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Poor long-term results from low-dose methotrexate therapy in rheumatoid arthritis.

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Modified method for testing human natural
thymocytotoxic antibody
To the Ediror:
Lymphocyte function is affected by natural thymocytotoxic autoantibody (N‘I’A) (1,2). Although the erythrocyte
rosette inhibition test for human NTA has many advantages
(3), this method has not been widely used in studies of
human autoimmunity.
In the course of our studies of human NTA, using the
above method, we have found it difficult to detect lymphocytes mixed with sheep red blood cells (SRBC). In order to
resolve this difficulty when counting rosetted or non-rosettcd cells, we used glass slides precoated with new methylene blue and cresyl violet (Blutstan, Daiichi Pure Chemicals,
Japan). As shown in Figure I , stained lymphocytes (Figure
I A ) could be observed much more easily than unstained
lymphocytes (Figure IB). With this staining method, the
distinction between non-rosetted lymphocytes and SRBC is
easily made, so one is able to examine many samples in less
Our recent data indicate that there is no significant
difference in results between the original and modified
methods (4). Additionally, from our experience, there is no
doubt that the selection of nontoxic complement is the most
critical factor in this assay.
Yasuko Takiuchi, MD
Naoki Maruyama, MD
Kyoto Universio
Kyoto, Japan
Hiroshi Hosokawa, MD
Kansai Medical University
Moriguchi, Japan
1. Shirai T , Hayakdwa K, Okumura K. Tada T: Differential cyto-
toxic effect of natural thymocytotoxic autoantibody of NZB mice
on functional subsets of T cells. J lmmunol 120:1924-1929, 1978
2. Koike T, Kobayashi S, Yoshiki T, Itoh T, Shirai T: Differential
sensitivity of functional subsets of T cells to the cytotoxicity of
natural T-lymphocytotoxic autoantibody of systemic lupus erythematosus. Arthritis Kheum 22: 123-129, 1979
3. Koike 1’. Kobayashi S, Yoshiki T, Itoh T, Shirai T: Erythrocyte
rosette inhibition as an assay for naturally occumng T lymphocytotoxic antibody in systemic lupus erythematosus. Arthritis
Kheum 22: 1064-1073, 1979
4. Hosokawa H , Horio S , Takiuchi Y, Maruyama N , Asada Y:
Naturally occurring 1’ lymphocytotoxic antibody in viral and
related skin diseases. Acta Derm Venereol (Stockh) (in press)
Poor long-term results from low-dose methotrexate
therapy in rheumatoid arthritis
Figure 1. A, Lymphocytes seen by erythrocyte rosette inhibition
test for human natural thymocytotoxic antibody, modified by use of
the staining method. B, Lymphocytes seen by the same test, but
without the staining modification.
To the Editor:
Several uncontrolled retrospective studies of methotrexate (MTX) therapy in progressive erosive rheumatoid
arthritis (RA) have been recently reported (1-7). All have
claimed a substantial degree of clinical benefit in patients
who had been unresponsive to standard remittive therapy.
Of particular interest is the claim that low-dose oral MTX
produces important clinical effects with minimal toxicity (810). Since 1979, 33 patients attending The Department of
Rheumatology, St. Vincent’s Hospital, Dublin, Ireland for
treatment of intractable RA have received low-dose oral
MTX. In contrast to the findings of other studies, there has
been a relatively low incidence of sustained improvement,
and side effects occurred in 30%.
At the onset of therapy, all patients had evidence of
persistent active disease judged by the severity of pain,
duration of morning stiffness, intensity of synovitis, and
presence of extraarticular complications. All patients had
received an adequate trial of at least 2 standard remittive
agents. Undesirable side effects or failure to achieve a
satisfactory response were the reasons for discontinuing
remittive treatment in each instance. In 22 patients, MTX
was started at a dosage of 7.5 mg orally Once weekly. Two
Patients with a history of severe drug intolerance were
started on 5 mg weekly. Four patients were started on 10 mg
and 5 patients on 15 mg once weekly. For 12 of the patients
receiving 5-7.5 mg weekly, the dosage of MTX was progressively increased to a maximum of 12.5 mg weekly. Patients
were followed at the outpatient department at I-3-month
intervals. Followup included an assessment of disease activity, complete blood counts, and an estimation of bilirubin,
alkaline phosphatase, and glutamyl transferase.
Of the 33 patients. 23 were female. The ages ranged
from 36-73 years and the duration of disease from 2-25
years. Twenty-eight patients were seropositive and 3 1 had
erosive disease. All patients had normal liver function before
beginning treatment. Previous treatment included Myochrysine in 30 patients, D-penicillamine in 28, and chloroquine in
13.,Thirty-two patients had received corticosteroid therapy
and in 14, the dose of steroids at the onset of treatment with
MTX was greater than the equivalent of 5 mg of prednisone
per day. Twelve patients had prior treatment with azathioprine and 2 with cyclophosphamide.
Assessment of the patients’ responses indicated that
2 groups could be distinguished at 4 months. In the first
group there were 23 patients who had responded satisfxtorily. The mean erythrocyte sedimentation rate had fallen from
72 to 36 (P = 0.001). However, after a mean of 16-months.
only 13 patients in this group maintained their response.
Four had relapsed on treatment and 6 had developed late
side effects. There were 10 patients in the second group who
failed to benefit within 4 months. Six of these developed
In all, 12 patients showed serious side effects. Abnormal liver function, seen in 6 patients, was the most commonly observed side effect. Dyspepsia, rash, and alopecia also
occurred. Two patients dicd during the course of followup
from causes thought to be unrelated to MTX. One patient
developed a gastric carcinoma 2 years after a total of 40 mg
of MTX, and 1 patient died suddenly of uncertain cause
while still receiving MTX.
Our observations are uncontrolled and retrospective
and therefore similar in this respect to all other reports. The
relatively poor long-term effects emphasize the need for a
randomized and properly controlled prospective study of
methotrexate in RA.
Oliver FitzGerald, MB, MKCP
John Hanly, MB. MRCPI
Jack Molony. MD, FRCPI
Barry Bresnihan, MD, MKCP
St. Vincent’s Hospital
Drihlin, Ireland
1. Gowans JDC. Arnold G , Kaplan MM, Wilgram G , Chang LW:
Long term therapy of psoriatic and rheumatoid arthritis with
oral methotrexate monitored by serial liver biopsies (abstract).
Arthritis Rheum 22:615-616, 1979
2. Willkens RF, Watson MA, Paxson CS: Low dose pulse methotrexate therapy in rheumatoid arthritis. J Rheumatol 7:501-505,
3. Wilke WS, Calabrese LIT, Scherbel AL: Methotrexate in the
treatment of rheumatoid arthritis. Cleve Clin Q 47:305-309,
4. Roth,SH: Comparison of pulse methotrexate therapy with gold
salt therapy in rheumatoid arthritis (abstract). Arthritis Rheum
(suppl) 24:S71, 1981
5 . Zeiders RS: Oral methotrexate therapy in rheumatoid arthritis
(abstract). Arthritis Rheum (suppl) 25:S65, 1982
6. Bachman DM: Pulsed intravenous methotrexate treatment in
rheumatoid arthritis (abstra’ct). Anhrilis Rheum (suppl) 25:S65,
7. 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
8. Steinsson K , Weinstein A, Korn J , Abeles M: Low dose
methotrexate in rheumatoid arthritis. J Rheumatol 9:860-866.
9. Wilke WS, Mackenzie AH, Scherbel AL, Groff GD, Taylor TH:
Toxicity from methotrexate may be dose related. Arthritis
Rheum 26: 119-120, 1983
10. Groff GD, Shenberger K N , Wilke WS, Taylor TH: Low dose
oral methotrexate in rheumatoid arthritis: an uncontrolled trial
and review of the literature. Semin Arthritis Rheum 12:333-347.
Response to letter by Benson et al
To the Editor:
In the letter to the editor by Benson et a1 (Benson
CH, Gibson JY, Harisdangkul V: Ultrasound diagnosis of
tophaceous and rheumatoid nodules [letter]. Arthritis Rheum
26:696, 1983), there is the following misinterpretation of the
ultrasonogram of their patient’s olecranon nodule. The published picture reveals a nonsolid, irregular, tophaceous formation adjacent to the bone, and surrounded by tissue of
various echodensities. These echodensities probably represent a fibrotic reaction with nonorganized crystal-like material. Standardized equipment and rather extensive experience are required for the appropriate reading of the periarthrosonograms.
Nicholas Tiliakos, MD
V A Medical Center
Atlcrnta, GA
To the Editor:
Our intent was to report equivocal findings when
using ultrasound to differentiate tophaceous from rheumatoid nodules. Our experience was not similar to that reported
in 5 patients by Tiliakos et a1 (Tiliakos N. Morales AR,
Wilson CH Jr: Use of ultrasound in identifying tophaceous
versus rheumatoid nodules [letter]. Arthritis Rheum 25:478479, 1982). Perhaps ultrasound is most useful when tophaceous material is organized into a solid nodule.
Chris H. Benson, MD
Gcidsden, A L
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terms, poor, dose, low, long, arthritis, methotrexate, results, therapy, rheumatoid
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