1160

BRIEF REPORT

COMBINATION METHOTREXATE AND SULFASALAZINE IN THE

MANAGEMENT OF RHEUMATOID ARTHRITIS: CASE OBSERVATIONS

J. B. SHIROKY, C. S. WATTS, and C. NEVILLE

Four patients with rheumatoid arthritis received a combination of methotrexate and sulfasalazine for a mean
of 24 months (range 20-28 months). All 4 patients experienced clinical improvement, with a reduction in the number
of involved joints and in morning stiffness. In all 3 patients who had previously taken methotrexate, we were able to
reduce the dosage, and the prednisone dosage was reduced in 2 of 3 patients who had previ-ously taken that drug. No
serious toxicity was observed in any patient.

Existing agents used to treat rheumatoid arthri-tis (RA) often fail to provide complete control of the disease
symptoms and processes. There is a subset of patients whose disease progresses inexorably and who experience
repeated drug therapy failures, either be-cause of intolerance or because of inefficacy of the drug itself. Currently, it is
believed that better disease control, rather than better symptomatic control, will result in better long-term functional
outcomes for RA patients. This has fueled an interest in the use of combinations of second-line agents in the hope of
obtaining either additive or synergistic effects ( I ) . The concept of second-line agent combinations is a natural

From the Division of Rheumatology. Department of Medi-cine, Montreal General Hospital. McGill University. Montreal, Quebec, Canada.
Supported by the Montreal General Hospital Foundation and by grants 5-269-88 and 5-270-88 from the Arthritis Society of Canada.
J . B. Shiroky, MD, FRCP(C): C. S. Watts, MD. FRCP(C):
C. Neville, BA, RN.
Address reprint requests to J. B. Shiroky, MD, FRCP(C).
Montreal General Hospital. 1650 Cedar Avenue, Montreal, Quebec.
H3G 1A4, Canada.
Submitted for publication January 3 I . 1989; accepted in revised form April 1 I , 1989.
extension of the current practice of combining a non-steroidal antiinflammatory drug (NSAID) (a second-line agent)
and intraarticular corticosteroids, with or without systemic corticosteroids. It is hoped that the benefits far outweigh
potential risks of serious adverse reactions engendered by drug interactions.
Recently, both methotrexate (MTX) and sul-fasalazine have gained acceptance as effective thera-pies for RA
(2,3). Although there is the potential for adverse interaction between sulfonamides and MTX
(4) , such interactions may not be clinically significant ( 2 ) . We report herein our observations of 4 patients with RA
who were treated with this drug combination for a mean of 24 months (range 20-28 months). The demographic and
disease characteristics of the pa-tients are summarized in Table l . These patients represent all the patients from 1
practice who were given this particular drug combination. We are un-aware of any other cases reported in the literature.

CASE REPORTS
Patient 1. Patient 1, a 56-year-old man, had a 23-year history of nodular, erosive, seropositive RA and stable
Caplan’s syndrome. His medical history included tuberculosis of the right kidney and recurrent peptic ulcers. He had
mild stable renal insufficiency (serum creatinine level 144 prnolesiliter) due to a nonfunctioning right kidney.
In March 1982, it was decided to begin treat-ment with MTX. At that time, he had 16 joints with active disease
and was experiencing more than 2 hours of morning stiffness. Although there was initial clinical improvement at a
dosage of 7.5 mg weekly (given in an oral pulse), in June 1985, his arthritis flared again, and

Arthritis and Rheumatism, Vol. 32, No. 9 (September 1989)

BRIEF REPORTS 1161

Table 1. Characteristics of 4 rheumatoid arthritis patients treated with a combination of methotrexate

and sulfasalazine
Duration of
arthritis Anatomic Prior second-line
Patient Ageisex (years) stage* therapies
I 561M 23 111 Gold ‴
Penicillamine ″
Hydroxychloroquine ‴
Azathioprine ″
Methotrexate ‴
2 63lM 15 111 Gold ‴
Penicillamine ‴
Methotrexate ‴
3 SOIF 9 11 Chloroquine ‴
Gold ″
Penicillamine ″
Methotrexate ‴
4 651M 6 111 Sulfasalazine ‴
Sulfasalazineigold ‴
* According to the criteria of Steinbrocker et al (15).
‴ Ineffective.
″ Toxic reaction.

he had 25 involved joints and at least 5 hours of morning stiffness. The MTX was switched to an intra-muscular (IM)
administration, and the dosage was steadily increased to 30 mg weekly over the next 12 months. His most severely
involved joints were treated with intraarticular corticosteroids.
Sulfasalazine (1.5 gm daily) was added to the MTX regimen in September 1986. By the end of 6 weeks of this
combined therapy, he had virtually no morning stiffness and minimal disease activity in 5 joints. The MTX dosage was
lowered to 20 mg weekly. In December 1986, the sulfasalazine was withheld because the patient had mild anemia
(hemoglobin level 10 gm/liter). Within 1 week, his arthritis flared. The anemia subsequently resolved, and the MTX
dosage was increased to 30 mg. Six weeks later, when there had been no improvement in the arthritis, it was decided to
restart the sulfasalazine. Within 6-8 weeks, he had no morning stiffness and only minimal disease activity in 5 joints.
Subsequently, the MTX dosage was tapered slowly until it was discontinued in No-vember 1987.

By January 1988, his disease was again flaring. The sulfasalazine dosage was increased to 3.0 gm daily, but this
resulted in no improvement over the next 3 months. The MTX was begun again, and within 8 weeks, the arthritis
subsided. At that time, the MTX dosage was 7.5 mg weekly, orally, and the sulfasala-zine dosage was 2.0 gm daily.
Over the ensuing 6
months, he had very little clinical evidence of disease activity .
Throughout the 27 months of therapy with the combined drugs, the patient’s rheumatoid factor titer and
erythrocyte sedimentation rate fluctuated, but this was not correlated with his clinical symptoms and other laboratory
findings.
No clinical side effects were identified. At the time the patient was receiving 30 mg IM MTX, tran-sient
elevations in the serum transaminase levels (as-partate aminotransferase and alanine aminotrans-ferase) were noted, but
they were well below twice the upper limit of normal. Although his blood cell levels remained normal after a
maintenance dosage had been achieved and the disease had stabilized, the mean corpuscular volume (MCV) rose to
approximately 1 0 4 . 0 ~ There~. was a transient increase to 116.0p3, which was associated with low serum and red
blood cell folate levels. This was treated with a brief course of oral folate supplementation, and no anemia was noted.
Patient 2. Patient 2 was a 63-year-old man with
a 15-year history of nodular, erosive, seropositive RA and stable Caplan’s syndrome. His medical history included
recurrent peptic ulcer disease, which was caused by NSAIDs, and mild hypertension. In 1984, methotrexate therapy
was begun. At that time, he had 26 involved joints, and was experiencing at least 1V2 hours of morning stiffness. His
initial dosage was 7.5
1162 BRIEF REPORTS

mg IM weekly, which was slowly increased to 15 mg 1M weekly. At that dosage, moderate pancytopenia (white blood
cell count 1.7 x IO’iliter, hemoglobin level 99.0 gm/liter, platelet count I10 x lO’/Iiter) developed. The MTX was
temporarily discontinued and then restarted at the initial dosage of 7.5 mg 1M weekly.

In 1986, the MTX dosage was slowly increased because the arthritis became more severe. He was given oral
and intraarticular corticosteroids to control his most acute symptoms. Within 12 months, he was receiving 35 mg IM
weekly, but there was still no improvement in his condition. In April 1987, treatment with sulfasalazine was started, and
the dosage was increased to 2.0 gm daily within 3 weeks. By June 1987, there was a notable improvement in his symp-
toms. By September 1987, there was no evidence of active synovitis, and he experienced fewer than 30 minutes of
morning stiffness. His dosage of sulfasala-zine was 2.0 gm daily, and the MTX had been tapered to 15 mg IM weekly.

In March 1988, when he was receiving 7.5 mg of methotrexate IM weekly and 2.0 gm of sulfasalazine daily, the
patient decided to try receiving his MTX every second week. By early May, his arthritis was Raring and he returned to
weekly injections. His condition finally stabilized at a dosage of 12.5 mg IM weekly. In mid-summer 1988, he
experienced a period of severe situational depression requiring a brief ad-mission to the hospital. After he was
discharged, he returned only erratically for his injections (every 2-3 weeks), and the arthritis subsequently flared. Once
again, weekly injections were initiated and resulted in a stabilization of his clinical symptoms.
As with the preceding patient, this patient’s serum rheumatoid factor titer and erythrocyte sedi-mentation rate
fluctuated considerably without consis-tently reflecting the changes in clinical status. No clinical or laboratory
evidence of an adverse reaction was noted after the disease stabilized. Serial serum and red blood cell folate levels also
remained normal.
Patient 3. Patient 3, a 50-year-old woman, had a 9-year history of erosive, seronegative RA in addition to
having Hashimoto’s thyroiditis. MTX therapy was begun in May 1984, at which time she had 26 involved joints and
was constantly stiff throughout the day. By January 1985, when she was receiving 15 mg IM weekly, there was a
notable improvement in her symptoms. There had been brief interruptions in the treatment because of transient mouth
sores. By May, her arthritis was inactive.
 In late spring of 1986, while still receiving the same dosage of MTX, she experienced a flare of the disease, and
by July she had 29 involved joints. Sulfasalazine (2.0 gm daily) was added to her regimen. Within 8 weeks, there was
some improvement, and by January 1987, she had no involved joints. Over the next 1 l/z years, there were 2
unsuccessful attempts to discontinue the MTX. Her arthritis became mildly active, and 5-8 joints were involved. The
symptoms did not subside when the sulfasalzine dosage was increased to 3.0 gm. With the restoration of MTX, 10 mg
orally, her arthritis once again became quiescent. She has been maintained on a regimen of MTX, 10 mglweek orally,
and sulfasalazine, 2 gmlday.
Her erythrocyte sedimentation rate never ex-ceeded 20 mm/hour, but after the disease stabilized, her
hemoglobin level rose from 108 gm/liter to 127 gmhter . There was also an increase in the MCV to 104.0p’. Serial red
blood cell and serum folate levels remained normal, and no other adverse effects of therapy were noted.
Patient 4. Patient 4 was a 65-year-old man with nodular, erosive, seropositive RA of 6 years duration and
Crohn’s disease. His medical history included a remote partial gastrectomy for peptic ulcer disease, iron and vitamin
B,, deficiencies, and seborrhea.
In June 1983, he had at least 14 joints with active disease and 5 hours of morning stiffness. He had been treated
with sulfasalazine and prednisone since the onset of the Crohn’s disease 5 years previously, and was currently
receiving 2.0 gm daily and 5 mg daily of the 2 drugs, respectively. There was no symptomatic improvement with this
regimen, and in early 1986, he began a brief course of treatment with sodium aurothiomalate. His daily dosage of 2.0
gm sulfasalazine was maintained because of recurrent bouts of diarrhea. After an initial period when he appeared to
improve, his arthritis flared once again in September 1986, and at least 27 joints were involved. Weekly injections of
gold were resumed, and the prednisone and sulfasalazine dosages were increased to 7.5 mg and 4.0 gm daily,
respectively.
No improvement was noted, and in early 1987, MTX (7.5 mg weekly, orally) was added to his treat-ment
regimen. By this time, he had 34 joints with active disease and morning stiffness varying between 1 and 3 hours. By July
1987, there was some improve-ment, and over the second half of that year, the MTX dosage was slowly increased to 12.5
mg weekly. By March 1988, he had 5-10 minutes of morning stiffness
BRIEF REPORTS 1163

Table 2. Details of treatment regimens of the patients studied*

MTX Sulfasalazine Prednisone Duration of
(mg/week) (gmiday) (mglday) combination
Patient Initial Final Initial Final Initial Final (months)
1 30.0, IM 7.5, IM - 2.0 10.0 5.0 21
2 35.0, IM 12.5, 1M - 2.0 - - 20
3 15.0, IM 10.0, oral - 2.0 1.5 5.0 28
4 - 12.5, oral 4.0 3 .O 1.5 7.5 20
* All patients received nonsteroidal antiinflammatory drugs. Patients 1,2, and 3 had taken methotrexate (MTX) for 2 4 years prior to the study.
* IM = intramuscular.

and 10 involved joints. In December 1988, only mild disease activity could be detected in 7 joints.
Throughout his course of treatment, his eryth-rocyte sedimentation rate (Wintrobe) had remained -40 mm/hour
until late 1988, when it decreased to -20 mm/hour. His rheumatoid factor titer fluctuated, but not in association with his
clinical condition. He had recurrent iron deficiency anemia, which was thought to be secondary to his gastrectomy and
Crohn’s dis-ease, and he also had 2 transient episodes of leukope-nia (white blood cell counts of 2.9 X 109/literand 3.4
X 109/liter, respectively), which did not require alter-ations in the therapeutic regimen. He noted an in-creased
frequency and loosening of his bowel move-ments the day after taking MTX. No changes in serum or red blood cell
folate levels were noted.

DISCUSSION
In general, combining drug therapies to treat a given disease has been based on the hope of achieving additive
or synergistic effects. This has always been balanced against the risk of increased toxicity. More-over, antagonism may
also occur, occasionally unex-pectedly, with certain drug combinations (5).
There is evidence to suggest that both meth-otrexate and sulfasalazine can alter folate metabolism. Should the
effects on folate metabolism be an impor-tant part of the mechanism of action of these agents, as well as an important
cause of their toxicity, then folate metabolism may be a pivotal point for a phar-macologic interaction. Such interaction
could result in synergy, antagonism, or increased toxicity. It has been suggested that adverse reactions occur when
trimeth-opridsulfamethoxazole is combined with MTX (6).
MTX competitively inhibits dihydrofolate re-ductase, with the resultant depletion of cellular folate stores. Other
enzymes, notably thymidylate syn-thetase and transformylase, are also affected by the
drug (7). Sulfasalazine has been demonstrated to com-petitively inhibit dihydrofolate reductase, methylene-
tetrahydrofolate reductase, and serine transhydroxy-methylase in vitro when rat liver extracts were used as a source of
the enzymes (8). An antifolate action of sulfasalazine has also been demonstrated on intact lymphocytes (9).
Antibiotics, including sulfonamides, alter bowel flora, which can result in decreased absorption of both folate
and MTX. Because MTX is metabolized by bowel flora, this may also be altered by sulfonamides (4,lO). Sulfasalazine
inhibits the metabolism process in the jejunum and the transport of dietary folate (1 I). Although red cell macrocytosis
and, rarely, macro-cytic anemias occur with sulfasalazine or MTX ther-apy, significant folate deficiency has not been
com-monly observed (2,3,12-14).
In this report, we describe our experience with 4 patients who received a combination of MTX and sulfasalazine
for approximately 2 years. With the exception of 1 easily treated episode of folate defi-ciency and macrocytosis, no
significant adverse reac-tions could be attributed to this combination of medi-cations. Patients 1 and 2 had active
arthritis that persisted despite relatively high doses of MTX that were administered for a sufficient time to have
achieved the anticipated response. Each had fairly quick responses to the addition of sulfasalazine. At-tempts to
discontinue one or the other agent resulted in flares of the arthritis, which resolved with the reintroduction of the
combination therapy. Moreover, the maintenance dosage of MTX was markedly re-duced in both cases (Table 2).

Patient 3 was concerned about increasing her dosage of MTX when she was receiving 15 mglweek.
Sulfasalazine was added to her therapy regimen, and she improved clinically. After the maintenance dosage was
achieved, an additional attempt to completely
1164 BRIEF REPORTS

withdraw the MTX w a s unsuccessful, but she contin-ued t o receive a lower dosage than w a s used initially (Table 2).

T h e final patient’s c a s e w a s complicated by the coexistence of Crohn’s disease and seropositive, nod-ular, erosive
polyarthritis. Sulfasalazine, which h e had been given for several years for his colitis, never
controlled his arthritis. T h e clinical improvement in
his arthritis can be attributed only to the addition of MTX. However, he is included in this study because, along with the
improvement of his symptoms, h e experienced no serious toxic reactions with 20 months of combination therapy.
These are observations involving only a f e w patients a n d no control subjects. However, t h e obser-vation periods were
lengthy, and t h e clinical courses of the first 3 patients would suggest that the combina-tion of methotrexate and sulfasalazine
merits further evaluation in larger controlled trials.

Acknowledgments. We thank Dr. John Esdaile and Carrie Kriticos for their assistance with the preparation of this report.

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