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Possible beneficial effects of phenytoin for rheumatoid arthritis.

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Protective effect of neural lesion on rheumatoid
To the Editor:
In response to a recent letter entitled “Unilateral
Rheumatoid Arthritis” by Hammoudeh et al (I), we would
like to report a case of seropositive nodular rheumatoid
arthritis that developed in a patient with poliomyelitis. We
confirmed Hammoudeh’s observation that rheumatoid arthritis symptoms do not occur in the paralyzed extremity.
A 73-year-old man had a history of poliomyelitis,
which developed when he was 3 years old and resulted in a
flail left leg. He was first seen by one of us in 1979 after he
had developed Raynaud’s phenomenon, morning stiffness,
and pain in his right knee. Arthritic changes were noted in
proximal interphalangeal, metacarpophalangeal, and both
wrist joints, and in the knee and metatarsophalangeal joints
of the right side. No signs of arthritis could be found in the
left leg. Subcutaneous nodules were found on both elbows.
Roentgenograms of the hands and right foot showed periarticular osteoporosis; there was an erosion in the first left
metacarpophalangeal joint, as well as osteoporosis, atrophy,
and thin cortices in the left foot. The patient’s rheumatoid
factor latex titer was I : 1,280.
In September 1981 he developed intermittent claudication of the right leg. Radioisotopic angiography showed
nearly complete obliteration of the left common iliac artery
and moderate narrowing of the right iliac artery.
The effect of hemiplegia on the development of
various types of arthritis has been described (2,3). In rheumatoid arthritis the protective effect is seen with both upper
and lower motor lesions (43). The mechanism for this
protection against the local development of arthritis is not
known, although the reduction of movement or disuse of the
paralyzed limbs has been proposed as one possible explanation. In studies of capillary resistance, response to cutaneous vasodilators, and temperature gradients, however, no
striking differences between the 2 sides (one paralyzed and
one nonparalyzed) were shown (4). Glick (6) reported this
phenomenon in patients previously paralyzed by poliomyelitis and suggested that decreased intraarticular pressure is an
important factor.
In patients with nodular rheumatoid arthritis, varying
degrees of arterial occlusion have been shown by brachial
arteriography. This occlusion seemed to be primarily ,a
lesion of the vessel wall. Microvascular disease is also
thought to be responsible for the proliferative process that
produces rheumatoid nodules or synovial hyperplasia (7,8).
However, in 1 patient with rheumatoid arthritis and hemiplegia, uniformly diminished main vessels on the paralyzed
side and small vessel occlusions on both sides were shown
by arteriography.
Our patient had nearly complete obstruction of the
iliac artery on the paralyzed side, possibly from atherosclerosis, and retained blood flow fairly well on the nonpara-
lyzed side. These changes in the main vessel blood flow may
be associated with the mechanism of the protective effect.
However, we believe that in addition to relative immobilization, vasomotor effects or hemodynamic changes should be
considered as possible explanations for the protection afforded by hemiplegia.
Yukio Ueno, MD
Kenzo Sawada, MD
Hiroo Imura, MD
K y o t o University Hospital
Sakyo-Ku, K y o t o , Japan
1. Hammoudeh M, Khan MA, Kushner 1: Unilateral rheumatoid
arthritis (letter). Arthritis Rheum 24: 1218. 1981
2. Winter S: Unilateral Heberden’s nodes in a case of hemiplegia.
NY State J Med 52:349-359, 1952
3. Glynn JJ, Clayton ML: Sparing effect of hemiparesis on tophaceous gout. Ann Rheum Dis 35534-535. 1976
4. Thompson M, Bywaters EGL: Unilateral rheumatoid arthritis
following hemiplegia. Ann Rheum Dis 21:370-377, 1962
5. Kamerman JS: Protective effect of traumatic lesions on rheumatoid arthritis. Ann Rheum Dis 25:361-363, 1966
6. Glick EN: Asymmetrical rheumatoid arthritis after poliomyelitis.
Br Med J 3:26-29, 1967
7. Bywaters EGL: Peripheral vascular obstruction in rheumatoid
arthritis and its relationship to other vascular lesions. Ann
Rheum Dis 16:84-103, 1957
8. Scott JT, Hourihane DO, Doyle FH, Steiner RE, Laws JW,
Dixon AS, Bywaters EGL: Digital arteries in rheumatoid disease. Ann Rheum Dis 20:224-234, 1961
Possible beneficial effects of phenytoin for rheumatoid
To the Editor:
Collagenase released by rheumatoid synovial cells
can degrade collagen from cartilage, joint capsule, and bone
(Harris ED, Krane SM: Collagenases. N Engl J Med
291 557-563, 605-609, 652-661, 1974). Collagenase which is
also found in rheumatoid nodules may play a role in the
pathogenesis of these lesions. Recently phenytoin has been
shown to be capable of inhibiting collagenase synthesis in
vitro by cultured human fibroblasts (Bauer EA, Cooper TW,
Tucker DR, Esterly NB: Phenytoin therapy of recessive
dystrophic epidermolysis bullosa. N Engl J Med 303:776781, 1980). This suggests that phenytoin may be beneficial in
the treatment of rheumatoid arthritis.
Over the past 6 years, 3 patients with inflammatory
arthritis (2 with rheumatoid arthritis and I with psoriatic
arthropathy) developed seizure disorders necessitating treatment with phenytoin. All 3 patients had been taking a
nonsteroidal antiinflammatory drug for arthritis with only
modest benefit. Within 6 months of instituting phenytoin, all
3 patients were noted to have definite and sustained improvement in their joint disease. There was a reduction in
morning stiffness and intensity and frequency of clinical
flares, and a reduction in the number of painful and swollen
joints. There was a modest reduction in the sedimentation
rate in the 2 patients with rheumatoid arthritis, but no change
in their rheumatoid factor titers.
Despite the unpredictable spontaneous variations in
rheumatoid and psoriatic arthritis, the observed clinical
improvement in these 3 patients while on phenytoin therapy
merits further study.
Arthur M. Bobrove, MD
Palo Alto Medical Foundation
Polo Alto, CA
Toxicity from methotrexate may be dose related
To the Editor:
We were interested to read the report by Michaels
and associates ( I ) suggesting that once-weekly intravenous
methotrexate doses ranging from 10 to 50 mg suppressed the
activity of unresponsive rheumatoid arthritis. The authors
raise some important questions concerning short term adverse effects and potential long term hepatic toxicity. We
offer commentary on these issues.
The apparent increased risk of neoplasia after the use
of chlorambucil, cyclophosphamide, and azathioprine (2.3)
tends to deter their use as therapy for other than serious
illness. Michaels et al(1) note that the carcinogenic potential
of methotrexate is minimal (2-4). This difference supports
the choice of methotrexate when an immunosuppressant,
cytotoxic drug is indicated. However, the mild, acute toxicity experienced by 12 of 14 patients in Michaels’ report
indicates that methotrexate is not necessarily clearly preferable to these other agents (5,6). The authors speculate that a
smaller weekly dose might reduce methotrexate toxicity.
Willkens and coworkers (7) reported some improvement in disease parameters in 26 of 32 patients treated with
weekly oral doses of methotrexate ranging from 7.5 to 15 mg.
Therapy was discontinued in 4 patients because of side
effects which could not be controlled by dosage manipulation. The incidence of mild effects was not detailed.
We have also performed retrospective studies on our
patients treated with methotrexate (8). Of patients treated at
the Cleveland Clinic for a mean length of therapy of 34
months at a mean weekly oral dose of 7.53 mg, only 8 of 45
were found to have signs and symptoms that might represent
methotrexate toxicity. Modest reduction of dosage and/or
modification of alcohol consumption were the only measures
necessary to deal with these mild adverse effects.
A second population consisting of 28 patients was
treated and studied at the Dartmouth-Hitchcock Center.
These patients were followed for a mean of 12 months and
received a mean weekly oral dose of 8.36 mg methotrexate.
Thirteen of the 28 patients showed some adverse signs or
symptoms which might have been the result of methotrexate
therapy. These effects were also easily controlled by dosage
modification in all but 1 patient, who experienced sufficient
nausea that the drug was discontinued. Response to treatment in both groups was similar to the response seen in
Willkens’ patient population (8). These preliminary findings
suggest that the incidence of acute toxicity is lowered when
weekly doses of methotrexate are lowered, while efficacy is
The second issue which Michaels et al (1) raise
involves hepatotoxicity and the need for liver biopsy. It has
been estimated that psoriasis patients treated with doses of
methotrexate ranging from 7.5 mg to 35 mg per week showed
3-5% incidence of cirrhosis and a 6% incidence of fibrosis
(9). Mackenzie has reported liver biopsy findings in 2 groups
of patients (10). The treatment group was composed of 60
patients with rheumatoid arthritis receiving prolonged methotrexate therapy (mean 4 years). They had received a mean
weekly dose of 8.67 mg and a mean total dose of 1,837 mg. A
matched group of 25 patients with rheumatoid arthritis who
were not taking the medication was also studied. Liver
biopsies were obtained from each patient in both groups.
The biopsy results showed changes of chronic inflammation
consistent with a diagnosis of severe rheumatoid arthritis in
each group but revealed little real difference between the
In some cases liver biopsy appears to be the only
accurate measure of hepatotoxicity (1 I ) . The incidence of
serious hepatic side effects with low doses of methotrexate
may be sufficiently small, however, that less invasive serologic and clinical followup could often be preferable to liver
biopsy. At the present time we favor the conservative
approach recently outlined for the treatment of psoriasis
We agree with Michaels et al that methotrexate
appears useful in the treatment of rheumatoid arthritis, and
we suggest that toxicity may be dose related. Furthermore,
the low incidence of toxicity may favor methotrexate as the
cytotoxic drug of choice in the treatment of rheumatoid
arthritis. Controlled prospective studies are indicated and
William S . Wilke, MD
Allen H. Mackenzie, MD
Arthur L. Scherbel, MD
Clevelrrnd Clinic
Cleveland, Ohio
Gerald D. Groff, MD
Thomas H. Taylor, MD
Dartmorcth-Hitchcock Center
White River Junction, Vermont
1. Michaels RM, Nashel DJ, Leonard A. Sliwinski AJ. Derbes SJ:
Weekly intravenous methotrexate in the treatment of rheumatoid arthritis. Arthritis Rheum 25:339-341, 1982
2. Grunwald HW, Rosner F: Acute leukemia and immunosuppressive therapy for non-neoplastic diseases. Arch Intern Med 139:
461-466, 1979
3. Casciato DA, Scott JL: Acute leukemia following prolonged
agent therapy. Medicine W32-47, 1979
4. Bailin PL, Tindall JP, Roenigk HH Jr, Hogan MD: Is metho-
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effect, beneficial, arthritis, possible, phenytoin, rheumatoid
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