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Experimental Radiation Synovectomy by 165Dy Ferric Hydroxide Macroaggregate.

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1334
EXPERIMENTAL RADIATION
SYNOVECTOMY BY 165Dy FERRIC
HYDROXIDE MACROAGGREGATE
CLEMENT B. SLEDGE, JONATHAN NOBLE, DONALD J. HNATOWICH, RICHARD KRAMER,
and SONYA SHORTKROFF
The short half-life beta emitter IssDy coprecipitated as a macroaggregate with ferric hydroxide (FHMA)
has been shown to destroy knee synovium in the antigeninduced arthritic rabbit. Using 163Gdas a gamma tracer
for leakage studies revealed that the leakage of this system from rabbit knee joints never exceeded 1.2%over 24
hours. This is much less than the leakage rates reported
from any human studies or our rabbit studies using leaAu.
In the management of rheumatoid arthritis, joint
replacement is generally reserved for treatment of the
destroyed joint (1). Alternatively, there is little or no
proof that anti-inflammatory drugs such as the salicylates, indomethacin, or even cortisone do more than
From the Department of Orthopedic Surgery, Harvard Medical School and Robert B. Brigham Hospital, Boston, Massachusetts,
and the Department of Nuclear Engineering, Massachusetts Institute
of Technology, Cambridge, Massachusetts.
Supported by Research Grant AM 17930 from the National
Institute of Arthritis, Metabolism, and Digestive Diseases.
Clement B. Sledge, M.D.: Professor of Orthopedic Surgery,
Harvard Medical School and Surgeon-in-Chief, Robert B. Brigham
Hospital; Jonathan Noble, M.B., Ch.B., F.R.C.S.: Research Fellow in
Orthopedic Surgery, Harvard Medical School and Robert B. Brigham
Hospital; Donald J. Hnatowich, Ph.D.: Research Associate, Department of Nuclear Engineering, Mass. Institute of Technology; Richard
Kramer, B.S.: Research Technician, Department of Nuclear Engineering, Mass. Institute of Technology; and Sonya Shortkroff, M.S.: Research Technician, Department of Orthopedic Surgery, Robert B.
Brigham Hospital.
Address reprint requests to Clement B. Sledge, M.D., Department of Orthopedic Surgery, Robert B. Brigham Hospital, 125
Parker Hill Avenue, Boston, Massachusetts 02120.
Submitted for publication March 14, 1977: accepted April 6,
1977.
Arthritis and Rheumatism, Vol. 20, No. 7 (September-October 1977)
mollify symptoms, rather than protect the joint from
progressive destruction (2). Between these extremes,
there remains a place for synovectomy which will abolish or improve the majority of symptoms for at least 3 to
5 years and in some cases longer (3-9).
What is more debatable is whether synovectomy
will interrupt or delay the destruction of articular cartilage, particularly in early cases. Both Goldie (10) and
Patzakis et a1 (1 1) have presented evidence that regenerated synovium morphologically and histologically resembles diseased synovium. Mitchell and Shepard, however, ( 12) studied the histology and electron microscopic
features of cartilage and synovium before and after
synovectomy for early rheumatoid arthritis and concluded that the regenerated synovium was essentially
normal. They also noted a tendency for the chondrocytes to revert to normal during the 5 years after
synovectomy. The evidence for symptomatic relief is
conclusive, but that for cartilage protection is not and
some surgeons may feel that the surgery and hospitalization involved in synovectomy are not easily warranted.
Over the last 20 years alternative methods of
securing a “medical” synovectomy have been sought
(13). The use of isotopes introduced into the knee was
first described in 1963 by Ansell et a1 (14) and subsequently has been widely reported from Europe
(15-22). Its promise has not been fulfilled, and this is
largely because of concern regarding leakage of radioactivity outside the joint. Most authors have agreed (IS)
that yttrium 90 (”Y)is safer than colloidal gold 198
RADIATION SYNOVECTOMY
(188A~),
and yet Gumpel (15) has stated that the leakage
of activity in patients injected with
resin colloid 5 days
after injection varied between 9% and 48% of the injected dose. Subsequently, he ( 1 6) quoted leakage of
various
preparations as being 4 to 1 1 % at 24 hours
and between 15 and 25% at 5 days. The leakage of
yttrium reported by Oka is similar (19), and Topp (23)
has assessed the leakage of 1B8Auat 24 hours to be as
high as 60%. Stevenson (24) has shown that 10% of
people receiving 5-10 mCi of either ls8Au or
have
chromosome aberrations a week or more later, although
he computed the cancer risk t o be less than in the
general population, a view not entirely upheld by Dolphin (25). Such problems are dependent on associated
gamma ray emissions and leakage (of beta-emitting particles) outside the joint.
There have been reports of skin necrosis when
wY has been used in the treatment of small joint synovitis (15). This may be the result of its energetic soft
tissue penetrance, which exceeds 1 cm. Menkes et al(26)
have warned against the use of both
and 1 g 8 Ain
~ the
hand. These concerns have prevented application of
these techniques in the U.S. However, surgical synovectomy is not without complications (4,9) and Gumpel
(27) has shown that in terms of symptomatic benefit and
duration of relief, radiation synovectomy compared favorably with surgical synovectomy in a controlled prospective trial.
One is left with the overall impression that if
leakage could be prevented or minimized there would be
a procedure as effective as surgical synovectomy but not
requiring the time, facilities, and dangers of anesthesia
and surgery. Moreover, unlike the surgical alternative,
radiation synovectomy can be repeated for recurrences
or poor clinical responses (15); it also has the potential
to reach all surgically inaccessible recesses of a joint
space.
We have addressed ourselves primarily to the
problem of leakage and wish t o report on the development and in vivo testing of a ferric hydroxide preparation that can be coprecipitated with the short half-life
isotope dysprosium 165 (‘“Dy), whose therapeutic efficacy has also been assessed. The development, preparation, and in vitro testing of this system have been reported elsewhere (28). ‘
METHODS
Selection of Isotope
An isotope ideal for synovectomy should have: I ) beta
emissions, 2) low (or no) gamma emission, 3) sufficient meV,
1335
< 10 mm, and 5) a short halflife. That it should be reasonably easy to obtain, nontoxic, and
chemically pure is self-evident. Tissue damage is best caused
by a beta emission of sufficient energy (mev) to effect adequate
tissue penetration within the synovium. To minimize unwanted whole body radiation it should have little or no associated gamma emission. Whole-body radiation due to leakage
can be reduced many times by using a short half-life isotope.
The characteristics of ISsAu,wY,erbium 169 (laeEr) and rhenium 186 (I’Re), and the rare earth isotope, ISsDy, are reviewed in Table I . IssDy is a beta emitter with little gamma
emission, a maximum tissue penetrance of 5.7 mm and a halflife of 140 minutes. It is well suited to our purposes and has
previously been used in the treatment of gliomata (30). It is
obtained at high specific activity (radioactivity per unit weight)
by the irradiation of dysprosium oxide with neutrons in a
nuclear reactor for 8 hours (28). Its purity has been demonstrated by gamma and beta spectrometry (28).
4) maximum tissue penetrance
Particle System
An isotope injected directly into a joint in solution
would rapidly diffuse out, producing unwanted effects, hence
the use of colloids to date. We have attempted to associate the
isotope with a particle whose physical and chemical characteristics will facilitate retention within the joint. The ideal particle
should have the following characteristics: 1 ) biodegradability,
2) good synovial uptake, 3) stable preparation in vitro, 4 ) little
or no leakage from the joint, 5) quick, easy and reproducible
preparation, and 6) no toxic or allergenic properties. Macroaggregates of ferric hydroxide appear to fulfill these criteria
very well.
Macroaggregates of ferric hydroxide (FH MA) containing technetium 99” (wmTC)have been used as a lung
scanning agent (31). and the affinity of synovium for iron in
rheumatoid arthritis has been well described (32-34). The
precise method of preparing the coprecipitate of ferric hydroxide with lesDyand the removal of colloidal particles (“fines”)
from that preparation have been described in detail elsewhere
by Hnatowich et al (28). This technique incorporates about
70% of the original activity with which it was prepared, and the
procedure takes approximately 20 minutes. Hnatowich et al
have shown that this preparation is very stable in vitro (28).
Animal Models
New Zealand white rabbits were used. A chronic condition very like rheumatoid arthritis is produced as described
by Steinberg et al (35) based on the original method of Dumonde and Glynn (36). Animals were sensitized by subcutaneous injections of ovalbumin with Freund’s adjuvant, which
was repeated 3 weeks later. Once the animal is sensitized, a
chronic monoarticular arthritis lasting up to 30 weeks can be
produced by the intra-articular injection of ovalbumin. Because the arthritis takes many weeks to develop and some
animals die during the induction period, normal rabbits were
used for preliminary studies. For therapy experiments, antigen
induced arthritis (AIA) was stimulated in both knees so that
one joint could be injected with a therapeutic dose of isotope
and the other could subsequently be used as a histologic control. In all experiments only 0.4 cc of material was injected into
1336
SLEDGE ET AL
Table 1. Characteristics of 5 Radionuclides
E max
Isotone
Half-Life
Radiation;
Y
(meV)
0.95
0.41 (96%)
P
P
P
0.34
I .07
~
lesAu
MY
Er
189
lssRe
2.7 days
2.7 days
9.4 days
3.7 days
P
Y
140minutes
Table 2. Experiment LI: Leakage by Organ Biodistribution in 12
,f3
~
~~~
2.3
~~~
Mean at 5 hours
(7 rabbits) f SD,
Mean at 24 hours
(5 rabbits) f SD,
YO
3.9mm
Organ
%
11.1 m m
0.9 m m
4.5 m m
Right lymph nodes
Left lymph nodes
0.001 f 0.001
0
0.017 f 0.01
0.027 f 0.026
0.059 f 0.038
0.003 f 0.003
0.14 (9%)
I .3
5.7 mm
0.0919%)
* Only y rays >2% abundance are listed, with the percentage abundance of y rays given in parentheses.
lssDy
Normal Knees Injected with ‘“Gd/FHMA
Soft Tissue
Maximum
Penetration
Y
each knee to avoid leakage due to increased intra-articular
pressure, which Edlund (37) has shown increases the absorption of fluid and hemoglobin.
Experimental Methods
These have fallen into two categories: I ) Studies to
measure the leakage of activity from the joint 2) therapy
trials to assess the effect of leaDy on the synovium. The short
half-life and beta emission of 1B6Dymake it unsuitable for any
type of tracer study whereby the proportion of an injected dose
that has leaked from the joint is expressed as a percentage of
the total dose injected. For either of the two techniques applied to the study of leakage, a gamma-emitting isotope with a
half-life of many days is preferred. Dysprosium 159 (‘“Dy), a
gamma-hitting isotope of dysprosium with a half-life of 144
days, is obtained with difficulty, and then only at low specific
activity, and it is expensive (28). W e therefore used gadolinium
153 (‘Wd), another gamma-emitter, with a half-life of 242
days. Its chemical properties are similar to those of dysprosium and it can be easily coprecipitated with ferric hydroxide.
The validity of using IssGd as a tracer rather than ‘“Dy was
assessed in experiment L3. We have also used cerium 144
(Ir4Ce) whose mixture of gamma and beta emissions makes it
suitable for autoradiography.
Leakage. Leakage was Studied with two techniques: 1 )
organ biodistribution by sacrifice and dissection of the animal
and 2) gamma camera counting studies of the intact animal.
The use of this latter technique has been fully described elsewhere by Noble er a1 (38). In each biodistribution experiment
half the rabbits were killed at 5 hours and half at 24 hours after
injection. Their right and left inguinal lymph glands, right
kidney, and right hepatic lobe were removed as well as 5 cc of
both urine and blood. In the 24-hour subgroup feces were also
collected. After weighing, these specimens were placed in vials
in a gamma well scintillation counter, with an aliquot of the
injected preparation for use as a standard. After adjustment
for. background radiation, the percentage of the injected dose
present in each sample was measured. An assumption was
made that the liver of a 7 to 10 pound rabbit weighs approximately 100 gm and its blood volume is approximately 120 cc.
With the gamma camera study it was possible, by
complete shielding, to measure the counts from only the knee
and then only the torso (from the level of the chin t o the pubis)
with the knee excluded (38). For the periods of study all urine
and feces were collected and the radiation therein was counted.
Blood
Kidney
Liver
Urine
Feces
0.003 f 0.005
0.003 f 0.004
0.034 f 0.028
0.140 f 0.120
0.340 0.044
0.044 f 0.061
0.008 f 0.007
-
By these means it was simple t o calculate the amount of
radiation that had escaped from the knee to both the torso
and/or excreta as a percentage of the total activity present.
The two methods were compared in experiment L5 in
which we conducted a gamma count a t lY2, 5, and 24 hours
and then sacrificed the animals to obtain biodistribution data.
In this same experiment the knee joints were carefully opened
and the synovial linings were rinsed with normal saline. These
rinsings were then counted and expressed as a percentage of
the total dose injected. lssDy was coprecipitated with 100 pCi
of lS3Gd/FHMA to discover if therapeutic levels of activity
affected the leakage of the particle system. This experiment
also gave the opportunity to assess leakage of the ferric hydroxide system under the circumstance of synovial destruction.
In summary, the following leakage (L) studies were
carried out:
LI: Approximately 100 pCi of ‘%d/FHMA were injected into 12 normal knees and the rabbits sacrificed at 5 and
24 hours (Table 2).
L2: Approximately 100 pCi of ‘“Gd/FHMA were injected into 1 1 AIA knees and the rabbits sacrificed at 5 and 24
hours (Table 3).
L3: Approximately 100 pCi of ‘“Dy/FHMA were injected into 7 normal knees and the rabbits sacrificed at 5 and
24 hours (Table 4).
L4: 350-450 pCi of ‘“Gd/FHMA were injected into 6
normal and 5 AIA knees and the leakage rate measured with
the gamma camera in the live rabbits a t time points over 10
days (Table 5).
L5: Three AIA knees were injected with 16aGd/FHMA
Table 3. Experiment L2: Leakage by Organ Biodistribution in I ! AIA
Knees Injected with “Wd/FHMA
Mean at 24 hours
Mean at 5 hours
(5 rabbits) f SD,
(6 rabbits) f SD,
Organ
%
%
Right lymph nodes
Left lymph nodes
Blood
Kidney
Liver
Urine
Feces
0.001 f 0.001
0.001 f 0
0.027 f 0.023
0.046 f 0.021
0.113f0.110
0.003 f 0.002
-
.
0.001 lk 0
0.001 f 0.001
0.015 f 0.021
0.075 f 0.072
0.300 f 0.122
0.017 f 0.012
0.002 f 0.001
1337
RADIATION SYNOVECTOMY
Table 4. Experiment L3: Leakage by Organ Biodistribution in 7 Normal
Knees Injected with "'DyIFHMA
Mean at 5 hours
(3 rabbits), %
Mean at 24 hours
(4 rabbits), %
0
0
0.023 f 0.010
0.049f 0.027
0
0
0.022 k 0.020
0.063 & 0.054
0.078f 0.055
0.004f 0.003
Oraan
Right lymph nodes
Left lymph nodes
Blood
Kidney
Liver
Urine
Feces
0.017& 0.018
0.003& 0.002
-
0
and the animals were studied by gamma imaging and organ
biodistribution (Table 6).
L6: F H M A was injected into 4 AIA rabbits with doses
of 4.5, 5.0, 5.5, and 6.0 mCi of lssDy and they were sacrificed at
24 hours and studied by biodistribution (Table 7).
L7: Gold-I98 colloid, whose average particle size was
0.3 p , was injected into 7 normal rabbits and the leakage rate
was studied using the gamma camera a t 24 hours.
Therapy Trials and Histology. A total of 16 rabbits
with bilateral AIA were injected with lo6Dyin doses varying
between 1 and 8 mCi. All but 4 were sacrificed at 4 weeks and
specimens of capsule with underlying synovium were cut from
the medial parapatellar area and stained with hematoxylin and
eosin and also with Perl's stain for iron (39). Both knees were
then removed, and after decalcification in formic acid coronal
sections were cut. In 4 rabbits 4.5 to 6.0 mCi of lssDy were
given with tracer lssGd (experiment L6) and the animals were
sacrificed a t 24 nours and the knees and synovium were studied histologically.
Two AIA rabbits were injected in both knees with
ferric hydroxide coprecipitated with ' Y e . The synovium was
taken at 5 and 24 hours and autoradiographs were made by
dipping 6 p deparaffinized sections in Kodak NTB-2 and exposing them in the dark for 7 days. These exposed slides were
then developed in Kodak D-19 and stained with hematoxylin
and eosin.
RESULTS
The biodistribution of leakage to the various sites
in both normal and A I A rabbits is shown in Tables 2
Table 5. Experiment L4: Comparison of 24-hour and IO-day Leakage by
Gamma Camera; Rates in Normal and AIA Rabbiis Injected with
"%dl FHMA
~~
10 Days
24 hours
Normal, %
0.29
0.47
1.10
0.99
0.74
AIA, %
0.56
1.16
1.14
0.37
0.98
Normal, %
0.78
f0.34
0.84
f0.36
P < 0.40
4.01
4.68
7.50
7.21
9.99
13.04
5.98
6.67
5.40
8.58
f2.92
f1.86
P
~~~
~
Rabbit
Number
Biodistribution,
1
< 0.10
70
0.49
0.49
0.59
2
3
Camera, 96
0.99
0.74
1.11
Percentage Injected
Dose-Free in Joint
at 24 Hours, 96
6.53
4.92
13.65
and 3. It can be seen that in most specimens less than
0.01% of the injected dose had leaked at 5 or 24 hours
and the highest mean leakage was to the liver in 12
normal rabbits at 24 hours (0.34%).The similarity of the
data, obtained using lsSDyto that obtained with IS3Gd,is
shown in Table 4. In Table 5 the leakage rates measured
on the gamma camera/counter at 24 hours and 10 days
in both normal and A I A rabbits are shown. In normal
rabbits this never exceeded 1.11% at 24 hours, and for
the A I A the figure was 1.16%, an insignificant difference. Over 10 days the cumulative leakage averaged
5.40% in normals and 8.58% in A I A rabbits (P < 0.1).
Leakage data were obtained at 24 hours (Table 6), using
both gamma camera and biodistribution techniques in 3
animals. The biodistribution figures are the sum of the
radioactive accumulation in the sites already described,
and the rates are approximately twice as high as those
with the gamma camera. The leakage rates obtained by
biodistribution in 4 rabbits in whom therapeutic Is5Dy
was incorporated with the ISSGdtracer are not higher
than the leakage rates of tracer IS3Gdalone (Table 7).
The mean value for the leakage rates at 24 hours
of gold colloid injected in 7 normal rabbits was 2.02%
(SD 1.49%). In 2 rabbits figures of 4.35% and 3.86%
were obtained, whereas with F H M A rabbits in whom
the mean at 24 hours was 0.78%, the highest degree of
leakage demonstrated in normal animals was 1.1 1%.
Table 7. Experiment L6: Leakage by Biodistribution of Therapeutic
Doses of FHMA '"Dy with Tracer ' W d in 4 AIA Rabbits SacriJiced at
24 Hours*
AIA, 96
1.11
Mean
SD
Table 6. Experiment L5: Biodistribution and Gamma Camera Leakage
Data at 24 hours Compared in 3 AIA Rabbits Injected with
lSaGdIFHMA
Organ
Right inguinal lymph nodes
Left inguinal lymph nodes
Blood
Right kidney
Liver
Urine
Feces
* l6'Dy
Mean Leakage Rates, %
0.001
* 0.001
0.001 f 0.001
0.058 f 0.049
0.113 f 0.021
0.107 f 0.049
0.004 f 0.008
0.010 f 0.012
Doses: 4.5 mCi, 5.0mCi, 5.5 mCi and 6.0mCi; approximately
100 pCi lS9Gd.
1338
SLEDGE ET AL
Fig. 1. Typical histologic features of A I A rabbit knee.
Fig. 2. Eflects of 7 mCi of ISsDyon the synovium of the other knee of rabbit shown in Figure I .
RADIATION SYNOVECTOMY
1339
This difference between the FH MA and gold colloid
data is significant ( P < 0.05).
I n Figure 1 the typical histologic features of AIA
are shown and in Figure 2 the effects of 7 mCi of lssDy
on the synovium of the other knee of the same rabbit
can be seen. The effects of decreasing dosages from 8 to
1 mCi on AIA synovium were varied. Widespread destruction of synovium was seen with as little as 2 mCi of
Is5Dy, whereas in 2 rabbits the response to 6 or 7 mCi
was disappointing.
The autoradiograph in Figure 3 shows that the
FHMA is well distributed in the synovium by 24 hours
and this is borne out further by applying Perl's stain for
iron as shown in Figure 4. In the rinse out study (L5)it
was found that only 6.5 to 13.6% of the activity could be
washed free at 24 hours.
DISCUSSION
Leakage Studies
In a recent human study (40) the leakage from
the knee at 2 days of
ferric hydroxide colloid was
shown to be 6% (SD = 6) and of "'Au colloid 4% (SD =
8). Therefore, in this carefully conducted human study
the leakages of ls8Au(average particle size 10 nm) and of
'OY ferric hydroxide colloid (average particle size 5 pm)
are similar. The leakage shown with ls8Au colloid in
normal rabbits is of a similar order. Thus the leakage
rates which we have demonstrated in both normal and
AIA rabbits with FHMA are strikingly lower. It remains to be seen if this observation in the rabbit will be
upheld in human studies.
It should be emphasized that statements of leakage at 5 or 24 hours indicate the leakage of the particle
system as reflected by laaGd and not that of the actual
activity given in the therapy trial which will be reduced
enormously by short half-life decay. For example, at 24
hours only 0.1% of an injected dose of 166Dyremains;
similarly the remainder of 5 mCi available to leak at 5
hours is approximately 1.25 mCi and at 7 hours is 0.625
mCi. On this basis we can calculate the whole body
radiation due to 1) known leakage rates, adjusted for
decay factor, 2) gamma emission, and 3) Bremstrahlung
(secondary gamma emissions).
The basis for these calculations is described elsewhere (27), where it was estimated that in terms of
different energies and half-lives a standard dose of 5 mCi
of
would be equivalent to 270 mCi of lE6Dy.The
whole body radiation due to gamma ray emission and
Fig. 3. Autoradiograph showing distribution of F H M A in synovium.
Bremstrahlung on this basis in the human would be 0.41
rads and that due to 1% leakage of, or from, the FHMA
system over 24 hours would be 3 millirads. From our
biodistribution data maximum radiation exposure
would be 2.0 rads to the liver. This is considerably less
than the total radiation exposure from an IVP (5-15
rads) and is a very much lower whole body radiation
than any previously described in therapeutic radiation
synovectomy. Dolphin (25) calculated that a 1% leakage
of 10 mCi lsaAu to the liver would deliver to it a radithe figure
ation dose of 4.5 rads, and for 5 mCi
would be 5.4 rads.
1340
SLEDGE ET A1
Fig. 4. Distribution of F H M A in the synovium shown in Figure 3 a / e r application of Perl's strain for iron.
The basis for these favorable comparisons lies
first in the selection of a beta-emitter with gamma emission whose half-life is approximately 1/28 that of 1 s 8 A ~
or
Secondly, it lies with the use of a particle system
whose leakage rate does not exceed 1.2% over 24 hours,
which is much better than anything previously described, except the results of Bowen er af (41) who
claimed a leakage rate at 24 hours of 0-4%, using
citrate colloid. However, this was from a series of 3
normal rabbits in whom the gamma emissions (notably
low with wY)were measured by collimated scintillation
counting. The only particles whose leakage rates are
lower than FHMA are carbonized microspheres and
albumin microspheres where the activity is incorporated
in the particle (38). However, the effects of leaving nonbiodegradable material in a joint are unknown.
We have shown by histologic, autoradiographic,
and washout studies that FHMA are taken up by the
synovium. We have also shown that leaDy is capable of
effectively destroying the synovium in a dose as small as
2 mCi. However, Ingrand (42) has shown with
that
the dose is not critical and he commented that his group
of patients had maintained clinical responses despite
reduction of dosage. Our experience with arthritic rabbits appears to be similar, although in retrospect 4 weeks
is a poor time to have selected for sacrifice and histologic study, since it is too late to see acute effects of
radinecrosis and too early to see the long-term synovial
effects. It is relevant to consider if a full-thickness synovectomy is in fact our objective and we are carrying out
further studies in this respect. Pavelka (43), studying the
histologic effects of small doses of 'OY on rabbit knees,
reported fibrosis of the stratum synovialis 1 to 4 months
after injection, associated with small vessel endarteritis
obliterans. He suggested that these changes may be sufficient to reduce symptoms in patients.
I t is likely that the appropriate dose of lesDy in
humans will ultimately be a matter for careful, empirical
human studies, possibly monitored by arthroscopy with
synovial biopsy (44). A quantitative bioassay for synovial activity is being developed in our laboratory now.
This is likely to be of some importance in trying to
measure response to therapy since Waxman and Sledge
(45) and Muirden (46) have demonstrated a correlation
between the clinical and histologic features of rheumatoid arthritis and lysosomal activity.
Before proceeding to human therapy trials we are
currently undertaking studies to discover whether ferric
hydroxide has any long-term effect on normal articular
cartilage and whether the irradiation of cartilage by
RADIATION SY NOVECTO M Y
Is5Dy causes histologic changes or perturbations of its
n o r m a l metabolism. Rubin et a1 (47) have s h o w n t h a t up
to a year after receiving as m u c h as 10 mCi o f lasAu t h e
rat's articular cartilage remains normal, b u t Pavelka
(43) sacrificing r a b b i t s 4 weeks to 4 m o n t h s after t h e
injection of 0.2 to 0.4 mCi of @"Yshowed cellular proliferation in anatomically thin areas o f articular cartilage.
ACKNOWLEDGMENTS
Thanks are due Drs. M .A. Davis and A. G. Jones for
the use of their gamma camera. We are also very grateful to
Mrs. Pat Mark for histology and autoradiography and to Mrs.
Phyllis White for preparing this manuscript.
REFERENCES
I . Poss R: Total hip replacement. Orth Clin N Am
6:801-810, 1975
2. Hall AP: The decision to operate in rheumatoid arthritis.
Orth Clin N Am 6:675-684, 1975
3. Geens S: Synovectomy and debridement in rheumatoid
arthritis. Part I. Historical review. J Bone Joint Surg
5 I A:6 17-625, 1969
4. Morgan ES, Boger WM, Gilliland BC, and Mererowitz S:
Synovectomy in rheumatoid arthritis. Arthritis Rheum
13:761-768, 1970
5 . Laurin CA, Desmarchais J, Daziano L, et al: Long-term
results of synovectomy of the knee in rheumatoid patients.
J Bone Joint Surg 56A:521-531, 1974
6. Geens S, Clayton ML, Leidholt J D , et al: Synovectomy
and debridement of the knee in rheumatoid arthritis. J
Bone Joint Surg 51A:626-641, 1969
7. Taylor AR, Harbison JS, Pepler C: Synovectomy of the
knee in rheumatoid arthritis. Ann Rheum Dis 31:159-161,
I972
8. Ranawat CS, Ecker ML, Straub LR: Synovectomy and
debridement of the knee in rheumatoid arthritis: a study
of 60 cases. Arthritis Rheum 15:571-581. 1972
9. Marmor L: Surgery of the rheumatoid knee. J Bone Joint
Surg 55A:535-544, 1973
10. Goldie I: Pathomorphologic feature in original and regenerated tissues after synovectomy in rheumatoid arthritis.
Clin Orthop 77:295-304. 1971
I I . Patzakis MJ. Mills D M , Bartholomew BA, et al: A visual,
histological and enzymatic study of regenerating synovium in the synovectomized knee, J Bone Joint Surg
55A:287-300, 1973
12. Mitchell N, Shepard N: The effect of synovectomy on
synovium and cartilage in early rheumatoid arthritis. Clin
Orthop 89:178-196, 1972
13. Editorial: Medical synovectomy. Brit Med J 2:682, 1974
14. Ansell BM, Crook A, Mallard JR and Bywaters EGL:
Evaluation of intra-articular colloidal gold lsaAu in the
1341
treatment of knee effusions. Ann Rheum Dis 22435-439.
1963
15. Gumpel JM: Symposium on radioactive colloids in the
treatment of arthritis. Ann Rheum Dis 32: 1973 (Suppl6)
16. Gumpel JM, Beer TC, Crawley JCW and Farran HEA:
Yttrium 90 in persistent synovitis of the knee: single centre
comparison of the retention and extra-articular spread of
radiocolloids. Brit J Radiol 48:377-381, 1975
four
17. Gumpel J M , Williams ED, Glass HI: Use of yttrium 90 in
persistent synovitis of the knee; retention of the knee and
spread in the body after injection. Ann Rheum Dis
32:223-227, 1973
18. Delbarre F, Cayla J. Menkes C , et al: La synoviorthese
par les radio-isotopes. Presse Med 76: 1045-1050. 1968
19. Oka M, Rekonen A, Ruotsi A and Seppala 0: Intraarticular injection of
resin colloid in the treatment of
rheumatoid knee joint effusions. Acta Rheum Scand
17:148-160, 1971
20. Oka M: Radiation synovectomy of the rheumatoid knee
with
Ann Clin Res 7:205-210, 1975
21. Bridgnan JF, Bruckner F, Eisen V, et a): Irradiation of the
synovium in the treatment of rheumatoid arthritis. Quart
J Med 42:357-367, 1973
22. Jalava S: Irradiation synovectomy: clinical study of 67
knee effusions intra-articularly irradiated with 'OY resin.
Current Therap Res 15:395-401, 1973
23. Topp J R , Cross EG, Fain, AG: Treatment of persistent
knee effusions with intra-articular radio-active gold.
CMAJ 112:1085-1089, 1975
24. Stevenson AC: Cytogenetic and scanning study of patients
receiving intra-articular'injections of gold 198 and yttrium
90. Ann Rheum Dis 32:112-123, 1973
25. Dolphin GW: Biological hazards of radiation, Symposium on radioactive colloids in the treatment of arthritis. Ann Rheum Dis 32:23-28, 1973 (Suppl 6)
26. Menkes CJ, Tubiana R, Gahriche B and Delbarre F:
Intra-articular injection of radio-isotopic beta emitters:
application to the treatment of the rheumatoid hand. Orthop Clin N Am 4:1I13-1117, 1973
27. Gumpel J M , Roles NC: A controlled trial of intra-articular radiocolloids versus surgical synovectomy in persistent
synovitis. Lancet 1 :488-489. 1975
28. Hnatowich DJ, Kramer RI, Sledge CB. et al: Dysprosium- 165 ferric hydroxide macroaggregates for radiation
synovectomy. Radiol submitted for publication
29. Gray DE: American Institute of Physics Handbook. New
York, McGraw-Hill, 1972, pp 8-296
30. Ojemann R G , Brownell G L , Sweet WH: Possible radiation therapy of cephalic neoplasms by perfusion of shortlived isotopes. 11. Dysprosium 165. Neurochirurgica
4:41-57, 1961
31. Davis MA: 8 g T ~ - i r hydroxide
~n
aggregates: evaluation of
a new lung scanning agent. Radiol 95:347-352, 1970
32. Ball J, Chapman JA, Muirden KD: The uptake of iron in
rabbit synovial tissue, following intra-articular injection
of iron dextran. J Cell Biol 22:351-364, 1964
SLEDGE ET AL
33. Muirden KD: Clearance of Fe6'-labelled erythrocytes
from normal and inflamed rabbit knee joints. I. Relationship to the anaemia of rheumatoid arthritis. Ann Rheum
Dis 28:548-55 I , I969
34. Muirden KD, Peace G , Rogers K: Clearance of 6eFe labelled erythrocytes from normal and inflamed rabbit knee
joints. 11. Autoradiographic and histological studies. Ann
Rheum Dis 28:630-636, 1969
35. Steinberg ME, McCrae C R , Berselli RA and Cram B:
Intra-articular 5-fluorouracil in antigen induced arthritis.
J Bone Joint Surg 53A: 514-522,1971
36. Dumonde DK, Glynn L E The production of arthritis in
rabbits by an immunological reaction to fibrin. Br J Exper
Path 43:373-380, 1962
37. Edlund T: Studies on absorption of colloids and fluid
from rabbit knee joints. Acta Physiol Scand 18: 1949
(SUPPI 62)
38. Noble J, Jones AG. Davis MA, et al: The measurement of
particle leakage from a synovial joint using a gamma
camera. In preparation
39. Pearse A G E Histochemistry, Theoretical and Applied.
London, JCA Churchill Ltd 1960. Second edition, p 961
40. Williams ED, Cayghey DE, Hurley PJ and John MB:
Distribution of Yttrium 90-ferric hydroxide colloid and
41.
42.
43.
44.
45.
46.
47.
gold 198 colloid after injection into knee. Ann Rheum Dis
35~516-520, 1976
Bowen BM, Darracott J, Garnett ES, Tomlinson RH:
citrate-colloid for radio-isotope synovectomy. Am J
Hosp Pharmacy 32:1027-1030, 1975
lngrand J: Symposium on radioactive colloi+ in the treatment of arthritis. Characteristics of radiosiotopes for
intra-articular therapy. Ann Rheum Dis 32:3-9, 1973
(SUPPI 6)
Pavelka K , Meier-Ruge W, Muller W, Fridrich R: Histological study of effects of colloidal 'OY on knee joint
tissue of rabbits. Ann Rheum Dis 34:64-69, 1975
Yates DB: Arthroscopy of the knee after the injection of
'OY. Ann Rheum Dis 32:48-50, 1973 (Suppl 6)
Waxman BA, Sledge CB: Correlation of histochemical,
histologic and biochemical evaluations of human synovium with clinical activity. Arthritis Rheum 16:376-383,
I973
Muirden KD: Lysosomal enzymes in synovial membrane
in rheumatoid arthritis: relationship to joint damage. Ann
Rheum Dis 31:265-271, 1972
Rubin P, Casarett G, Farrer P: The effects of intra-articular IWAu instillations on articular cartilage. Radio1
103:685-690, 1972
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