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Intra-Articular Thiotepa in Rheumatoid Disease. A Clinical Analysis of 123 Injected MP and PIP Joints

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Intra-Articular Thiotepa in Rheumatoid Disease
A Clinical Analysis of 123 Injected MP and PIP Joints
Monty R. Ellison and Adrian E. Flatt
This report deals with 30 patients with established rheumatoid disease who
received an intra-articular injection of Thiotepa into the small joints of the hands.
One hundred twenty-three individual joints have been injected, and the follow-up
period averages 4.8 years. The study represents a follow-up report on an original
trial begun in 1962 by Dr. Adrian E. Flatt at the University of Iowa Hospitals.
Our results are assessed on the basis of four parameters: symptomatic pain
relief, clinical response to injection, postinjection radiographic progression, and
postinjection progression of clinical deformity. An attempt i s made to relate the
results to the stage of local disease in the injected joints, as well as t o the
systemic disease state in each individual. Only 7 of our 30 patients had a good
result when all four parameters were considered. Our analysis of these 7 patients,
and our indications for the continued use of Thiotepa are included in this report.
T h e multiplicity of joint involvement in
rheumatoid disease has led many investigators to search for chemical agents which
might be used to effect a “medical synovectomy” in joints involved with the rheumatoid process. T h e desirability of such a
drug is obvious when compared with the
surgical alternative in a patient in whom
many joints are simultaneous candidates
for synovectomy.
T h e finding by Becker that an alkylating
agent, nitrogen mustard (HN,), suppressed
local tissue reactivity stimulated the beginning of clinical trials in which this agent
was utilized to treat certain diseases characterized by local and systemic tissue inflam-
mation (1). T h e first of these trials was
reported by Diaz in 1951 (2). I n this report,
Diaz described the results in 32 patients
with rheumatoid disease after the intravenous administration of nitrogen
mustard, noting a “startling” improvement
in pain, with a definite decrease in joint
size and inflammation. Paul et al, administered nitrogen mustard intravenously to 17
patients in a carefully controlled series in
which improvement was evaluated on the
basis of several hematological parameters,
as well as clinical observations (3). Sixteen
of the 17 patients showed improvement
which persisted for as long as twelve weeks.
T h e first directly intra-articular trial of
nitrogen mustard in rheumatoid disease
was reported by Scherbel and Schucter in
MONTY R. ELLISON, MD: Anderson-Ellison Orthopedic Clinic, 2120 S. Pacific Blvd., Albany, Oregon. 1957 (4). I n 24 of 130 patients, nitrogen
ADRIAN E. F L A ~ ,MD: Division of Hand Surgery,
University of Iowa, College of Medicine, Iowa City, mustard was injected into the involved
joint on three separate occasions, with a
Iowa 52240.
Address reprint requests to: Monty R. Ellison, marked decrease in pain and synovitis. I n
MD.
1960, Vainio a n d Julkunen reported the
Submitted for publication Oct 9, 1970; accepted
use of nitrogen mustard intra-articularly in
Dec 7, 1970.
I
. .1
LlL
Mhritis and Rheumrtism, Vol. 14, No. 2 (March-Apdl 19n)
INTRA-ARTICUIAR THIOTEPA
59 patients with rheumatoid disease (5).
They concluded that remission in local
synovitis did occur after the injection. I n
n o case did nitrogen mustard effect a lasting local remission if systemic disease activity persisted.
Certain chemical characteristics of nitrogen mustard require that special care be
taken when the drug is administered, locally or systemically. T h e main hazards of
nitrogen mustard therapy are severe leukopenia and thrombocytopenia. There is ,also
a theoretic hazard of inducing mutations in
the children of patients treated with this
drug (3). Locally, extreme irritation can
result i f the drug comes into contact with
skin or mucous membrane. Because of
these disadvantages, other, chemically
related agents were sought which might
have the same effect on rheumatoid synovium.
I n 1962, Flatt reported the beginning of
a n experimental trial i n which a pharmacologically related drug, Thiotepa+, was
selected for intra-articular injection into
digital joints involved with rheumatoid disease (6). At the time of his original report,
the overall clinical impression in a small
number of patients was one of rapid relief
of clinical signs and symptoms after injection. Since this early report, several investigators have published reports concerning
the efficacy of intra-articular Thiotepa in
the treatment of rheumatoid disease. I n
1966, Zuckner et al, injected Thiotepa into
the knee joint of 19 patients with rheumatoid disease (7). They concluded that no
benefit occurred in their patients after Thiotepa injection. Howes et al reported
more favorable results after the intraarticular administration of Thiotepa i n 68
rheumatoid joints (8). Thirty-five of these
*Lederle Laboratories, N, N', N"-triethylenethiophosphoromide, a polyfunctioning alkylating agent.
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
68 joints showed increased stability after
Thiotepa had been administered, with benefit lasting for as long as eighteen months.
Currey found clinical and subjective improvement in joints treated with Thiotepa
and with procaine alone, and concluded
that Thiotepa had no advantage over procaine in his series of patients (9).
We have recently reviewed 30 patients in
whom Thiotepa had been injected into 123
digital joints of their hands as a treatment
for local rheumatoid synovitis (Table 1).
This report is a follow-up analysis of the
trial begun in 1961 o n the hand service of
the University of Iowa Hospitals. T h e
effect of intra-articular Thiotepa injection
in these 30 patients is evaluated in terms of
immediate, as well as long-term benefits. I n
10 of our patients, an effort has also been
made to determine if there is any consistent
histologic change in the synovium after
injection.
MATERIALS AND METHODS
Technic of Injection
Thiotepa is supplied in powder form in 15 mg
vials. Three milliliters of sterile water are injected
into the vial, making a solution in which 0.5 ml
contains 2.5 mg of Thiotepa. The manufacturers
state that such a solution may be kept for five days
in a refrigerator without substantial loss of potency.
The only technical problem in the injection is
ensuring that the needle point is intra-articular. It
Table 1. Number of Joints Injected
(30 Patients)
Joint
Finger
Metacarpophala ngeal
Proximal interphalangeal
Distal interphalangeal
Thumb
I nterphalangeal
Metacarpophalangeal
TOTAL
Number
41
66
10
1
5
123
213
is wise to use a syringe containing some innocuous
fluid to flush the joint and determine the position
of the needle point. One percent Xylocaine may be
used as the fluid, since it will prevent any immediate pain reaction. I t is probably unnecessary to use
a local anesthetic to flush out the joint. Xylocaine is
essential only when nitrogen mustard is being
used, since this injection can cause considerable
pain. We occasionally use physiologic saline instead
of Xylocaine and have not encountered. any complaints of pain. An infrequent accidental injection
of Thiotepa into the periarticular tissues has caused
n o adverse reaction.
After adequate skin preparation a No. 25 needle,
on a 5-ml syringe containing 1% Xylocaine, is
passed into the joint. Both the metacarpophalangea1 and proximal interphalangeal joints are best
approached from the dorsilateral side to avoid the
extrinsic extensor tendon and the thick collateral
ligament. T h e needle should slant obliquely
through the tissues to prevent the Thiotepa from
leaking out after the needle is withdrawn. T o test if
the needle point is within the joint cavity, two
fingertips are placed on either side of the joint. If
the needle point is truly intra-articular. the tension
within the joint can be felt to rise and fall as the
plunger of the syringe is pushed-home and withdrawn. If several joints are to be injected, the
needle is left in situ, and the syringe containing the
Xylocaine used to place the other needles.
A second syringe is filled with the Thiotepa
solution, and each joint is then injected with as
much solution as i t will comfortably hold. T h e
average digital joint will accept about 0.5 ml of
solution and, therefore, receives about 2.5 mg of
Thiotepa. T h e needle is withdrawn immediately
after the injection and the joint is massaged. Early
movement must be encouraged (10).
ly” local disease in the injected joints. T e n patients
were in an intermediate stage, and 7 were in a late
stage of local disease. Our criterion for assessing the
stage of disease locally is listed in Table 3. In our
patients, there was no direct relationship between
stage of local disease and response to injection.
All of our patients were referred to the surgical
clinic from the rheumatology service. Persistent
synovial swelling, despite efforts at medical control,
was the most frequent reason for surgical consultation. In the majority of joints, synovitis was active
and pain in the involved area was a significant
component of the symptom complex.
T h e decision to utilize Thiotepa-injection in
preference to surgical synovectomy was based upon
a number of factors. Patients considered to be poor
candidates for anesthesia generally were given the
injection to avoid the risk of a formal surgical
procedure. Patients with multiple digital joint
involvement frequently had surgical synovectomy in
some joints, and Thiotepa-injection in others. This
Table 2. Classification of Patients
at the Time of Injection
(ARA)
Stage
No. of
patients
Percent of
total (30)
I
II
Ill
IV
6
8
16
0
20
26.6
53.4
Table 3.
Clinical Material
Thirty patients with rheumatoid involvement of
the digital joints of their hands are included in this
report. These patients have had a total of 123 joints
injected with Thiotepa over the last nine years. No
patients are included in the study who had more
than one injection in the same joint.
T h e patients were in different stages of systemic
illness and local disease at the time of referral and
subsequent injection, and are classified in the ARA
scheme as shown in Table 2. Eight patients had
complete remission of their general disease subsequent to the injection of Thiotepa. We could not,
however, attribute their remission to Thiotepa.
Thirteen patients were considered to have “ear214
-
Classification of Disease State
in Injected Joints*
Disease state
Early
Intermediate
Late
TOTAL
No. of
Datients
13
10
7
30
* Classification based upon radiographic appearance, (ie joint space narrowing and destruction), clinical examination (ie ligamentous
stability and range of motion), and duration of
disease i n involved joints.
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
INTRA-ARTICUUR THIOTEPA
was necessary to avoid excessive operative
procedures in the same hand, and to keep tourniquet-time within reasonable limits. Patients with
single joint involvement were treated with Thiotepa
in the outpatient clinic as a matter of convenience
to the patient.
Only one complication occurred as a result of
Thiotepa-injection in our patients. In one patient
who had three PIP joints treated, a painful cutaneous vesicle developed at the injection site in each
joint. The lesions appeared five days later, and were
accompanied by a generalized cutaneous eruption of
“hives” (Fig 1 ) . The local and generalized reaction
responded to oral benadryl treatment, regressing
systemically in a period of 72 hours, but persisting
locally for three weeks. Later skin tests with dilute
Thiotepa confirmed the clinical impression of a
true drug allergy.
RESULTS
The result of Thiotepa-injection in our
patients is assessed according to four
parameters. T h e immediate effect of the
injection was evaluated in terms of symptomatic pain relief and clinical observation
of the injected joint. This information was
available from records made at the time of
treatment, and in the ensuing few months.
Frequently, interview at the follow-up examination yielded pertinent information
concerning pain relief. Long-term benefit
from the injection is based upon a comparison of clinical photographs and X-rays,
taken prior to injection and at follow-up
examination. In each patient, the effect of
systemic disease activity is considered in
relation to the result obtained.
Very little variation in response occurred
from one injected joint to another in the
same patient. This “all or none” response
lends support to our belief that the course
of the systemic disease is essential in dictating the outcome of this form of treatment.
Fig 1. This Caucasian female patient (KP) with severe systemic disease had Thiotepa injected into the PIP
joints of the right index, long and ring fingers at the time of extensor tendon synovectomy. Fig 1A shows
the preoperative appearance of the right hand. Fig 1B shows cutaneous vesicles developed at the injection sites in the long and ring fingers. This photograph was taken almost two weeks following injection,
and shows the persistence of the lesions.
Mhritis and Rheumatism, Vol. 14, No. 2 (Mamh-April 1971)
215
Five patients had single joint injection.
There was no significant difference in their
response when compared with the remaining 25 patients who had multiple joints
treated.
Sixteen patients (53%) obtained symptomatic relief
after injection. The duration of this relief
varied widely. In two patients, relief was
felt by the patients to have been persistent
to follow-up, two and seven years later.
The other 14 patients had relief lasting
from 10 days to six months (Table 4).
Fourteen patients had no relief from
pain after the injection. I n no case were
symptoms made worse by the Thiotepa.
Symptomatic pain relief.
Table 5.
Clinical Response to Injection;
No. of Percent No. Percent
Response
patients
of
total
of
joints
of
total
Improved
Possible
i m provement
Not improved
7
23
26
21.6
3
20
10
67
14
83
11.0
67.4
TOTAL
30
123
* Clinical improvement is based upon change
in joint size, change in local joint inflammation,
and change in active, painless range of motion
of the injected joint
patients had no progression in the injected
joints, or in any other joint. In each of
these eight patients, the systemic disease
Clinical response to injection. Clini- underwent complete remission. Seven pacal response to injection was based on tients had no progression in the injected
observations of the changes in joint size, joints, but definite progression was presen,t
local inflammation, and painless, active in adjacent, noninjected joints. In all seven
range of motion. The periods of observa- patients, systemic disease activity persisted
tion were recorded at three days, one week, to the time of follow-up. We feel that in
three weeks, and six weeks after injection. these seven cases, Thiotepa retarded the
Only seven of our patients showed a defi- disease process in the injected joints (Table
nite objective response to the injection.
6).
Three patients showed possible benefit,
and in the remaining 20, no objective cliniProgression of clinical deformity.
cal improvement could be demonstrated Progression of clinical deformity (ie, laxity
(Table 5).
of supporting structures, boutonniere dePostinjection radiographic progression. Progression of skeletal rheumatoid
lesions following injection occurred in
fifteen of the thirty patients (500/,).Eight
Table 4.
Pain
relief
Significant
No relief
216
Relief of Pain
No.
Percent
of
of
patients
total
16
14
53
47
No.
of
joints
Percent
of
total
67
56
54.5
45.5
formity, joint subluxation or dislocation,
and ulnar drift) following injection occurred in 50y0 of our cases, and was
present in all instances where radiographic
progression occurred. Seven patients had
no progression in the injected joints, but
did have progression in adjacent, untreated
joints. Once again, this is felt to represent a
long term beneficial effect of the Thiotepa
injection in these seven patients (Table 6).
SUMMARY OF RESULTS
The interpretation of results after any
isolated procedure in rheumatoid disease is
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
INTRA-ARTICUIARTHIOTEPA
the injected joint. In all of these patients,
active systemic illness persisted after injection. This suggests that no benefit was
No. of Percent No. Percent derived from the injection, since progrespaOf
Of
Of
sion in these treated joints was largely
Progression
tients total joints total
commensurate with that in adiacent. unProgression in intreated ioints.
jected joints and
Only seven of our patients had symptoadjacent, unmatic
relief, objective clinical improve15
50
63
51.2
treated joints
ment,
and
lack of clinical and radiographic
No progression in
progression
in the presence of continuing
injected joints
or adjacent, unsystemic disease. Two of these seven patreated joints
Z6
32
26
tients had permanent symptomatic relief in
No progression in
the injected joints. Clinical photographs at
injected joints,
the time of follow-up document the persistprogression in
ent effect of injection in these two patients
adjacent, untreated joints
7
24
28
22.8
(Fig 2 and 3).
A retrospective analysis of the seven pa* X-ray lesions include joint space narrowing, tients in whom a beneficial response to the
subluxation, osteoporosis. and subcortical bony
erosion
- injection was obtained failed to demont Clinical deformity includes laxity of supporting strate any consistent clinical parameter
structures, boutonniere deformity, joint sub- which might be used to effectively predict
uxation or dislocation, and Ulnar drift deformity
this response. Because of the favorable response to injection locally, none of these
joints was subsequently explored surgically
subjected to many uncertainties. The exand examined histologically.
treme variability of the disease process in
most patients is well established. General
DISCUSSION
disease remission and effective medical conThe use of alkylating agents in the treattrol probably account for the majority of
ment
of rheumatoid disease has a sound
good results from isolated joint procedures.
theoretical
basis (7). The potential antiThe subjective improvement in 53% of
inflammatory
and anti-immune activity of
our patients is interesting in view of the
these
agents
has
been well-established exmuch smaller percentage in whom objecperimentally
(1,
11,
12). T h e exact mechative clinical benefit was present. ,Currey’s
nism
by
which
this
influence
might be effectobservation that symptomatic improvement
ed
in
rheumatoid
disease
is
unknown.
Paul
occurred in a control series injected with
et
al,
have
recorded
Karnofsky’s
views
that
procaine may cast some light upon our own
the
toxic
effect
of
nitrogen
mustard
on
experience. He suggests that the patient’s
awareness of and curiosity in the trial may tissues is directly proportional to the rate
have stimulated increased exercise of the of mitotic division and the metabolic activinjected joint, resulting in symptomatic im- ity of the tissues (13, 3). One would expect,
if this is the case, to see a more favorable
provement (9).
Radiographic and clinical progression response in patients with acute, florid synooccurred in 50% of our patients, indicating vitis. This has not been observed in our
a continuing influence of general disease in patients.
Table 6. Progression of Radiographic Lesions.
and Clinical Deformityt After Injection
J
Arthritis and Rheumatism, Vol. 14, No. 2 (Yamh-April 1971)
217
It is possible to speculate that the action
of alkylating agents on a biologic system,
such as the immunologic protein mechanism, may be as important as their action on
rapidly dividing cells (6). If the plasma cell
secretes rheumatoid factor, as suggested by
Mellors, and if rheumatoid factor has an
antibody function in rheumatoid disease,
the effect of the alkylating agents might be
implicated at this level of cellular activity
(14, 15). However, Currey, using immunofluorescent technics, was unable to
demonstrate any decrease in the population of rheumatoid factor-containing cells,
despite a n overall decrease in inflammatory
cells, after the injection of Thiotepa (9).
Histologic studies have been accomplished in a number of our patients after
the injection of Thiotepa. Joints scheduled
for subsequent surgical synovectomy have
been injected with Thiotepa. An adjacent,
similarly involved digital joint was used as
a control specimen. Synovial tissue from
the injected and control joints were submitted for routine and electron microscop
ic examination after surgical excision.
These studies failed to substantiate our
earlier hope that some consistent histologic
difference exists after the injection of Thiotepa. In each instance, the tissues were
similar i n regard to cellular populations
and other histologic characteristics.
Fig 2. This 42-year-old male (AS) had Thiotepa injected into the MP joints of the left hand in 1962.
Fig 2A is the radiographic appearance of the hands at the time of injection. Fig 2B shows the appearance
eight years later. Progression is present in the untreated joints. Fig 2C shows the clinical appearance of
the hands at follow-up (1970). Local disease has continued in all but the injected MP joints of the left
hand, and systemic disease activity was present a t follow-up.
218
Mhritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
INTRA-ARTICULAR THIOTEPA
Althritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
219
ELLISON & FIATT
We must conclude, therefore, that sufficient information is not currently available
t o explain the mode of action of these
chemical agents in rheumatoid disease. It is
probable that this will continue to be true
until the etiology of the disease has been
more clearly established.
CONCLUSIONS
a n accurate prediction of the joints most
suited for this mode of therapy.
T h e use of Thiotepa should be confined
to patients in whom specific indications
exist. These patients include those with
multiple joint involvement in the same
hand, poor risk patients, and the occasional
individual with single joint involvement.
An accurate appraisal of the result after
injection must be related to the systemic
disease activity in each patient.
T h e effectiveness of alkylating agents
used intra-articularly in joints involved
with rheumatoid disease is, at best, unpreSUMMARY
dictable in terms of potential benefit. NO
Thirty patients with rheumatoid disease
common clinical characteristic could be
defined in our patients which might enable involving the digital joints of their hands
Fig 3. This 46-year-old female patient (AL) had Thiotepa injected into the MP and PIP joints of the
right hand in 1965. Fig 3A shows the radiographic appearance of the joints at the time of injection. Some
joint destruction has already occurred. Fig 3 8 shows the appearance five years later. Progression is
dramatic in the untreated hand. Fig 3C shows the clinical appearance of the hands at follow-up, with a
marked difference in the two hands. Systemic disease activity was present at follow-up.
220
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
INTRA-ARTICULAR THIOTEPA
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
221
ELLISON & F u l l
have been treated with the intra-articular
administration of Thiotepa, a n alkylating
agent. One hundred twenty-three joints
have been injected i n this group of patients.
T h e results from t h e injection are evaluated on ,the basis of four separate categories: relief of pain, objective clinical observations, progression of clinical deformity,
a n d progression of radiographic lesions.
Only seven of our 30 patients had a good
result when all four categories were considered in each patient.
Histologic examination of injected synovium failed to demonstrate any consistent
difference from synovium not injected. O u r
limited indications for the continued use of
Thiotepa are presented.
REFERENCES
Becker RM: Suppression of local tissue
reactivity (Schwartzman Phenomenon) by
nitrogen mustard, benzol, and X-ray irradiation. Proc Soc Exp Biol Med 69:247,
1948
D i n CJ: Treatment of dysreactive diseases
with nitrogen mustards. Ann Rheum Dis
10:144, 1951
Paul WD, Hodges RE, Bean WB, et al:
Effects of nitrogen mustard therapy in patients with rheumatoid arthritis. Arch Phys
Med 35:371-380, 1954
Scherbel AL, Schucter SL, Weyman JJ:
Intra-articular administration of nitrogen
mustard alone and combined with corticosteroid for rheumatoid arthritis. Cleveland Clin Quart 24:78-89, 1957
222
5. Vainio K, Julkunen H: Intra-articular
nitrogen mustard treatment of rheumatoid
arthritis. Acta Rheum Scand 6:25-30, 1960
6. Flatt AE: Intra-articular Thiopeta in rheumatoid disease of the hands. Rheumatism
18:70, 1962
7. Zuckner J, Uddin J, Ramsey RH, et al:
Evaluation of intra-articular Thiotepa in
rheumatoid arthritis. Ann Rheum Dis 25:
178, 1966
8. Howes RG, Isdale IC, Rose BS, et al: Experiences with intra-articular Thiotepa in
rheumatoid arthritis. New Zeal Med J 66:
667-669,1967
9. Currey HLF: Intra-articular Thiotepa in
rheumatoid arthritis. Ann Rheum Dis 24:
382, 1965
10. Flatt AE: T h e Care of the Rheumatoid
Hand. Second edition. St Louis, CV Mosby
CO, 1968, pp 101-102
11. Bennett IL, Cluff LE: Influence of nitrogen
mustard upon reactions to bacterial endotoxins: Schwartzman phenomenon and
fever. Proc SOCExp Biol Med 81:304, 1952
12. Schlang HA: Schwartzman phenomenon.
11. Suppressive action of HN, on antigenantibody provocation. Proc SOC Exp Biol
Med 79:639, 1952
13. Karnofsky DA: Nitrogen mustards in treatment of neoplastic disease. Advances Intern
Med 4:l-76, 1950
14. Mellors RC, Nowoslawski A, Korngold L:
Cellular origin of rheumatoid factor. J Exp
Med 110:875-886, 1959
15. Mellors RC, Nowoslawski A, Korngold L:
Rheumatoid arthritis and the cellular origin of rheumatoid factors. Amer J Path
395:533-546, 1961
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
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