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Treatment of Felty's syndrome with low-dose oral methotrexate.

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Recent studies of methotrexate in the treatment
of patients with rheumatoid arthritis have precluded
patients with neutropenia. We present a patient with
rheumatoid arthritis complicated by severe neutropenia
and recurrent infections, who was treated with low-dose
methotrexate, orally, for 30 months. The patient experienced symptomatic improvement and a significant
increase in granulocyte count, and the dosage of steroids
was reduced. Low-dose oral methotrexate may be
a therapeutic option in select patients with Felty’s
Rheumatoid arthritis (RA) associated with
splenomegaly and neutropenia is the hallmark of
Felty ’ s syndrome. The syndrome is occasionally complicated by life-threatening infections which result
from the marked neutropenia. Patients with this clinical picture pose significant therapeutic challenges.
Previous therapies have included splenectomy (1-3),
prednisone (2), lithium (4,5), penicillamine (6), and
gold (7-10). We describe a patient with Felty’s syndrome and vasculitis who was treated successfully
with Ilow-dose oral methotrexate (MTX).
MTX has been used with increasing frequency
in patients with RA that was unresponsive to other
theralpies (11,12). Because of the risk of bone marrow
From the Department of Medicine, Section of Rheumatology, Lehigh Valley Hospital Center, Allentown, Pennsylvania.
Supported in part by a grant from the Dorothy Rider Pool
Health Care Trust Fund.
Lisa Sherbin Allen, MD; Gerald Groff, MD.
Address reprint requests to Dr. Gerald Groff, Department
of Medicine, Mary Imogene Bassett Hospital, Cooperstown, NY
Submitted for publication November 12, 1985; accepted in
revisedl form February 10, 1986.
Arthritis and Rheumatism, Vol. 29, No. 7 (July 1986)
suppression, prior studies have excluded patients with
leukopenia. Our patient was treated for 30 months
with low-dose oral MTX, without experiencing significant side effects. The patient’s general status improved, she had fewer infections, and her neutrophil
count increased.
Case report. The patient, a 70-year-old white
woman, had a 35-year history of erosive, seropositive
RA which was complicated by Felty’s syndrome and
vasculitic ulcers. The diagnosis of Felty ’s syndrome
was made in January 1982, during hospitalization for
abdominal pain and neutropenia. A liver-spleen scan
revealed modest splenomegaly. Bone marrow aspirate
showed increased cellularity, with a shift to the left in
the granulocytic series, which is consistent with peripheral white blood cell (WBC) destruction.
The patient was treated unsuccessfully with
courses of prednisone, gold, and lithium. Her clinical
course was marked by serious infections, including
recurrent Candida esophagitis, recurrent sinusitis, and
urinary tract infections, with bacteremia. These resulted in 5 hospitalizations in a 1-year period prior to
initiation of MTX therapy.
On November 11, 1982, following several days
of odynophagia, fever, and chills, the patient was
admitted. At that time, she complained of joint stiffness lasting 1% hours, and a new large, dusky skin
ulceration of her right inferior calf. Her medications on
admission included prednisone, 5 mg in the morning
and 2.5 mg in the evening, and ascriptin, 2 tablets 4
times daily.
The physical examination revealed an elderly
woman with cushingoid features and classic rheumatoid deformities. She was afebrile, and her vital signs
were stable. Her oropharynx had a diffuse, white,
patchy exudate consistent with candidiasis. Lymphadenopathy was not noted.
The cardiac examination revealed a regular
rhythm, with a grade II/VI systolic ejection murmur
heard at the apex and left sternal border. Inspiratory
rales at the left lung base were heard. Results of the
abdominal examination were not significant. There
was no appreciable hepatosplenomegaly .
Examination of her musculoskeletal system
showed severe rheumatoid deformities, including
ulnar deviation with swan neck deformities, elbow
contractures, severe valgus deformity of both knees,
and limited range of motion of the cervical spine. She
had mild, active synovitis. A large, central, necrotic
skin ulcer surrounded by erythema was located on the
right inferior calf, and there was a small dark eschar
and ulceration of the left great toe. The neurologic
examination yielded normal results.
Initial tests revealed normal blood chemistries,
including normal liver function and level of creatinine.
Her urinalysis gave negative results, and the electrocardiogram and chest roentgenogram revealed no abnormalities. The complete blood count yielded a hemoglobin level of 11.5 gm/dl, a hematocrit value of
33.8%, a platelet count of 182,000, and a WBC count
of l,200/mm3, with 76% lymphocytes and 24%
monocytes. Her erythrocyte sedimentation rate (ESR;
Westergren) was 55 mmlhour, and her serum complement levels were: C3 103 mg/dl (normal 94-214), C4 13
mg/dl (normal 1749), and CH5O 312 units/ml (normal
330-730). Two blood cultures were positive for
Staphylococcus saprophyticus.
Table 1. Clinical course of a patient with Felty’s syndrome treated with methotrexate (MTX)*
Physical examination findings
Right heel ulcer; chronic draining
purulence of right ear
Hospitalization for staphylococcal
sepsis (see Case Report)
Vasculitic ulcers resolving,
except in left leg and right great
Vasulitic ulcers healed; very little
active synovitis
Left great toe cyanotic, with
ulceration; fine livedo
reticularis; typical of indolent
Hospitalization for right maxillary
sinusitis, treated with
intravenous cephalosporin
Cyanosis left great toe, but
Arthritis stable; stable ulcer of
left great toe
Vasculitic ulcers healed
I 1/82
No ischemic lesions
Ulcer (1 cm) with purulent base
and surrounding erythema of
left great toe
No ulcerations
No ulcerations; arthritis stable
Nodules resolved; no synovitis;
no vasculitis
Global assessment
Pertinent data
10 mg/day
7.5 mglday
5 mglweek
Relative improvement of arthritis,
except for jaw pain
10 mglday
5 mg/week
Joint pain increased
10 mglday
5 mglweek
Joint pain increased
7.5 mg A M ,
1 mg PM
5 mg/7.5 mg
alternate weeks
7.5 mg A M ,
1 mg PM
5 mgl7.5 mg
alternate weeks
10 mg/day
5 mgl7.5 mg
alternate weeks
5 mg17.5 mg
alternate weeks
5 mgl7.5 mg
alternate weeks
5 mg17.5 mg
alternate weeks
5 mgI7.5 mg
alternate weeks
General status improved;
arthralgias well controlled
Joint pain and swelling almost
completely resolved
Joints not inflamed, although stiff
9 mg/day
No joint symptoms
6 mg/day
Joint pain minimal
6 mglday
6 mglday
Morning stiffness for 30 minutes;
no arthralgias
8 mg/day
7 mg/day
5 mglday
5 mgI7.5 mg
alternate weeks
5 mgI7.5 mg
alternate weeks
5 mgl7.5 mg
alternate weeks
MTX begun; C3 103;
C4 13; ESR 55
ESR 30; R F + at 500
Anspor, 250 mg 4
times a day for 10
Sacral coccygeal
abscess treated
with Anspor, 250
mg 4 times a day
for 14 days
C3 91; CH50 312;
ANA-; ESR 20;
R F-
erythrocyte sedimentation rate; RF = rheumatoid factor; ANA = antinuclear antibodies. Values of C3 and C4 are in mgldl; ESR is
in m d h o u r ; CH50 is in unitdml.
A diagnosis of staphlycococcal sepsis complicated by oropharyngeal candidiasis was made, and the
patilent was given a 2-week course of intravenous
cephalosporin and stress-dose steroid treatment. She
also received mycostatin suspension, orally, until the
cantiidiasis in her mouth cleared. She responded well
to the treatment, and a plan for long-term therapy was
Due to her severe disability, the patient was not
considered a suitable candidate for splenectomy . At
the same time, a trial of lithium therapy, consisting of
300 mg 3 times a day from November 4, 1982 to
November 24, 1982, yielded no benefit. Previous gold
ther,apy had been ineffective. Of the remaining remittive agents, cyclophosphamide and azathioprine were
considered to carry too great a risk of bone marrow
suppression. Experience with MTX had suggested that
there was a low incidence of leukocyte suppression
with this treatment (12). In addition, preliminary evidence suggested that MTX had a more rapid symptomatic effect (3-6 weeks) than did gold or penicillamine
(3-4 months). Because of the increasing frequency and
severity of the patient's infections, MTX therapy was
recommended, with the hope that disease amelioration
would occur as soon as possible. With the patient's
informed consent, she was started on a regimen of
MTX, 5.0 mg weekly, given in 2.5-mg oral doses every
12 hours for 2 doses.
The patient's clinical course over the next 30
months (summarized in Table 1) showed gradual and
significant overall improvement. One further hospitalization was necessary in March 1983, but she has not
been hospitalized since that time. Subsequent infections were limited to local involvement of a pressure
ulcer of the sacrum and an ulcer of the toe. An
imprlovement in general status, with reduction in
arthralgias, was noted approximately 6 months after
initiation of MTX therapy. Vasculitic ulcers were
healed within 9 months and have not recurred. During
this time, medications were limited to stable doses of
salicylates, methotrexate, and prednisone. The dosage
of prednisone was gradually tapered from 10 mg/day to
5 mglday, and has been maintained at this level.
Laboratory studies during the 30 months the
patient was receiving MTX demonstrated a mild reductiton in her ESR, a conversion to seronegativity,
and a modest increase in serum complement levels.
More significantly, the total peripheral WBC count
and iIbsolute granulocyte count increased steadily.
Over the 30-month period, the granulocyte count
increased from 0 to approximately 2,500 (June 18,
1985), and this level has been sustained (Figure 1).
Discussion. The patient described here had a
complicated clinical course of RA associated with
Felty's syndrome and vasculitis. She exhibited persistent neutropenia, with multiple infectious episodes
that required repeated hospitalizations. Previous trials
of prednisone, gold, and lithium treatments were unsuccessful. Prior experience with MTX had suggested
that this therapy offered a lesser risk of bone marrow
suppression as compared with cyclophosphamide or
azathioprine. Subsequently, the patient was started on
a regimen of low-dose oral MTX. Followup evaluations were continued for approximately 30 months,
and the patient showed significant improvement in
clinical status. She experienced marked symptomatic
improvement in morning stiffness and generalized fatigue. Objectively, she has experienced a decrease in
synovitis, complete resolution of vasculitic ulcers, an
increase in her neutrophil count, and the dosage of
prednisone has been reduced.
Methotrexate is a potent antimetabolite that
acts as a folic acid analog and binds with dihydrofolate
reductase, thus inhibiting the transfer of methyl groups
in the synthesis of DNA, RNA, and proteins. The
theoretical value of MTX therapy for proliferative
' '
I ' "" "'
'1 ''
Figure 1. Leukocyte count (0-0)
and granulocyte count
(0- -0) during initial 30-month treatment with methotrexate in a
patient with Felty's syndrome.
inflammatory disease has been demonstrated clinically
by trials of low-dose MTX in patients with psoriasis,
polymyositis, and refractory RA.
Recent studies using low-dose oral MTX in the
treatment of RA include a double-blind, controlled
trial by Thompson et a1 in 1984 (48 patients) (13) and
similar trials by Weinblatt et a1 in 1985 (28 patients)
(1 1) and Andersen et a1 in 1985 (12 patients) (14). Each
of these studies has shown that there was statistically
significant improvement, according to physician and
patient assessments, in patients treated with low doses
of MTX. However, these studies excluded patients
with leukopenia or, as defined in the trial conducted by
Weinblatt et al, WBC counts of <3,500/mm3. Additionally, patients were withdrawn from Weinblatt and
coworkers’ study when their WBC counts decreased
to <3,300/mm3 or when their polymorphonuclear cell
count fell to < 1 ,200/mm3.
In the study by Groff et al, each patient had a
normal WBC count at the beginning of MTX therapy.
Patients with leukopenia were excluded because
myelosuppression can occur with the low-dose regimen, especially if the patient has decreased renal
function or is receiving concomitant drug therapy with
organic acids.
Since our patient had severe leukopenia and
granulocytopenia, she would have been excluded from
these other trials with MTX therapy. The use of MTX
in the treatment of Felty’s syndrome has not been
documented previously. We do not know the mechanism of benefit to this patient’s RA or neutropenia.
However, we do know that she improved clinically,
showed no increase in the number of infections, and
had a definite increase in her neutrophil count. This
experience suggests that MTX can be used in the
treatment of select patients with Felty’s syndrome,
Acknowledgments. The authors thank the Research
and Publication Support Service for assisting in the preparation of the manuscript and Dr. Glenn Kratzer for assisting
in the patient’s care.
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treatment, felt, syndrome, dose, low, methotrexate, oral
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