in juvenile
`rheumato id arthritis noted
`that
`methotrexate at a dose of 10 mg per m2 per week
`was more effective than placebo. 61 Methotrexate at
`doses of 30 to 50 mg per week was also effective in
`glucocorticoid-resistant polymyositis and dermato(cid:173)
`myositis. 62
`Open studies in sarcoidosis,~ sclerosing cholan(cid:173)
`gitis, 64 primary biliary cirrhos is, 65 and inflammatory
`bowel disease 66 all suggested efficacy with low-dose
`methotrexate . Short-term randomized trials67• 68 and
`a longe r-term study69 reported efficacy with low-dose
`methotrexate
`in glucocorticoid -dependent asthma.
`Studies of methotrexate are continuing in these dis(cid:173)
`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(cid:173)
`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