818
`
`THE NEW 13NGl.AND_]0URNAl. OF MEDICINE
`
`March 28. I985
`
`NP
`toP‘
`
`2|. watt BK. Merrill AL. Composition of foods: raw. processed. prepared.
`(Agricultural handaoolt no. 8). Washington, D.C.: United States Deput-
`rncnt of Agriculture. 1963.
`Patti AA. Soutltgalc DAT. McCunce tutd \Viddowson's the composition of
`foods. 4th ed. London: Her Majesty's Stationery Office. I973.
`Health Care Financing Administration. Public Health Service. international
`classification ofdircaso. 9th revision. Clinical modification. 2nd ad. Wash-
`ington. D.C.: U.S. Govemrnent Printing Oftice. I980. (DHHS publication
`no. (PHS)B0-I260).
`24. Call DR. Rcgressiort models Iili life tables. I ll Stat Soc ]B| i972: 34:l87-
`220.
`l‘-‘
`Kalbfleilcii JD. Prentice RL. The statistical analysis of failure time data.
`Now York: John Wiley. 1980.
`26. Haipcrin M. Blackweidcr WC. Vertcr ll. Estimation of the multivariate
`logistic risk function: a comparison of the discriminant function and maxi-
`mum ltkcilltood npprnacires. 1 Chronic Dis 1971'. Z4:l25-58.
`27. Havllk IU. Fclnlr.-lb M. eds. Proceedings of the Conference onthc Decline in
`Coronary Heart Disease Mortality. Washington. D.C.: National institutes of
`Health. 1979.
`28. Ruane P. Muicahy R. Hickey N, Graham I. Factors influencing recent
`secular changes in mortality from coronary heart disease and stmlte. J Irish
`Med Assoc I978; 7i:533-7.
`
`19. Stallone: RA. The tire and full of lschcmic heart disease. Sci Am I980;
`2-t3(5J:53-9.
`30. Muriynmn IM. Knrogcr DE. Siamlerl. Cardiovascular diseases in the Unit-
`ed States. Cambridge. Mass.: Harvard University Pica. 197i.
`3!. Friend 8. Page L, Mamba R. Food consumption patients in the United
`States: I909-13 to 1976. In: Levy RI. ltifltlnd BM. Dennis E. Ernst N. eds.
`Nutrition.
`lipids. and coronary heart disoinse. New York: Raven Pres,
`l979:4ll8-522.
`32. Fraser OE. Jacobs DR Jr. Anderson .lT. Fostor N. Pnila M. Blncitbum H.
`The elfoct of various vcgctuble supplements on serum cltulcstt.-ml. Am J
`Clin Nutr 1981: 34:I272-7.
`33. Wright A. Btntyn PG. Giimcy Ml. Dicttry fibre and blood pressure. Br
`Med! 1979: 2:l54l-3.
`34. Fehily AM. Milbank JE. Yamell .l\VG. Hayes TM. Kubild Al. Eutlram
`RD. Diclary determinants or Iipoproteins. total cholesterol. Viacosily, ri-
`brinogen. and blood prcmue. Am J Clin Nutr I932: 36:890-a.
`35. Kunncl WB. Update on the role or cigarette smoking in coronary artery
`disease. Am Hcanl i981: i0l:3l9-28.
`36. Pooling Projoct Research Group. Relationship of blood pressure. serum
`cholesterol. smoking habit. relative weight and ECG abnormalities in inci-
`dence of major coronary events: final report of the Pooling Project. J Chron-
`ic Dis 1978; 3l:20l-306.
`
`EFFICACY OF LOW-DOSE METHOTREXATE IN RHEUMATOID ARTHRITIS
`
`MICHAEL E. WE.INBi.A1‘T, M.D.,_IoNA1'IIAN S. Com.vN, M.D., DAVID A. Fox. M.D., PATRICIA A. FRASER, M.D.,
`Donam E. HOLDSWORTH, M.D., DAVID N. GLASS, M.B., CH.B., AND DAVID E. TRENT}-IAM, M.D.
`
`Abstract Twenty-eight patients with refractory rheuma-
`toid arthritic completed a randomized 24-week double-
`bllnd crossover trial comparing oral methotraxate (2.5 to
`5 mg every 12 hours for three doses weekly) with place-
`bo. The methotrexate group had significant reductions
`(P<0.01 as compared with the placebo group) In the
`number of tender or painful Joints. the duration of morning
`stiffness. and disease activity according to physician and
`patient assessments at the 12-week crossover visit; re-
`ductions in the number of swollen joints (P<0.05) and
`15-m walking time (P<0.03) also occurred. These varia-
`btas. as well as the grip strength and erythrocyte sedimen-
`tation rate. showed significant (P<0.01) Improvement at
`24 weeks in the population crossed over to methctrexate.
`
`A significantly Increased frequency (P<0.03) of the HLA-
`DR2 haplotype occurred in the eight patients with the moat
`substantial response to meihotroxate. Adverse reactions
`during methotrexate therapy included transamlnasa ale-
`vation (21 per cent). nausea (18 per cent), and diarrhea
`(12 per cent); one patient was withdrawn from the trial
`because of diarrhea. One patient died while receiving the
`placebo. Methotrexate did not affect measures of humcral
`or cellular immunity.
`We conclude that this trial provides evidence of the
`short-term efficacy of methotrexate In rheumatoid arthritis,
`but the mechanism of action is unknown. Longer trials will
`be required to determine the ultimate safety and effective-
`ness of this dmg. (N Engl J Med 1985; 312:818-22.)
`
`ERTAIN cases of rheumatoid arthritis are refrac-
`tory to conventional therapies because of lack of
`benefit or the occurrence of unacceptable side effects.
`The antimctabolite methotrexatc was reported to pro-
`duce favorable effects on rheumatoid arthritis by
`Gubncr at al.
`in l95l,' and since that time, other
`open trials have suggested that
`the drug is clTec-
`tive in this disease.’-3 This experience prompted the
`following randomized double-blind crossover study
`of low-dose oral weekly methotrcxatc for patients
`with severe adult-onset rheumatoid arthritis in whom
`
`From the Departrnatrt of Medicine. Harvard Medical School. the Department
`of Rheumatology and immunology. Brigham and WorrIen's Hospital and Beth
`Israel Hospital. and the Dana—Farber Cancer institute. Boston. Address reprint
`requests to Dr. Wcinblntt at Beth Israel Hosphal. 330 Brookilnc Ave.. Boston.
`MA 022l5.
`Supported by grants (AM-21490. AM-20580. AM-30486. and RR-05669)
`from the National Institutes of Houith and by grants tram Lothria Laboratories
`and the New England Peabody Home Foundation. Dr. Fox is the recipient of a
`postdoctoral fellowship from the Arthritis Foundation.
`
`gold-salt therapy had failed to produce a response or
`had been toxic.
`
`Patients
`
`METHODS
`
`'l‘hirty-five patients witlt rheumatoid arthritis fulfilling the Amer-
`ican Rhcumatisrn Association‘: criteria for definite or classic dis-
`ease‘ gave informed consent and entered the study. All had received
`[raid-salt tiIerIPYl 28 (80 per cent) had received penicillamine. 23
`(66 per cent) hydroxycltloroquine, and 2 azathioprine. These drugs
`had been discontinued because ofinelfectiveness or toxicity.
`Other criteria for entry were onset ofthe disease after the age of i6
`and the presence of active disease, defined by at least three of the
`following: 3 or more swollen joints. 6 or more tender joints. 45
`minutes or more of morning atiilhess. a Westcrgren erythrocyte
`sedimentation rate of 28 mm per hour or higher. and a mean grip
`strength for both hands of I92 mm Hg or less in men and H-5 mm
`Hg or less in women. averaged from three measurements.‘ Two
`bone radiologists agreed that the anatomic stage ofditease° war II
`or greater in all patients, according to plain radiograpl-Ia of the
`hands obtained at entry. Women either had no childbearing poten-
`tial or were practicing contraception.
`
`The New England Journal ofhledhno
`Downloaded furl main in: ii HARVARD UNIVERSFTY on Fcbruiy I4. 2012 Far perscni tsacrly. No other uses without aavnssicn.
`From the NEJM Archie. Copyright 9 mm Maasaahuadts ll.1edioa|Soeia¢y.AlIlghtsresarved.
`
`Page 1 of 5
`
`ANTARES Exhibit 1021
`
`Page 1 of 5
`
`ANTARES Exhibit 1021
`
`

`
`Vol. 31? No.13
`
`METHOTREXATE IN RHEUMATOID ARTHRITIS — WElNliLA'l'l‘ ET AL.
`
`819
`
`Excluded from the study were patients with a serious concomitant
`medical illness, judged to be in Functional Class IV by the criteria
`of the American Rheumatism Association.‘ or with a history of
`cancer, liver or renal disease, insulin-dependent diabetes, obesity
`(more than 10 kg above ideal body weight), liver enzyme levels at
`least twice the upper limit of normal, white-cell counts oflcss than
`3500 per cubic millimeter, platelet counts below 1.5x I05 per cubic
`millimeter, or therapy with methotrexate or total lymphoid irradia-
`tion.‘ Patients were not accepted into the trial until gold, pcnicilla-
`mine, or hydroxychloroquine had been withdrawn for at least two
`months and azathioprine for at least six months.
`During the study each patient remained under the care of his or
`her personal rheumatologist, abstained from alcohol, and continued
`to receive stable dmes of aspirin or another nonsteroidal antiinfiam-
`matory drug; those taking prednisone at entry were maintained on a
`stable dose not exceeding l0 mg a day.
`
`study Design
`
`This was a double-blind crossover study of 24» weeks‘ duration.
`Patients were randomly assigned in blocks of four to receive initially
`indistinguishable tablets consisting ofeither methotrexate (2.5 mg)
`or placebo for I2 weeks (Period 1). Tablets were ingested in equal
`numbers on three consecutive occasions at l2-hour intervals begin-
`ning on the same day of each week. For the first 6 weeks, three
`tablets were taken weekly; at 6 weeks, the dose could be increused to
`six tablets weekly if a satisfactory response was not noted by the
`physician investigator. At
`l2 weeks. crossover occurred; patients
`initially assigned to mcthotrexate received placebo for the final I2
`weeks of the study (Period 2), and patients originally assigned to
`placebo received rnethotrcxate. Again, elective increases in dosage
`were incorporated into Week 6 of Period 2. Patients and their rheu-
`matologists, as well as the investigators. remained unaware of drug
`assignments until the study was completed.
`
`Cllnlcal Aaaeasrnonts
`
`Each patient was examined by the same physician investigator
`every three weeks, and pill counts were performed; the entry, cross-
`over, and final visits occurred early in the morning. The clinical
`disease variables determined at each visit consisted of (1) the nutri-
`her among 66 diarthodial joints with swelling;
`(2) the number
`among 68 joints with tenderness on pressure or pain on passive
`motion (or both); (3) thejoint-swelling index, expressed as a sum itt
`which each joint was graded for swelling as 0 (none),
`I (mild), 2
`(moderate), or 3 (severe); (4) the joint-tenderness/pain index, rep-
`resenting the sum for joints graded according to the above scale;
`(5) mean grip strength for both hands; (6) l5-m (50-ft) walking time
`without assisting devices; (7)
`the duration of morning stiffness;
`(8)
`the physician's assessment of disease activity graded as 0
`(asymptomatic),
`1 (mild), 2 (moderate), 3 (severe), or 4 (very se-
`vere); and (9) the patient’: assessment of disease activity graded on
`the same scale.
`Overall responses to treatment were derived with the following
`arbitrary designations modified from those proposed by Williams et
`al.‘*’: (1) therapeutic remission, defined by the preliminary criteria
`of the American Rheumatism Association’; (2) marked improve-
`ment in the joint-swelling index and in the joint-tenderness/pain
`index, defined as a decrease of50 per cent or more in their values at
`the l2-week or 24-week visit, as compared with their values at entry
`or crossover; (3) moderate improvement, defined as decreases of 30
`to 49 per cent in these indexes; (4) no change, it‘ the value for an
`index remained within 30 per cent of the original value; and
`(5) worsening, if the value for an index increased 30 per cent or
`more. Improvement and worsening in the physician and patient
`assessment ofdisease activity represented changes of at least 2 inte-
`gers in their live-point scales.
`
`Laboratory Asuaamenta
`
`Every three weeks, a complete blood count, including platelets
`and the erythrocyte sedimentation rate, and liver-enzyme tests, con-
`sisting of measurement ofscrum aspartute and alanine uminotrans-
`
`fcrase, alkaline phosphatase, and total hilirubin, were obtained;
`serum creatinine was measured every six weeks. Patients were with-
`drawn from the study if the white-cell count decreased to less than
`3300 per cubic millimeter, the polymorphonuclenr leukocyte count
`decreased to less than i200 per cubic millimeter, the platelet count
`decreased to less than l.5X IO’ pcr cubic millimeter, or the creati-
`nine level rose above l.8 mg per deciliter (160 nmol per liter). lfthe
`values for liver enzyme increased to more than twice the upper limit
`of normal, the tablets were withheld and the tests were repeated
`weekly. Abnormalities persisting for more than three weeks also led
`to withdrawal. Typing for HLA~A', B, C, and D polymorphism was
`perforrned in the tissue-typing laboratory of the Department of
`Rheumatology and Immunology; the reagents included antiserums
`tested during the lith Histocompatibility Workshop.’
`
`Immunologic Assessments
`
`At the entry, crossover, and final visits, 80 ml of blood was ob-
`tained for immunologic studies. Serum aliquots were analyzed for
`titers of rheumatoid factor by nephelometry and for concentrations
`of immune complexes by Clq binding.” Cytoliuorographic enu-
`meration of blood mononuclear cells by surface antigens was per-
`formed as described elsewhere.‘ Anti-T3 reacted with all mature
`T cells, whereas anti-'I‘4 and anti-'l'8 identified functiottstlly distinct
`T-cell subsets.‘ Anti-la reacted with activated T cells as well as cells
`of B-lymphocyte and monocyte lineage." Anti-Bl identified 3 lym-
`phocytcs," and anti-Mo. reacted with monocytts and a majority of
`null cells. '3 Anti-Tl la and anti-Ta. identified '1'-cell-specific mark-
`ers of activation.“'”‘ Tritiatcd thymidine incorporation by blood
`mononuclcar cells in response to an optimal quantity of the mito-
`gens phytohemagglulinin and concansvrtlin A and the antigens
`streptokinastrstreptodornase, candida, and purified protein deriva-
`tive of tuberculin was also measured.”
`
`Statistical Analysis
`Continuous disease variables were analyzed as the difference in
`group means between the crossover visit and entry visit, as well as
`between the final visit and the crossover visit, by covariance.“ Oth-
`cr indexes were analyzed in terms of their group means (by Stu-
`dent's two-tailed I-test), and dichotomous variables by their propor-
`tionate group frequencies (by the chi-square test). P values smaller
`titan 0.01 are not given.
`
`RESULTS
`
`Patients and Study course
`
`Of the 35 patients enrolled, 17 were initially as-
`signed to receive methotrexatc and I8 to placebo (Ta-
`ble 1). All but two patients had their close oftest medi-
`cation increased to six tablets; the two patients were
`receiving methotrexatc. Pill counts suggested a high
`degree of compliance with the prescribed regimen.
`There were four withdrawals before the crossover
`visit; the data from these patients were excluded from
`the elficacy analyses in Table 2. Two ofthesc patients
`were receiving placebo; one was withdrawn because of
`a ccrebrovascular accident and the other because of a
`
`protocol violation (a persistent elevation in alkaline
`phosphatase was detected after entry into the trial).
`One of the patients receiving methotrexate was with-
`drawn at Week 9 because of diarrhea, and the other
`withdrew after one week of treatment with methotrex-
`
`ate, during an exacerbation of rheumatoid arthritis
`requiring hospitalization. Three patients, all receiving
`placebo, did not finish Period 2. One withdrew be-
`cause of an arthritic flare at Week 18, after benefiting
`from methotrexatc. One was withdrawn at Week 21
`
`The New Enghod Journal ol‘ Madlfirto
`Dwntloadad hut new In: it HARVARD UNNERSITY on Febtuzy 14. 2012. For persona tse crly. No other uses without DattI's9'cn.
`From the NE.ln.1Arohive.copyrinhtt‘,‘ ZOIO Massaahuasts Medical Society. A I rights reserved.
`
`Page 2 of 5
`
`

`
`820
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`March 28, [985
`
`Table 1. Demographic and Clinical Characteristics of the Patients
`at Study Entry.‘
`V.mAIi.u
`Mmcamu SIOUINCI
`MnrIrons;u'm-
`unrem-
`uammuxars
`FLACIIO
`(N - 11)
`(N - I8)
`
`60
`45-70
`
`59
`44-1 3
`l5
`l7
`
`Age (yr)
`Average
`Ilanpc
`No. female
`No. while
`Disease duration (mo)
`Average
`Rinse
`Functional class
`II
`III
`Rheumatoid factor
`(titer 3 H60)
`HLA-DR4
`
`Prednisone (‘ID in; per day)
`Previous hip. knee, or
`ankle anhroplssty
`
`‘Patients were grouped aeconllnuowlierherlhey wemladoully unanod Io lrnatotremc In
`Period I. a-ituubuoqucnt erosaovertoplaeebo in Period 1. umwlvodtlme numedieatlou In
`the reverse sequence during these two painds. The values listed did mi differ Iiutitluntly
`between the group.
`
`in the methotrexate group. Again,
`mentation rate,
`there was no change in blood-cell components in this
`period. Because of the crossover design, patients who
`received methotrexate initially were examined for a
`change in the measured variables at the end of Period
`2. In this subgroup, a significant (P<0.0l) flare in
`rheumatoid arthritis was noted, as measured by the
`' joint-swelling index, grip strength, morning stiffness,
`and physician assessment of disease activity; the walk-
`ing time (P<0.04) and patient assessment of disease
`activity (P<0.02) had also worsened.
`A total of 33 patients received methotrexate during
`this study. The number who responded to the drug
`was calculated by using the arbitrary definitions, and
`the frequency and degree ofthcse responses were com-
`pared with those observed in a control group consist-
`ing of 18 patients randomly assigned to placebo in
`Period I (Table 3). No remissions occurred with meth-
`otrexatc thc1'3PY. but there was a marked improve-
`ment in thejoint-tenderness/pain index in 18 patients
`(54 per cent) and a moderate improvement in 6 (I8
`per cent). Thus, 24- of the patients (73 per cent) receiv-
`ing methotrexatc had at least a 30 per cent improve-
`men: in thejoint-tenderness/pain index. A marked or
`moderate improvement
`in this index was found at
`Week 3 of methotrexate therapy in 36 per cent of the
`patients. A marked improvement in the joint-swelling
`index occurred in 13 (39 per cent) of the patients tak-
`ing mcthotrcxatc, and a moderate improvement oc-
`curred in 7 (2! per cent). Thus, 20 patients (61 per
`
`because of not keeping a visit appointment, and the
`other (a 66-year-old woman who had moderate im-
`provemcnt in the joint-swelling index and joint-ten-
`derness/pain index and had alopecia during treatment
`with methotrexate) died suddenly
`at Week I8 during a recrudescence
`ofarthritis. A patient taking place-
`bo had an intraarticular injection of
`a glucocorticoid into a knee in Peri-
`od I; this joint was excluded from
`analysis in the study.
`Effects on Dlaoaae
`
`Table 2. Clinical and Laboratory Variables In Patients Completing Period 1
`ol the Study.-
`Vuue A1
`Dirnxuncu AT
`Emu Von’
`annoys: Visit 3
`Ivan 2.9.5.
`
`numutr t
`
`P vu.uI I
`
`No. oljoints swollen
`
`No. ofjointa tender
`Io pressure or pain-
`ful on passive motion
`Joint-swelling index
`
`Iolntdendernessl
`pain index
`Grip strength (mm Hg)
`
`I5-m (30-ll) walking
`time (sec)
`Duration of morning
`stiffness (min)
`Physician assessment of
`disease activity
`Patient assessment oi’
`disease activity
`Erythrocyte sedimentation
`me irnmlhour)
`
`<0.05
`
`<0.0l
`
`<0.0l
`
`<0.0l
`
`NS
`
`<0.03
`
`Methouexsne (IS)
`Placebo (I6)
`Methotmxete ( I5)
`Placebo (I6)
`
`Methmrexute (I5)
`Placebo (I6)
`Muthou-ante ( I 5)
`Placbo (I6)
`Methutrexate (I5)
`Placebo (I6)
`Methotrexale (I5)
`Placebo (13)
`Melhotrente (IS)
`Placebo (I6)
`Methorrexue (I5)
`Placebo (I6)
`Metllotrexue (IS)
`Placebo (I6)
`Melhotrexue ( I 5)
`Placebo (I4)
`
`3423
`28:2
`37:4
`36:3
`
`5l=5
`40:4
`58:8
`52:4
`6I:z6
`4325
`l7:I
`22:2
`Il2:6O
`lO3:l8
`2.1:i:0.2
`2.6203
`2.8t0.2
`2.720.!
`7719
`50:7
`
`I422
`5:2
`26:4
`4:4
`
`30:3
`10::
`4627
`6:6
`-2I::7
`-4:3
`5:!
`Stl
`134258
`-36:32
`l.5:0.2
`0.0:0.2
`I.6:0.2
`0. 130.2
`I717
`-415
`
`When the I5 patients receiving
`methotrexate and l6 patients re-
`ceiving placebo who completcd the .
`initial
`I2-week trial were com-
`
`pared, significant degrees of im-
`provement were found in the meth-
`otrcxate group, versus the placebo
`group, in all the clinical variables
`measured except the grip strength
`(Table 2). There was no significant
`change in the sedimentation rate,
`hemalocrit, total white-cell count,
`platelet count, or absolute lympho-
`cyte count.
`Analysis of the 16 patients
`crossed over to mcthotrexate and
`
`the I2 crossed over to placebo who
`completed Period 2 revealed a sig-
`nificant (P<0.0l) improvement in
`all variables,
`including the sedi-
`
`‘Period I eueornpasesthelultial I2 weekloitiieundy.
`iFl|lll!I In puentheaes are Innben olpatienu in when the variable was analysed.
`tlkultive vniucuepmeni 1 decrease In nae dlllcrence from the nun.
`IP values were determined by analysis of covariance using nliuned means. NS denotes not significant.
`
`The New Enghnd Journal olMediu'ne
`Dmmioaded hm najn on at HARVARD UNNERSTTY on Februzy 14. 2012. For persona tse orly. No other uses wilhuut :ram's9'cn.
`From the NEJM Arciave. copyright L‘: ZDIO Massachusetts Meeieal Society. A I rlntrts reserved.
`
`Page 3 of 5
`
`

`
`Vol. 3l2 No.
`
`if!
`
`METHOTREXATE IN RHEUMATOID ARTHRITIS -— WElNBLA'I"l' ET AL.
`
`cent) taking methotrcxate had at least a. 30 per cent
`improvement
`in the joint-swelling index. Again, a
`marked or moderate improvement in this index was
`present at Week 3 in 24 per cent of the patients. An
`improvement in the physician's assessment of disease
`activity occurred with methotrexate in 36 per cent of
`the patients, and an improvement in the patient’s as-
`sessment occurred in 42 per cent.
`Eight (24 per cent) of the 33 patients had the most
`substantial response to methotrexate, which was arbi-
`trarily defined as achieving a marked improvement in
`the joint-swelling and joint-tenderness/pain indexes
`as well as improvement in both the physician and pa-
`tient assessments of disease activity. No patient taking
`placebo fulfilled these criteria. There was no signifi-
`cant difference in the demographic or disease varia-
`bles at study entry, or in the frequency of concomitant
`prednisone therapy, between these 8 patients and the
`other 25 patients. Of potential interest. 4 of these 8
`patients with a substantial response were typed as
`I-ILA-DR2, as compared with 3 (12 per cent) of the 25
`patients who did not have such a response (chi-
`square = 5.2, P<0.03).
`Adverse Occurrences
`
`Side ellects occurred with equal frequency during
`treatment with the 7.5-mg and 15-mg doses of metho-
`trcxate, except that nausea developed only at the high-
`er dose. During methotrcxate administration, 17 (52
`per cent) of the 33 patients had one or more types of
`adverse reactions, chiefly gastrointestinal, that were
`considered to be attributable to the drug; similar reac-
`tions were noted in 5 (15 per cent) of the 33 patients
`during administration of placebo (P<0.0l) (Table 4).
`The one patient withdrawn from the trial because of
`a drug reaction had severe diarrhea after nine weeks
`of methotrcxate therapy (cumulative dose, 90 mg);
`without the drug,
`the diarrhea resolved during a
`seven-day hospitalization. The side ellects in the
`other patients were clinically mild. Elevated serum
`
`Table 3. Patients‘ Responses to Treatment.--
`Tuxmeur
`Deuau or Rssnuu
`IODBMI
`IIPIOVBIIN1’
`
`MAIIHD
`HHCWEII-NT
`
`IMFIOVIIMINI
`
`Table 4. Adverse Occurrences.-
`
`Momu Evmt
`
`Duuuc Anumurrunon av:
`PIACEIIU
`Ml'I|I!'I'IEXAT1E
`(N = 33)
`in = 3.1)
`
`In. d']1urk'nls
`
`Abnonnul Iransnminuse
`Nausea
`Dianne:
`Alupecia
`stomstitls
`Headache
`Skin infection
`Anomxis
`Vomiting
`Rash
`Buck pain
`Cough
`Chest pain
`Sinoite
`Death
`Abdominal pain
`Depression
`
`7 (21%)
`6 (18%)
`4 (I295)
`2
`
`GGQQNIIJNINI--—ld!JhI
`
`—_...._.....—.Q8A._o..-Qooc
`
`‘Then wen 383 patient-weeks of nteihoueute ndltiniwulion and 369
`patient-weeks oi placebo adrni-iniratiun In this study. 111: mass. bath or
`chm pain. and cough were MI conlideteil tu he drug-reiued.
`
`levels of aspartate and alanine aminotransfcrase oc-
`curred in seven (21 per cent) of the patients taking
`methotrcxate and returned to within normal
`limits
`after the medication was withheld for one to three
`
`weeks. One patient taking placebo had a transient
`elevation of both enzymes.
`
`Immunologic Studios
`
`There were no significant dilferences between the
`methotrcxate group and the placebo group in the
`mean titers of rheumatoid factor, the level ofimmune
`complexes, or the number and percentage of blood
`mononuclear cells expressing the phenotypic and acti-
`vation markers measured in either Period 1 or 2 of
`the trial (data not shown). No func-
`tional
`indication of methotrcxate-
`
`N0
`CIIANIJI WOIIINING
`
`loiril-tends:-nan!
`pain index
`Physician ussemucnt
`
`Joint-swelling index Methoucxue
`Placebo
`Metlioucxlie
`Plheebo
`Methotrexsle
`Placebo
`Methotrexue
`Pluedao
`
`Patient usesuntent
`
`13 (39%) l‘
`2 (ll ‘M
`13 (54%) 3
`3 (17%)
`
`—
`—-
`
`no. 0/pollutlr
`
`—
`—
`-
`—
`12 (36%) 1
`0
`14 (42%) 3
`I (696)
`
`2l
`l1
`l9
`l6
`
`—o—-cweso
`
`‘Thefrequencyoltclponses undetermined tors: puientswhunaivuimnthmmatshieithuietiod l arPu'iuti2olIhI
`study. and was cumpsnd with the pnltsmotuorved in: control group of Iiipotlau randomly assigned to placebos! nary.
`1‘h:deye¢afreuponserqu=ents:iIi::rtIuecMngnotn-rvedaitsr llweeluofleu miiicdan or. forth twopuknugiven
`nmuwtrexuesndttiswvogiveapiaeebowlto dldootaomplcte l2 wulusoluuunut. themponne recnniatl tstlllofinclvibll.
`iP<0.05.
`N’<0.0l .
`
`The New Enwno Journal at Medlehe
`Downloaded hm nejn org at HARVARD UNIVERSITY en February 14. 2012 Fcrpanand uuenly. No ehor uni wilhcul aerm’ss5m.
`From the l\E.M Archive. Copyri_:1h:>Zi2IJI0t.1nssehusettshIedia sodoty. All rights reserved.
`
`attributable immunosuppression
`was found in the thymidine-incor-
`poration assays. Likewise, no distin-
`guishing immunologic alterations
`occurred in the subgroup of eight
`patients with dramatic responses to
`methotrexate. Six (18 per cent) of
`the 33 patients who received meth-
`otrcxate in the trial had stimulation
`
`indexes of less than 2 in response to
`all antigen challenges at study en-
`try. These anergic patients had a
`lower T4/T8 ratio at entry than the
`27 patients with responses to anti-
`gens in vitro, although this tenden-
`cy was not statistically significant
`(mean ratio :tS.E., 1.6=0.7 for the
`
`Page 4 of 5
`
`

`
`822
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`March 28. I985
`
`anergic group vs. 2.410.? for the immunocompetent
`group). This functional alteration in immunqcompe-
`tencc was not associated with prednisone therapy.
`DISCUSSION
`
`The results of this study confirm uncontrolled re-
`ports of the antiinflammatory effect oflow-dose meth-
`otrexate in patients with advanced rheumatoid arthri-
`tis that is resistant to conventional therapy.“ The
`recrudescence of the disease after methotrexate ther-
`
`apy and the significant methotrcxate-associated diiI'er-
`ence in disease variables between the groups at cross-
`over make it ditiieult to determine the degree of benefit
`attributable to the drug in the Period-2 trial. Gastro-
`intestinal problems were the most common adverse
`reactions to methotrexate in this short-term trial. The
`relatively small number of patients involved may ex-
`plain why the more serious adverse reactions that can
`occur with low-dose methotrexate administration —
`e.g.. bone-marrow suppression” or acute pulmonary
`toxicitym” — were absent in this study. Transami-
`nase elevation occurred in 2| per cent of the patients
`receiving methotreitate. The importance of these en-
`zyme elevations is uncertain; long-term administra-
`tion of low doses of methotrexate may be associated
`with hcpatotoxicity. "'9"
`One important question is whether subsets of pa.-
`tients with rheumatoid arthritis will have a better re-
`
`sponse to methotrexate. There was no indication that
`patients receiving concomitant low-dose prednlsonc
`therapy benefited more from methotrexate than pa-
`tients not taking this glucocorticoid. The results of this
`study are consistent with the proposal that a small
`subpopulation ofanergic patients with rheumatoid ar-
`thritis existsmm; the response of the patients to meth-
`otrexate did not exceed that of the immunocompetent
`participants, and they relnained anergic after therapy
`with this drug. The observation, which requires con-
`firmation, that patients with the HLA-DR2 haplotype
`respond markedly to low-dose methotrexate therapy
`is of interest. Earlier reports have related HLA-
`DR2/Dw2 with a better outcome in rheumatoid
`arthritis.”"""
`This trial, as well as the initially reported results of
`a randomized multicenter study.’-" provides evidence
`of the short-term value of low-dose methotrexatc in
`patients with rheumatoid arthritis uncontrolled by
`more conventional therapy. Lengthy prospective trials
`are required to determine ‘the ultimate benefits and
`disadvantages of this treatment.
`We nre indebted to Drs. Ronald Anderson, William Docken,
`Matthew Liang, and Jean Jackson for referring patients to this
`study; to Drs. Barbara Weissman and Leland Sosman for analysis of
`radiographs; to Ms. Agnes Maier [br administrative assistance; to
`Dr. Peter Schwartz and Ms. Kathleen Benfell for distributing the
`test medications; to Dr. K. Frank Austen for helpful discussions; to
`
`Ms. Donna Rowland. Rust-lynn Dynesius-Trentltam. Lynn Collins.
`and Lorie Lyrinlt for technical assistance; and to Ms. Dee Condor:
`and Irene Jordan for assistance in preparing the manuscript.
`
`Raransucas
`
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