`
`9
`
`THE EFFECT OF FOLIC ACID SUPPLEMENTATION
`ON THE TOXICITY OF LOW-DOSE METHOTREXATE
`IN PATIENTS WITH RHEUMAT_OID ARTHRITIS
`
`SARAH L. MORGAN, JOSEPH E. BAGGOIT, WILLIAM H. VAUGHN, PEGGY K,. YOUNG,
`JANET V. AUSTIN, CARLOS L. KRUMDIECK, and GRACIELA S. ALARCON
`
`Thirty-two patients with rheumatoid arthritis
`completed a 24-week, placebo-eontroUed, double-blind
`trial of foUc add (FA) supplementation during low-dose
`methotrexate (MTX) therapy. Administration of the
`daUy FA supplement slgnUlcantly lowered toxicity
`scores without aft'eding efftcac:y, as measured by joint
`counts, joint indices, and patient and physician evalua(cid:173)
`tion of disease ac:tfvity. Fifteen patients experienced
`some sort of toxicity; 67% were In tbe placebo group,
`and 33% were in the FA supplement group. Four
`patients In the placebo group bad toxicity levels serious
`enough to require discontinuation of the MTX, wbile no
`patients In the FA supplement group discontinued MTX
`because of toxicity. Low-normal Initial plasma and n,l
`blood ceO folate levels were predictive or future toxicity
`with MTX therapy. We conclude that a dally supple(cid:173)
`ment of 1 mg of FA during low-dose MTX therapy
`(median dose 7.5 mglweek [16.4 pmoles]) is useful In
`lessening toxicity without altering eJBcac:y during the
`ftnt 6 months or treatment.
`
`From the Department of Nutrition Sciences and the Divi·
`sion of Clinical Immunology and Rheumatology, Department or
`Medicine, 1bc University of Alabama at BlrJniniham.
`Supported by NIH grants SPOI-CA-28103·10 and !iP«).
`AR-20614. Dr. Morgan is the recipient or a Future Nutrition
`Leader's Award from the International Life Sciences Institute/
`Nutrition Foundation {1986-1988).
`Sarah L. Morgan, MD, RD. PACP; Joseph E. Baggott,
`PhD; William H. Vaughn, BS: Peggy K. Young, CMA; Janet V.
`Austin, BS; Carlos L. Krumdietk, MD. PhD; Graciela S. AJan;6n,
`MD, MPH, PACP.
`Address reprint requests to Sarah L. Morgan, MD, RD,
`FACP, The University of Alabama at Birmingham, Dcpanment of
`Nutrition Sciences. Webb Buildins--202, UAB Statio11, Binning·
`bam, AL 35294.
`Submitted for publication May 26. 1989; Ke:Cpted in revised
`form August 21. 1989.
`
`Ar1llritfJ 11DC1 Rheumatism, Vol. 33, No. 1 (JaniW')" 1990)
`
`The use ofthe folic acid (FA) antagonist, amin(cid:173)
`opterin, for the treatment of rheumatoid arthritis (RA)
`was first reported by Gubner et a1 in 1951 (1). Numer·
`ous double-blind, placebo-controlled trials have since
`established the efficacy of N-10-methylaminopterin
`(methotrexate; MTX) in the treatment of RA (2-7). A
`meta-analysis of numerous studies has shown that
`patients receiving MTX for RA have a 26% greater
`improvement in their joint counts and a 39% greater
`improvement in pain scores than do control patients
`receiving nonsteroidal antiinflammatory drugs
`(NSAIDs) with or without prednisone. The mejor
`factor limiting MTX treatment seems to be its toxicity
`(9,10). Toxic manifestations, suclt as nausea, stomati·
`tis, abnormal liver function, cytopenia, and pulmonary
`toxicity, have generally been reported in 30-60% of
`patients (7-10), and in 1 study, 90% of patients expe(cid:173)
`rienced toxicity (6).
`The folate status of patients before and during
`MTX therapy has received little attention, even
`though some clinical manifestations of folate defi(cid:173)
`ciency, such as cytopenia, anorexia, stomatitis, and
`gastrointestinal (GI) intolerance (11,12), are also ob(cid:173)
`served as toxic reactions during low~ose MTX treat(cid:173)
`ment for RA. It was therefore postulated that the
`administration ofF A would be useful in reducing toxic
`manifestations that occur during long-term treatment
`with low-dose MTX for RA. We report herein the
`results of a double-blind, placebo-controlled study
`designed· to test thi~ hypothesis.
`
`PATIENTS AND METHODS
`PaUents. Thirty-nine patients with RA that fulfilled
`the American Rheumatism Association 1958 criteria for
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`MORGAN ET AL
`
`Table 1. Baseline clinical and demographic characteristics of the
`rheumatoid arthritis patients studied•
`
`sulfasalazine, or hydroxycloroquine treatment had been
`discontinued for at least 10 days.
`During the study, each patient remained under the
`care of his or her rheumatologist, abstained from alcohol,
`and continued to receive stable doses of aspirin and/or
`NSAIDs. For those taking prednisone at study entry, the
`dosage was kept stable, not to exceed 10 mglday. It was
`required that both male and female patients either be prac(cid:173)
`ticing contraception or have no reproductive potential.
`Study design. The study was a double-blind, placebo(cid:173)
`controUed trial of 24 weeks duration. Patients were assigned
`to receive folate (I mg [2.2. p.moles]lday) or placebo. The 2
`groups were matched, by the study statistician, on the basis
`of sex, previous use of folate-containing vitamins, rheuma(cid:173)
`toid factor (RF) serology, and age. Identical FA- and placebo(cid:173)
`containing capsules were prepared by the Investigational
`Drug Service of the University of Alabama Hospital. using
`capsules provided.by Capsugel (Warner Lamben, Green(cid:173)
`wood. SC). Folic acid (pteroylglutamic acid) was obtained
`from Lederle Laboratories (Pearl River, NY). Spectropho(cid:173)
`tometric analysis indicated that the mean ± SD folate
`content was 1.03 ± 0.16 mg per capsule.
`Folate-containing vitamin preparations, if previously
`used, were stopped for the duration of the study. Oral MTX
`was begun at a dosage of 2.5-7.5 mg per week, and was
`increased in 2.5-mg increments at the discretion of the
`treating rheumatologist. The weekly dosage of MTX did not
`exceed 15 mg, and the median dosage for both groups was
`7.5 mg/week. The MTX tablets were generally ingested in
`equal numbers on 3 consecutive occasions at 12-hour inter(cid:173)
`vals, always beginning on the same day of the week. Neither
`the investigators, the patients, nor the treating rheumatolo(cid:173)
`gists were aware of the placebo/folic acid capsule assign(cid:173)
`ments until the study was completed. Patients were with(cid:173)
`drawn from MTX therapy at the discretion of the treating
`rheumatologist.
`Patients were evaluated immediately prior to initia(cid:173)
`tion of MTX (visit 1), and after approximately 12 weeks
`(range 10-14 weeks; visit 2) and 24 weeks (range 22-26
`weeks; visit 3) of MTX therapy. Patients were withdrawn
`from the study if they missed more than 3 weeks of MTX
`treatment for any reason.
`Clinical assessment. Each patient was examined and
`interviewed by the same physician/nutritionist (SLM) and
`rheumatology research assistant (JV A or PKY). Medication
`compliance was determined by direct questioning, and by
`pill counts when possible.
`The following clinical variables (5) were determined
`at each visit: I) the number of joints with swelling (of 58
`diarthrodial joints); 2) the number of joints with tenderness
`on pressure, pain on passive motion, or both (of60joints); 3)
`the joint swelling index, expressed as a sum, in which each
`joint was graded for swelling as 0 (none), I (mild), 2
`(moderate), or 3 (severe): 4) the joint tendemessJpain index,
`expressed as a sum with joints also graded on the above
`scale ofO (none) to 3 (severe); 5) mean grip strength for both
`hands; 6) the duration of morning stiffness, to the nearest
`hour; 7) the patient's assessment of disease activity, graded
`as 0 (asymptomatic), 1 (mild), 2 (moderate), 3 (severe), or 4
`(very severe); 8) the physician·s assessment or disease
`activity. graded on the same scale; 9) 1-day dietary recall,
`
`Age
`Maleslfemales
`Previous use of folate-
`containing vitaminst
`Years of disease
`Rheumatoid factor
`positive
`Initial serum folate, nglml
`
`Initial RBC folate, ng/ml
`
`Cancurrent use of
`NSAIDslaspirin
`Concurrent ·use of
`prednisone
`Anatomic stage§
`Cal')lal: metacarpal ratio§
`
`Folate group
`(n = 16)
`
`.52.0 ± 14.6
`3/13
`s
`8.7 ± s.s
`"
`8.0 ± .s.o
`(2.~20.9)
`3.55.9 ± 222.8
`(101-.539)
`14
`
`Placebo group
`(n = 16)
`.50.9 ± 13 . .5
`J/13
`2
`
`1~.3 ± 11.():1:
`16
`
`8.~ ± 6.0
`(l.l-23.1)
`361.3 :!: 193.4
`(146-m>
`16
`
`9
`
`8
`
`3.9 ± 1.1
`0.51 ± 0.03
`
`3.6 ± 1.3
`0 . .50 ± 0.03
`• Values are tbe mean :!: SD or tbe number of patients. Numbers in
`parentheses are ranges. RBC '"" red blood cell: NSAIDs = nonster(cid:173)
`oidal antiinflammatory drugs.
`* p < 0.0.5.
`t Mean 400 p.g folatelday.
`
`§ For explanation, see refs. 14-16.
`
`definite or classic disease (13) gave informed consent and
`entered the study, which was approved by the Institutional
`Review Board of The University of Alabama at Birmingham.
`Seven patients could not be included in the data analysis: 4
`because of noncompliance with the MTX regimen, 2 because
`of administration of intramuscular MTX, and 1 because of
`self-medication with large amounts of FA. None of these 7
`patients were withdrawn because of the occurrence of toxic
`manifestations. Demographic and clinical characteristics of
`the 32 patients who completed the study arc presented in
`Table 1.
`Criteria for entry into the study included RA of more
`than 6 months duration, with onset after 16 years of age, and
`at least 3 of the following: <=::) swollen joints, ~6 or more
`tender joints, 2:45 minutes of morning stiffness, and a
`Westel'l!ren erythrocyte sedimentation rate (ESR) of ~28
`mmlbour. Radiographs were read by the project rheumatol·
`ogist (GSA) in a blinded manner. The anatomic grading
`criteria of Berens and Lin (14), as modified by Trentllam and
`Masi (15), as well as the carpal: metacarpal (C:MC) ratio (l.S),
`were used to assess the radiographs. These measurements
`had been previously used and validated at our institution and
`had been found to be reliable (16).
`Patients with serious concomitant medical illnesses
`such as cancer, liver or renal disease. liver enzyme levels
`more than twice the upper limit of normal, white blood cell
`CWBC) counts <3,5001mm3 , or platelet counts <I 50,0001
`mm3 were excluded from the trial. Previous use of MTX
`within the past 6 months and treatment with total lympho(cid:173)
`cyte irradiation were also exclusion criteria. Patients were
`not accepted into the trial until gold salts, D-penicillamine,
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`FOLIC ACID SUPPLEMENTS IN MTX-TREATED RA
`
`11
`
`using food models, which was coded using the Ohio State
`Nutrient Data Base (Unison Systems Associates, Colum(cid:173)
`bus, OH); 10) current medications and dosages; and 1 I) toxic
`side effects. Before beginning MTX, each patient was coun·
`seled by his or her attending rheumatologist with regard to
`possible toxic side effects. The presence of such side effects
`was investigated by asking the question, "Is the MTX
`medication causing you any problems?" Toxicity was also
`noted and recorded every 3 weeks by telephone interview.
`A toxicity score (TS) was determined for each pa·
`tient. The scoring system was based on the clinical experi(cid:173)
`ences of the investigators and represents an attempt to
`distinguish mild and marginal toxic symptoms (e.g., alope(cid:173)
`cia) from severe and medically important ones (e.g., cytope·
`nias) (10). As shown below, it was designed to increase in
`proportion to the duration of toxic events, their intensity,
`and their clinical significance, and to decrease with the time
`on the protocol at which the toxic manifestations first
`appeared (i.e., if a toxic reaction occurred early in the course
`of treatment, this would result in a higher toxicity score than
`if the same reaction occurred only after a longer course of
`treatment). The duration of the toxic event was placed in the
`numerator of the toxicity score, in order to quantitatively
`emphasize persistent morbidities while minimizing the con·
`tribution of transitory morbidities and spurious abnormal
`laboratory values. The TS was calculated as follows:
`
`TS=I [
`
`(duration of toxic events [weeks]) x (intensity)]
`x (clinical severity factor)
`weeks on protocol
`where intensity = 1 (mild), 2 (moderate), or 3 (severe); and
`clinical severity factor = J (alopecia, nausea, pruritus,
`anorexia and/or general GJ intolerance [pyrosis, cramps,
`etc.]), 2 (vomiting, diarrhea, stomatitis and/or rash), 3 (ele·
`vated liver enzyme levels and/or elevated serum creatinine
`level), or 4 (cytopenia, documented infections, and/or pul·
`monary toxicity).
`Abnonnal results on liver function tests were defined
`as transaminase and/or alkaline phosphatase values > 2 times
`the baseline levels; cytopenia was defined as a WBC count
`<3S,OOO/mm3 or a platelet count <150,000/mm'; elevated
`serum creatinine level was defined as > 1.5 mg/dl; and
`pulmonary toxicity was defined as evidence of new intersti·
`tial pulmonary infiltrates compared with the baseline chest
`radiograph, with evidence of restrictive changes seen on
`pulmonary function tests (i.e., vital capacity <80% of pre(cid:173)
`dicted, normal expiratory flow rates, normal maximal vol·
`untary ventilation, and carbon monoxide diffusing capacity
`<70% of normal [17]). Infection was defined as a docu(cid:173)
`mented viral, bacterial, or fungal infection that compromised
`the patient's condition significantly, require;d hospitaliza(cid:173)
`tion, and/or required administration of systerpic antibiotics
`or antlfunp.l agents. Any abnormality in transjlminase level,
`alkaline phosphatase level, WBC count, or platelet count,
`documented infection believed to be related 10 the MTX, or
`pulmonary toxicity was given an intensity score of 3
`(severe).
`Overall respanse to treatment was determined by a
`modification of the criteria developed by the Cooperative
`Systematic Studies of the Rheumatic Diseases group (18,
`
`Table l. Mean ~ SO cumulative doses of methotrexate (MTX) and
`dietary intake or folate and vitamin 811
`Visit I
`
`Visit 2
`
`Visit 3
`
`Cumulative MTX dose, mg
`Folate group
`Placebo group
`Dietary folate intake,
`J.Lg/day
`Folate group
`Placebo group
`Dielary vilamin 8 11 intake,
`J.LWrJay
`Folate group
`Placebo group
`
`80 ~ 21
`70 ~ 25
`
`183 ~ 64
`ISO ~ 37
`
`196:!: 112
`206:!; 176
`
`274 ~ 189
`ISO :t: 90
`
`220 ± 135
`131 ~ 53
`
`2.1 ~ 1.4
`2.2 ~ 1.0
`
`3.2 ± 2.6
`1.5::!: 0.9
`
`2.0 ~ 1.8
`2.0::!: 1.2
`
`19), as follows. The score on the joint swelling index and the
`joint tenderness/pain index at visit 2 and/or visit 3 was.
`compared with the score at visit I. Marked improvement
`was defined as a <!:.50% decrease in these scores, moderate
`improvement was defined as a 31-49% decrease in the index,
`no change was defined as a score remaining within 30% of
`the original value, and worsening was defined as a >30%
`increase in the score. Improvement and worsening in the
`physician or patient assessment of disease activity were
`defined as changes of at least 2 integers on the 5-point scales.
`Laboratory assessment. At visit 1, the complete blood
`cell count (CBC) including platelet count, Westergren ESR,
`liver enzyme levels (aspartate aminotransferase [AST] and
`alkaline phosphatase), RF titer, and serum creatinine level
`were determined. Followup CBC, creatinine studies, and
`liver function tests were performed at the discretion of each
`patient's rheumatologist and were generally repealed at each
`followup visit. Tests were performed more often ·(usually
`weekly) if an abnormal value was obtained.
`Biochemical assessment. At visits 1, 2, and 3, blood
`was obtained for a vitamin screen (serum and red blood cell
`[RBC) folate, serum vitamin BIZ, vitamin C, vitamin A,
`,:H:arotene, vitamin 8 6 , thiamine, and riboflavin) and for
`determination of the C 1 index, by methods previously de(cid:173)
`scribed (20,21). The C 1 index measures the activity of a
`folate-dependent enzyme system in peripheral blood mono(cid:173)
`nuclear cells by assaying the fonnation of serine from
`glycine and radiolabeled formate.
`StatisUcal analysis. Either Student's l·test or analysis
`of variance folloWed by the least significant difference test
`was used to compare means of normally ~istributed data.
`The Wilcoxon signed rank test was used with C 1 index data.
`Speannan's rank correlation test and chi-square analysis
`were used when appropriate (22). P values less than or equal
`to O.OS were considered significant.
`
`RESULTS
`Characteristics of the patient groups. Sixteen of
`the 32 patients were in the folate supplement group,
`and 16 were in the placebo group. Findings from pill
`counts and questioning suggested a high degree of
`compliance wilh the MTX and FA/placebo regimen.
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`
`MORGAN ET AL
`
`Table J. Patient response to methotrexate treatment•
`
`Variable,
`patient group
`
`Marked
`improvement
`
`No. of patients
`Marked or
`moderate
`improvement
`
`Moderate
`improvement
`
`No
`change Worsening
`
`6
`5
`
`7
`3
`
`s
`7
`s
`7
`
`3
`4
`
`8
`3
`
`s
`7
`
`4
`6
`
`3
`2
`
`3
`s
`
`3
`2
`
`s
`3
`
`2
`3
`
`I
`0
`
`4
`1
`
`·Swelling index
`Visit 2
`Folate
`Placebo
`Visit 3
`Folate
`Placebo
`~nhenderness index
`Visit 1
`Folate
`Placebo
`Visit]
`· Folate
`Placebo
`Joint swellill8 count
`Visit 2
`Folate
`Placebo
`· Visit 3
`Folate
`Placebo
`Joint pain/tenderness count
`Visit 2
`Folate
`Placebo
`Visit3
`Folate
`Placebo
`Physician assessment
`Visit 2
`Folate
`Placebo
`Visit 3
`Folate
`Placebo
`Patient ~sment
`Visit 2
`Folate
`Placebo
`Visit 3
`Folate
`Placebo
`
`5
`s
`4
`3
`
`s
`2
`
`4
`0
`
`4
`s
`3
`s
`
`6
`2
`
`4
`2
`
`13
`II
`
`11
`10
`
`11
`8
`
`12
`10
`
`0
`2
`
`3
`4
`
`3
`3
`
`2
`2
`
`2
`1
`
`2
`s
`3
`3
`
`0
`I
`
`0
`0
`
`0
`2
`
`0
`D
`
`I
`0
`
`2
`0
`
`3
`4
`
`3
`2
`
`• The initial study population consisted or 16 patients in the folate group and 16 in the placebo group.
`Numbers shown total less than 16 for each visit because patients dropped out of the study, missed
`visits, or the variable was not determined.
`
`The mean duration of disease was longer in the placebo(cid:173)
`treated group; other baseline demographic and clinical
`characteristics, including disease severity as measured
`by joint counts, anatomic stage, and C:MC ratio, were
`not difl'erent between lhe groups (Table 1). There
`were no statistically significant differences between
`the groups in baseline hemoglobin or hematocrit
`values, mean corpuscular volume (MCV), WBC
`counts, or AST, alkaline phosphatase, or serum ere-
`
`atinine levels. The groups did not differ in their initial
`mean serum and RBC folate levels. In addition, there
`was no significant difference between the groups in
`their mean dietary intake of folate or vitamin B 12, or in
`the cumulative MTX intake at any of the visits (Table
`2). While there was a trend toward higher dietary
`folate consumption in the folate supplement group. it
`was not biologically important. given the much larger
`amount of FA that these patients received in the form
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`FOLIC ACID SUPPLEMENTS IN MTX-TREATED RA
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`13
`
`• ....
`
`•
`
`I
`
`...
`1•
`
`u .. 55
`
`j I
`
`•
`
`• •
`
`0
`
`0
`
`' r.
`§
`,.. ll
`....
`~ 2
`0 .... ,
`>C
`
`0
`
`•
`
`• •
`
`•
`
`- •
`
`A
`
`• •
`
`•
`
`•
`
`15
`10
`PLASMA FOLATE
`
`10
`
`25
`
`8
`
`••
`•
`
`
`• •
`
`•
`
`•
`
`• •
`
`of the supplement. In addition, the patients' mean
`dietary intake of folate was below the recommended
`dietary allowance of 400 JJ.g/day (23).
`Efficacy. Table 3 shows a comparison between
`the folate supplement and the placebo groups in their
`degree of response to MTX treatment. Chi-square
`analysis failed to show any statistically significant
`difference between the 2 groups in the degree of
`improvement.
`Toxidty and patient dropout. Fifteen patients
`(47%) experienced some form of toxicity; of these, 10
`(67%) were· in the placebo group, and S (33%) were in
`the folate supplement group. The toxic manifestations
`observed and the number of patients experiencing the
`reaction,· in the placebo group and the folate supple(cid:173)
`ment group, respectively, were as follows; nausea 8
`and 5, elevations in liver enzyme levels 3 and 0,
`cytopenia 1 and I, anorexia 2 and 0, alopecia 0 and 2,
`constipation/bloating 1 and 0, pyrosis I and 0, stomach
`cramps 0 and 1, stomatitis 0 and 1 , and transiently
`elevated creatinine levels 1 and 0.
`
`•
`
`•
`•
`
`......
`•
`.,
`.....
`
`w4
`a::
`0
`0
`(I)
`>-.....
`u x
`0 .....
`
`y
`
`-·-
`••••• ••• •••
`
`FOLATE
`PLACEBO
`Fipre 1. Toxicity scores in the folate supplement and placebo
`aroups. Horizontal bars show the mean SCOTC3 (0.21 and 1.06,
`respectively; P = 0.027). See Patients and Methods for explanation
`or toxicity score calculation.
`
`100
`
`100
`
`zoo
`
`500
`
`400
`500
`RBC FOlATE
`Figun 2. Correlation of toxicity score (TS; see Patients and Mcth·
`ods) with initial plasma (A) and red blood cell (RBC) {B) folate levels
`<n&'ml) in the placebo group. Speannan's rank correlation coeffi(cid:173)
`cient was -0.84 (P < 0.01) and -0.66 (P < 0.01) for plasma and
`RBC folate levels, respectively. Normal levels of plasma and RBC
`folate are 2:2 nglml and 2:140 ngfml, respec:tivcly.
`
`Five of the patients (16%) dropped out of the
`study before visit 3. Four of these patients were in the
`placebo group; their toxicity scores were t .0, 2.67,
`3.0, and 5.1. MTX had to be discontinued in these
`patients because of toxicity. The toxic reactions ob(cid:173)
`served in the 4 patients were severe nausea, anorexia,
`constipation, persistently elevated liver enzyme levels
`(2 or more determinations 1 week apart), cytopenia,
`and elevated creatinine levels. Elevated creatinine
`levels were attributed to MTX toxicity since they
`normalized following discontinuation of the drug. In
`the 1 patient in the folate supplement group who was
`withdrawn from the study, MTX treatment was
`stopped, not because of toxicity, but in preparation for
`surgical joint replacement .
`The mean toxiCity score in the folate supple(cid:173)
`ment group was significantly lower than that in the
`placebo group (Figure 1). Minor toxicity (i.e., toxicity
`score <0.2) or no toxicity occurred in 12 patients in
`the folate supplement group, whereas only 7 patients
`in the placebo group were in this category.
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`I~
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`10
`
`•
`•
`
`•
`•
`••
`_!.L. •
`•
`••
`•
`•
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`:E 5
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`-5~---------------------------
`FOLATE
`PLACEBO
`Figure 3. Changes in mean corpuscular volume (MeV) (in ft) from
`visit 1 to visit 3 in the folate supplement and placebo groups.
`Ho!Uontal bars show the mean changes (1.9 0 (not significallt} in the
`folate group and .5.8 ft [P < O.OS) in the pla«bo group). The mean
`c:hangc in the placebo sroup was significantly higher than that in the
`folalc group (P < 0.01). Mean :t SO MCV values ia the folate group
`and the placebo group, respectively, were 86.4 ± 8.8 fl and 84.0 ±
`8.3 ft at visit 1, and 89.3 ± 8 • .5 ft and 89.8 ± 6.2 Rat visit 3.
`
`MORGAN ET AL
`
`A significant increase over time in the mean MCV was
`not seen in the folate supplement group. The increase
`in the mean MCV was significantly higher in the
`placebo group than in the folate supplement group.
`Biochemical analysis. As seen in Table 4, there
`was a decrease over time in the mean C1 index from
`visit 1 in the group of patients as a whole, but this was
`statistically significant only at visit 2. However. when
`the treatment groups were compared. the mean de(cid:173)
`crease in the C 1 index in the placebo group was greater
`than that in the folate supplement group. Thus, the
`drop in the C 1 index reflects not only the expected
`MTX antagonism of folate-requiring pathways, but
`also the partial protection conferred by the simulta·
`neous administration of the FA supplement.
`A severe decrease in the mean C1 index was
`associated with moderate toxicity, while minor or no
`toxicity was associated with no change in the C 1 index
`(Table 5). In patients with improved swelling and
`improved pain/tenderness indices (i.e.. marked im·
`provement or moderate improvement), toxicity was
`also associated with a severe drop in the mean C 1
`index, while patients who showed clinical improve(cid:173)
`ment without nuUOr to~icity had only a moderate
`decrease in the C1 index. Some degree of suppression
`of the C1 index was associated with, and may be
`necessary for, efficacy, regardless of toxicity. As
`shown in Table 5, patients with improved pain/
`tenderness indices and patients with improved swell(cid:173)
`ing indices had mean decreases in the C1 index of31%
`and 42%, respectively, whereas patients with no im(cid:173)
`provement in these joint indices had little or no sup(cid:173)
`pression of the c1 index.
`
`DISCUSSION
`The efficacy of low-dose methotrexate in the
`treatment of RA was not compromised by supplemen·
`
`Table 4. Mean pcn:ent chanp in the C 1 index, from visit 1•
`Visit 3
`Visit 2
`Group
`-4J(26)t
`-12 (24)
`All patients
`s (12)
`-18 (12)
`Folate
`-&.5 (14)1
`-3-4 (12)t
`Plac:ebo
`• The C1 index measures the activity or a folate-dependent enzyme
`system in peripheral blood mononuc:lcar c:cDs (see refs. 20 and 21).
`Suteen patients in the folate aroup and I 6 patients in the placebo
`group were evaluated at visit I. Numben in parcnthesea are o values
`at visits 2 and 3.
`t P < 0.01 venus visit 1.
`t P < 0.0.5 venus visit I.
`
`The toxicity scores in the placebo group
`showed significant negative correlation with the initial
`plasma (Figure 2A) and RBC (Figure 2B) folate levels.
`These correlations were not found in the folate sup(cid:173)
`plement group, even though 4 patients in this group
`had low·nonnal initial plasma folate levels (i.e., <3.5
`ng/ml). Of the 4 patients in the placebo group who
`discontinued MTX treatment. 3 had initial plasma
`folate levels of <3.5 ng/ml, while the remaining patient
`had a level of 5.3 ng/ml.
`Laboratory findings. The mean values for hem(cid:173)
`atocrit, WBC count, platelet count. creatinine, AST.
`and alkaline phosphatase did not differ significantly
`between or within the groups at any of the visits.
`Compared with visit 1, there was a significant increase
`in the MCV at visit 3 in the placebo group (Figure 3).
`
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`
`FOLIC ACID SUPPLEMENTS IN MTX-TREATED RA
`
`15
`
`Table 5. Mean pertent change in the C, index from visit I. by
`degree of toxicity or improvement with methotrexate treatment•
`
`Minor or no toxicity
`Moderate toxicity
`
`Swelling index improved(cid:173)
`Swelling index not improved
`
`Pain and tenderness index improved
`Pain and tenderness index not improved
`
`Swellill8 index improved/minor or no toxicity
`Swelling index improved/moderate toxicity
`
`Pain and tenderness index improved/minor or no
`toxicity
`Pain and tenderness index improved/moderate
`toxicity
`
`0 (30)
`-54 (20)t
`
`-42"(28)t
`5 (22)
`
`-31 (23)1
`-23 (25)
`
`-24 (17)
`-60 (ll)t
`
`-16(17)*
`
`_,. (8)*
`
`• The C1 index measures the activity of a folate-dependent enzyme
`system in peripheral blood mononuclear ceUs (sec refs. 20 and 21).
`Values are the mean from visits 2 and 3 combined. Numbers in
`parentheses are n values used to calculate the mean. Moderate
`toxicity was defined as a toxicity score >0.2 (sec Patients and
`Methods). Improvement in joint indices was defined as a decrease of
`> 30% from visit I.
`t P <: 0.01 versus visit I.
`* P < 0.05 versus visit I.
`
`tation with daily FA during the period investigated in
`this tria], i.e., the first 6 months of therapy. Since
`35-40% of the US population uses nonprescribed,
`over-the-counter vitamin supplements (24, 25), and
`FA is among the supplements that are available over
`the counter, this finding of a lack of a detrimental
`effect is useful information for clinicians whose pa(cid:173)
`tients are taking MTX. Our results with folic acid are
`in contrast with those of studies on the effect of folinic
`acid (leucovorin) on MTX efficacy (26-30). In I recent
`study, folinic acid at 4S mg/week (beginning 4 hours
`after MTX administration) lessened GI and other toxic
`manifestations, but completely negated the efficacy of
`the MTX (26). Since folinic acid is a stable reduced
`folate (S~formyl-tetrahydrofolic acid) that bypasses
`dihydrofolate reductase inhibition, dosage levels and
`intervals of administration may be more critical than
`with the fully oxidized (i.e., FA) form of the vitamin (30).
`Supplementation with FA, I mglday, signifi(cid:173)
`cantly reduced toxic manifestations of treatment with
`low-dose MTX. Although the placebo group had a
`longer mean duration of disease, the 2 study groups
`were comparable in all other paramet~rs m~ured,
`suggesting that longer disease duration could not have
`accounted for the differences observed. The median
`weekly dosage of MTX in the folate supplemept group
`was 7.5 mg. Patients treated with substantially higher
`
`doses of MTX may require supplementation with >I
`mg of FA per day to reduce toxicity.
`There has not been a controlled trial of the
`effect on MTX toxicity with the use of FA supplemen(cid:173)
`tation at higher doses. Some investigators have pre(cid:173)
`scribed FA at> 1 mg/day for MTX-treated RA patients
`(31,32), but its use has been controversial because of
`potential effects on disease response (33,34).
`The concurrent administration of a drug and its
`antagonist is not without precedent in RA, as indicated
`by reports of successful l).penicillamine therapy with
`vitamin B6 supplementation (35,36). It should be
`pointed out that FA is a weaker MTX antagonist than.
`is leucovorin. Therefore, concerns that FA supple(cid:173)
`mentation wiU cause loss of therapeutic efficacy of
`MTX are not well founded.
`Low-normal initial folate levels in our placebo
`group were correlated with a high probability of even(cid:173)
`tual MTX toxicity, strongly suggesting that MTX
`therapy in a folate-depleted patient predisposes that
`individual to toxicity. A similar correlation between
`initial folate status and MTX toxicity has been ob(cid:173)
`served in patients treated for tumors of the head and
`neck (37). Such a correlation was not found in our
`folate supplement group, because patients with mar(cid:173)
`ginal baseline folate levels in this group underwent
`repletion of their folat.e stores concurrently with MTX
`therapy. Therefore, low-norrruil folate status should be
`included among ·other well-reoognized factors (38-42)
`as a contrnindic~tion for M* treatment in patients
`with RA. This observation tak'es on added importance
`since marginal fE)Iate nutritu~ may be fairly common
`in RA (43,44). ·it is hlso likely that marginal· folate
`nutriture is an uqreco311ized determinant of toxicity in,
`and hence a contraindication for the initiation of MTX
`therapy for, psoi'iasis (4S), asthma (46), and a variety
`of other conditions (4.7).
`Af\alYsis of la~er numbers of patients over time
`will help to detem:tine if MTX toxicity is less likely in
`patients with normal ~initial folate status; it is known
`that folat.e stat\J~, be~omes i:mpaired with long-term
`administration of MTX (20). The impaired utilization
`of folates' in patients with vitamin Bu deficiency (48)
`would Su~est that vitamin 9~2 levets should also be
`checked prior to initiation of 'MTX therapy, although
`the imPOrtance of low B.:z values in RA is not com(cid:173)
`pletely udderstood (49).
`Th~ data in Table 4 suggest that careful adjust(cid:173)
`ment of ~he extent of folate. antagonism and of the
`dosage-o(FA is necessary in order to maintain clinical
`
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`•
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`16
`
`response without toxicity. Patient improvement, as
`judged by joint indices, was associated with a decrease
`in .the folate-dependent enzyme activities reflected in
`the.C1 index, whereas those patients with no improve(cid:173)
`ment had a smaller decrease, or even an increase, in
`the C1 index. 1Jtis is consistent with the fact that
`sulfasalazine, also an inhibitor of folate-dependent
`enzymes including those involved in the C 1 index, is,
`like MTX, useful in the treatment of RA (5~52). The
`association of severe folate antagonism with toxicity is
`demonstrated by the fact that the C 1 index dropped to
`significantly lower levels in the patients with toxicity,
`versus those with no toxicity. Clinically, this is c