close

Вход

Забыли?

вход по аккаунту

?

Experimentally induced corticosteroid arthropathy.

код для вставкиСкачать
Experimentally Induced Corticosteroid Arthropathy
Roland W. Moskowitz, Wirt Davis, James Sammarco, William Mast
and Samuel W. Chase
lntraarticular injections of triamcinolone acetonide resulted in deleterious
changes in living rabbit articular knee cartilage. These changes were characterized by an increased frequency of chondrocyte nuclear degeneration and prominent cyst formation as compared with control animals. Degenerative changes
were localized to the cartilage of the medial tibia1 plateau. This localization may
be related to the different histologic pattern seen i n this cartilage surface as
compared to other areas of the knee. The correlation between certain pre-existing
patterns of cartilage histology and susceptibility t o degenerative change may
provide a clue to the localization of degenerative joint disease i n humans.
Clinical (1-5) and experimental (6-8)
observations have demonstrated that
steroid medications may damage articular
structures. The pathogenesis of these chan-
ges has been attributed to a number of
possible factors: increased coagulability
(9) , vasculitis ( 5 ) , and local inhibition of
pain sensation with secondary degenerative
From the Departments of Medicine and Surgery, change (2). Mankin and Conger (8)
Division of Orthopedics, Case Western Reserve
demonstrated in rabbits, a decrease in glyUniversity School of Medicine, Cleveland, Ohio.
cine-H3 incorporation in the presence of
Supported by General Research Support Grant
intra-articular hydrocortisone acetate. They
SO 1 -FR05410-07, Case Western Reserve University;
I'nitetl Health I~oundations. Inc, Sew York, NY;
interpreted these findings as evidence that
Grant TI AM-5437-05 from the US Public Health
cortisol caused a decrease in cartilage maService; the C. C. Frackelton Fund and E. S. Prentrix synthesis. Silberberg et ul ('i),
noted
tiss Foundation of the Benjamin Rose Hospital.
ROLAND
W. MOSKOWITZ,
MD: Assistant Professor
that cortisone acetate when administered to
of Medicine, Case Western Reserve University
mice
disturbed organellar development of
School of Medicine, Cleveland, Ohio 44106. WIRT
UAVIS,MD: Assistant Professor of Surgery, Division
the cell, with a decrease in chondrocyte
o!: Orthopedics, Case Western Researve CJniversity; size. Their studies suggested a direct cataformerly Special Fellow, US Public Health Service.
JAMESSAMMARCO,
MD: Rcsearch Fellow in Ortho- I d i c or antianabolic effect of the corticospedics, Case Western Reserve University. WrLLiAnr
teroid. The present study, which evaluates
MAST,MD: Assistant Clinical Profcssor of Surgery,
the effects of long-acting corticosteroid
Division of Orthopedics, Casc Western Resen e
University. SAMUEL
W. CHASE,PHD: Associate Pro- preparations on living rabbit articular carfessor Emeritus, Histology and Embryology, Case
tilage, was carried out in an effort to eluWestern Rcserve University.
cidate in further detail the pathology and
Reprint requests should be addressed to Dr.
Moskowitz, 2073 Abington Rd, Cleveland, Ohio
pathogenesis of any steroid-related degener44106.
ative
changes. Since corticosteroids are used
Submitted for publication Sept 10, 1969; accepted
frequently for therapeutic purposes, furJan 13, 1970.
236
Arthritis and Rheumatism, Vol. 13,
No. 3 (Mry-lune 1970)
CORTICOSTEROID ARTHROPATHY
ther understanding of any pathophysiologic effect would be of value, both clinically
and experimentally.
formation, loss of metachromasia, nuclear degeneration characterized by decreased intensity of nuclear
staining, variation in nuclear stain charac,terized by
change in staining color, matrix fibrillation, fissure
formation and cyst formation.
MATERIALS AND METHODS
New Zealand white rabbits, varying in weight
from 1445 to 3600 g (mean weight, 2475 g) were
utilized. The animals were divided into 5 study
groups: (1) normal knees (8 rabbits, 11 knees),
(2) intra-articular saline (3 rabbits, 4 knees), (3)
intra-articular suspending vehicle for triamcinolone
acetonide (12 rabbits, 15 knees), (4) intra-articular
corticosteroid (triamcinolone acetonide aqueous
suspension [Kenalog]," (18 rabbits, 18 knees), and
(5) parenteral triamcinolone acetonide, intramuscularly administered (4 rabbits, 8 knees).
Intra-articular injections were made with a 25
gauge, 5/s inch disposable needle. A lateral approach
was utilized routinely. Triamcinolone acetonide
suspension, 0.3 ml, containing 3 mg active steroid
was injected weekly for 2-6 weeks. Control joints
included normal knee joints, knees receiving 0.3 ml
in tra-articular sterile saline, and knees receiving 0.3
ml sterile suspending vehicle without steroid. Animals were sacrificed 1 week after the final injection.
The triamcinolone acetonide aqueous suspension
contained triamcinolone acetonide. 10 mg/ml, in a
vehicle consisting of benzyl alcohol (0.9y0); sodium
carboxymethyl-cellulose (0.75%) : polysorbate 80
(0.04%) ; and sodium chloride (0.9%). T h e vehicle
for injection was prepared according to the specifications of the manufacturer and was examined
periodically for evidence of bacterial contamination.
Rabbits studied for the effects of intramuscularly
administered steroid received 40 mg triamcinolone
acetonide once weekly for 2 4 weeks. Sacrifice was
carried out 1 week after the final injection.
All animals were sacrificed by intravenous injection of sodium pentothal (Diabutal) ,f for gross and
histologic examination of the distal femur and
proximal tibia. Tissue for histologic examination
was fixed in 10% formalin and then decalcified with
a formic citrate solution. Coronal sections of the
distal femur and proximal tibia were embedded in
paraffin and cut in 10 sections. Hematoxylin and
eosin and toliiidine blue stains were made, and the
tissues were mounted in synthetic mounting medium for study. Slides were reviewed without prior
knowledge of the source of the specimen. Parameters evaluated includ~tl: fihrillation-fraying, ulcer
"E.R. Squibb & Sons, New York, NY.
tDiamond Lab Inc, Des hloines, Iowa.
Arthritis and Rheumatism, Vol. 13, No. 3 (May-lune 1970)
R ESULTS
Normal Rabbit Knees
The cartilaginous surface of the
Gross.
medial tibial plateau differed from those of
the lateral tibial plateau and distal femur.
T h e cartilage of the medial tibial plateau
had a dull, cobblestone appearance in contrast to the glistening, smooth surface characteristic of normal hyaline cartilage.
These unusual surface characteristics extended over the midline to involve part of
the lateral tibial plateau.
The cartilage of the lateral
Histologic.
tibial plateau and femoral condyles could
be divided into tangential, transitional, radial and calcified layers (Fig 1). Chondrocytes were arranged in well-defined linear
arcades. The cartilage of the medial tibial
plateau (Fig 2) was thicker, and frequently
less readily defined into four discrete layers; it also showed increased cellularity in a
more random pattern. The cell capsules
took on a heavy basophilic stain, and
prominent basophilic tailing was observed.
Changes of a degenerative nature were
frequently seen in knee joints of normal
rabbits (Table 1) . Particularly prominent
findings were fibrillation-fraying of the surface, a fibrillary appearance of the matrix
and fissure formation. Many- of the chondrocyte nuclei had a homogeneous,
ground-glass appearance and took an eosinopliilic stain. Chondrocyte degeneration,
characterized by loss of nuclear stain, was
seen in the tangential and transitional layers in 2 cases. Cyst formation was noted in
1 of the 11 normal knees. Only one or two
small cysts were seen in each section. A
small amount of nonspecific detritus was
237
seen lying within .an unlined space in the prominent in the medial tibial plateau,
cartilage matrix. There was no tissue reac- with only minimal changes observed in the
tion surrounding the cysts, Almost all de- lateral tibial plateau and the femoral congenerative changes described were more dyles.
Fig 1 (top). Lateral tibial plateau, normal knee: cartilage can be divided into tangential, transitional,
radial, and calcified layers with chondrocytes arranged in well-defined linear arcades (H&E x 80). Fig 2
(bottom). Medial tibial plateau, same knee: cartilage is less readily defined into 4 discrete layers, is
thicker, and shows increased cellularity in a more random pattern. Cell capsules take on a heavy basophilic
stain with prominent basophilic tailing (H&E x 80).
238
Arthritis and Rheumatism,'Vol. 13, No. 3 (May-June 1970)
CORTICOSTEROID ARTHROPATHY
Table 1. Pathologic Changes Related to Experimental Procedure*
~
Frequency of various degenerative changes observedi
No. of Matrix Fissure
Nuclear Variation
Cyst
No. of injec- Fibrillationdegener- in nuclear fibrilla- forma- formaknees tions/
stains
tion
studied knee fraying Ulcers ationf
tionll
tion
Groups
11
Normal
Intra-articular
injection*
Saline
Vehicle
Triamcinolone
acetonide
Intramuscular
injection
Triamcinolone
acetonide
0
5
0
2
7
5
4
1
1
0
3
0
0
3
1
1
3
1
1
4
1
10
2
1
2
0
5
1
3
6
1
5
3
5
1
1
7
2
0
4
0
0
3
4
2
2
3
4
3
1
10
5
1
4
5
6
4
5
6
9
4
6
1
5
4
4
4
<4
6
1
3
0
0
2
3
5
0
3
0
5
1
4
3
4
2
2
0
1
0
~
* Data for
intra-articular injection series include only knees receiving 4 or more injections.
presence or absence of each type of degenerative change.
f Characterized by decreased intensity of nuclear stain.
8 Characterized by nuclei having a homogeneous, ground-glass appearance taking an eosinophilic
stain.
11 Two or more fissures seen.
t Table based on absolute
Knees Receiving Intra-Articular Saline or
Steroid Vehicle Injections
Gross.
No differences from the normal
were noted.
Histologic. Ulcerative lesions were noted
the normal controls (Fig 3 ) . All drgenerative changes were more prominent in the
medial tibial plateau.
Knees Receiving Intra-Articular
Triamcinolone Acetonide Injections
in 5 knees. Otherwise, the microscopic apGross. Gross abnormalities were noted
pearance of the knees in these study g r o u p
only in those knees treated with 6 injecwas similar to that of the normal control
tions of steroid. White deposits, which apanimals (Table 1) . Fibrillation-fraying, peared to lie under the most superficial
matrix fibrillation and fissure formation
layer of cartilage, were observed in scatwere common. Changes in chondrocyte tered areas of the medial tibial plateau.
stain, characterized by homogeneous,
These deposits felt gritty and crystallineground-glass eosinophilic staining, were
like when cut with a scalpel. T h e deposits
seen in all specimens. Chondrocyte nuclear
disappeared after decalcification of specidegeneration in tangential and transitional
mens.
layers was seen in 4 of the 19 knees studied.
Cysts, seen in 4 knees, were small in size
Histologic.
Compared to the control
and generally few in number in each sec- series (Table 1) , the prominent differences
tion. T h e appearance of the matrix sur- in the effects noted with intra-articular
rounding the cysts was similar to that of corticosteroids were: a n increased frequenArthritis and Rheumatism, Vol. 13, No. 3 (MapJune 1970)
239
Flg 3 (top). Medial tibial plateau, knee receiving 4 weekly intra-articular injections of vehicle: Cysts
composed of nonspecific detritus lying within unlined space cartilage matrix. Similar cysts noted at times
in normal knees and in’knees receiving intra-articular saline injections (H&E x250). Fig 4 (bottom).
Medial tibial plateau, knee receiving 4 weekly intra-articular injections of triamcinolone acetonide: Nuclear
degeneration in tangential layer characterized by loss of nuclear stain and empty lacunae (H&E x 400).
240
Arthritis and Rheumatism, Vol. 13, No. 3 (May-June 1970)
CORTICOSTEROID ARTHROPATHY
cy of chonclrocyte nilclear degeneration in
the tangential aiicl transitional layers, atid
extensive cyst fornia tion. Nuclear degeneration was characterized by loss of nuclear
slain arid empty lacunae (Fig 4) . Numerous, small to very large cysts containing
dying or dead chondrocytes and fibrillar
detritus were present (Fig 5 ) . T h e larger
cysts paralleled the rows of chondrocytes
and frequently appeared to be the result of
small cysts coalescing into larger ones. T h e
matrix surrounding the cyst areas was often
very fibrillar, and in the same area, degeneration of chondrocytes and matrix material seemed to be evident. Although cysts
were occasionally observed after only 2
injections, their size and number seemed to
parallel the number of injections given;
the most prominent cyst formation was
seen in the 6-injection series. Again the
tendency of all pathologic changes to localiLe in the medial tibial plateau was seen
(Fig 6) .
Other degenerative changes similar in
degree, distribution and frequency to those
described earlier in the control series, were
also seen in the group given triamcinolone
acetonide intra-articularly (Table 1) .
Studies of Metachromasia
In all series, loss of l~letilcllrot~l~~sia
was
erratic and inconsistent; no difference was
noted between control and steroid treated
animals.
DISCUSSION
T h e present studies demonstrate a significant, deleterious effect on in vivo r a l h i t
articular knee cartilage after intra-articular
injections of triamcinolone acetonide. Degenerative changes were characterized by
a n increased frequency of nuclear degeneration in the tangential a n d transitional
layers of cartilage and by prominent cyst
formation. These findings are in accord
with the observations of Salter et al (6),
who noted cyst formation related to intraarticular injections of 17-hydrocorticosterone-2 I-tertiary butylacetate. Gross deposits oE a crystalline-like material were
noted o n the articular surface of the medial
tibial plateau in all animals receiving 6
intra-articular injections of corticosteroid.
After decalcification of specimens, the gross
deposits disappeared. Studies by Salter et 01
(6) suggest that these deposits are calcific
in nature.
T h e changes observed after the intraarticular administration of corticosteroids
Knees Receiving Parenteral
may be the result of a number of factors.
Triamcinolone Acetonide Intramuscularly
Degenerative lesions may represent an acGross, N o variations from thz normal centuation of those degenerative changes
seen, to a lesser degree, in control animals.
were noted.
I .eukocytosis, related to corticosteroid crysHistologic.
Degeneration of chondro- tal injection (10) with possible release of
cyte nuclei in the tangential and transition- chemical mediators, must also be considal layers occurred in all animals receiving 4 ered i n the etiology of the findings. Since
injections. Other degenerative changes oc- similar transient increases in intra-articular
curred with the same general frequency as pressure were present i n all intra-articular
in the control group. Cyst formation, how- test and control animals in our study, these
ever, was absent. Marked muscle atrophy increases would not appear to account for
and weight loss were noted in all animals the characteristic, pathologic lesions seen
studied, thus demonstrating a potent, over- only in the cor t icosteroid inject ion series.
a11 corticosteroicl effect on the animal.
T h e studies of hlankin arid Conger (8)
Arthritis and Rheumatism, Vol. 13,
No. 3 (May-lune 1970)
241
and of Silberberg et al (7), noted earlier,
suggest either a direct, steroid induced
catabolic or anti-anabolic effect on cartilage.
The absence of severe degenerative changes
of ;L similar nature with parenterally administered steroids may reflect either diminished dose or duration of effect within the
joint.
Fig 5 (top). Medial tibial plateau, knee receiving 5 weekly intra-articular injections of triamcinolone
acetonide: Numerous cysts of varying size contain dying or dead chondrocytes and fibrillar detritus. Larger
cysts parallel mws of chondrocytes and frequently appear to be the result of coalescence of small cysts.
Surrounding matrix at times appears fibrillar and degenerative (H&E X 80). Fig 6 (bottom). Lateral tibial
plateau, same knee. Absence of cysts is striking.
242
Arthritis and Rheumatism, Vol. 13, No. 3 ?(&June
1970)
CORTlWSTEROlD ARTHROPATHY
T h e tendency of pathologic changes to
localize in the medial tibial plateau in both
control and steroid treated animals was
striking. T h e localization of degenerative
changes paralleled the difference in histologic pattern frequently observed in this
region, when compared to the lateral tibial
plateau and femoral condyles. T h e increased cellularity observed in the cartilage
oE the medial tibial plateau may represent
a response to increased pressure over this
area, since proliferation of chondrocytes
has been shown by others to occur in the
presence of such increased pressure (1 1) .
hloreover, proliferating chondrocytes, with
an increased rate of metabolism, might be
more susceptible to mechanical and chemical injury. The observation that pathologic
changes may be related to pre-existing histologic differences in cartilage may provide
a clue to the localization of degenerative
joint disease in human joints.
T h e pathologic effects of corticosteroids
given intra-articularly to rabbits cannot be
related directly to humans because of the
many variables involved. The demonstrated clinical benefit of intra-articularly injected corticosteroids in rheumatic disease,
based on their ability to decrease inflammation, may outweigh their possible pathologic effects when used with proper caution.
On the other hand, experimental findings
described here support the clinical and
experimental observation of others that
degenerative effects may be associated with
the use of these corticosteroids.
ACKNOWLEDGMENTS
T h e valuable technical assistance of Miss
Arthritis and Rheumatism, Vol. 13, No. 3 (May-June 1970)
Kathryn Toulmin and Mr. David M. Becker is
gratefully acknowledged.
REFERENCES
1 . ALARCON-SEGOVIA
D, WARDLE: Marked
destructive changes occurring in osteoarthritic
finger joints after intra-articular injection of
corticosteroids. Arthritis Rheum 9:443, 1966
2. CHANDLER
GN, JONES DT, WRIGHTV,
et al: Charcot’s arthropathy following intraarticular hydrocortisone. Brit bled J I :952, 1959
3. MILLER
WT, RESTIFO
RA: Steroid arthropathy. Radiology 86:653, 1966
4. STEINBERC
CL, DUTHIE RB, PIVA AE:
Charcot-like arthropathy following intra-articular hydrocortisone. J A M A 281:851, 1962
5. JOHNSON
RL, SMYTHCJ, HOLTGW, et al:
Steroid therapy and vascular lesions in rheumatoid arthritis. Arthritis Rheum 2:224, 1959
6. SALTERRB, GROSSA, HALLJH: Hydrocortisone arthropathy-An experimental investigation. Canad Med Ass J 97.374, 1967
7. SILBERBERC
M, SILBERBERC
R, HASLER
M:
Fine structure of articular cartilage in mice receiving cortisone acetate. Arch Path 82:569.
1966
8. MANKINHF, CONGER
KA: The acute effects of intra-articular hydro-cortisone on articular cartilage in rabbits. J Bone Joint Surg 48-A:
1383, 1966
9. COSCRIFF
SW, DIEFENBACII
AF, VOGTW
JR: Hypercoagulability of blood associated with
ACTH and cortisone therapy. Amer J Med 9:
752, 1950
10. MCCARTY
DJ JR, HOGANJM: Inflammatory reaction after intrasynovial injection of
microcrystalline adreno-corticosteroid esters. Arthritis Rheum 7.559, 1964
1 1 . COPLINES, SOUTHWICK
WO: Mitosis of
chondrocytes induced in the knee joint articular
cartilage of adult rabbits. Yale J Biol M e d 33:
243, 1960
243
Документ
Категория
Без категории
Просмотров
1
Размер файла
1 891 Кб
Теги
arthropathy, induced, experimentale, corticosterone
1/--страниц
Пожаловаться на содержимое документа