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Erosive arthritis associated with apatite crystal deposition.

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31
EROSIVE ARTHRITIS ASSOCIATED WITH
APATITE CRYSTAL DEPOSITION
H. RALPH SCHUMACHER, JEFFREY L. MILLER, CHARLES LUDIVICO, and RALPH A. JESSAR
Apatite crystals can be associated with erosive
arthritis. This report describes 3 such patients, 2 of
whom had idiopathic apatite crystal deposition and 1
who had apatite related to renal failure and chronic dialysis. Diagnosis was delayed for several years in 1 patient. Roentgenograms showed calcifications in all patients. Synovial fluid had non-birefringent chunks and
globules suggestive of apatite. Diagnosis was established by electron microscopy in all 3 patients and verified by x-ray diffraction in 2.
Hydroxyapatite crystals have been widely recognized in association with bursitis (l), periarthritis (2),
and inflammatory reactions in subcutaneous sites (3),
but only recently in actual arthritis (4-6). In most reports, periarthritis or arthritis has been intermittent and
apparently nonerosive. In our study of 1977 (4)only 1
patient of the 5 with idiopathic apatite deposition had
any chronic arthritis and roentgenographic evidence of
joint damage. This report describes further details on
this patient and 2 others with documented apatite crystals in joint fluid and erosive arthritis in one or more
joints with no other identified cause for arthritis.
MATERIALS AND METHODS
The patients described here were identified from a
group of 21 in whom we have now confirmed the presence of
From the Philadelphia VA Medical Center and the Hospital
of the University of Pennsylvania, Philadelphia, PA.
H. Ralph Schumacher, MD; Jeffrey L. Miller, MD; Charles
Ludivico, MD; Ralph A. Jessar, MD.
Address reprint requests to H. Ralph Schumacher, MD, Professor of Medicine, Director, Arthritis-Immunology Center, VA Medical Center, Philadelphia, PA 19104.
Submitted for publication April 4, 1980; accepted in revised
form September 8, 1980.
Arthritis and Rheumatism, Vol. 24, No. 1 (January 1981)
synovial fluid apatite crystals. Effusions were examined as wet
preparations with a Zeiss compensated polarizing light microscope. When sufficient fluid was available, leukocyte counts
were done by using 0.3% saline as a diluent with a standard
hemocytometer. Wright’s stained smears were made of each
fluid and Von Kossa stain for phosphate was done on two
smears. The remaining fluid was centrifuged, supernatant decanted, and the pellet fixed promptly in one half strength Karnovsky’s glutaraldehyde-paraformaldehydefixative. After 15
minutes fixation, the pellet was minced in 1 X 1 mm pieces
and fixed for an additional 4 hours at room temperature.
Pieces were then washed four times during 1 hour in 0.1M cacodylate buffer at pH 7.4, dehydrated with alcohol, placed in
a 50% propylene oxide and Epon 812 mixture for 2 hours, and
then embedded in Epon 812. Thin sections were cut with a
diamond knife and examined in a Zeiss EM 10 transmission
electron microscope with a 60 kV beam. Specimens were examined both unstained and after staining with uranyl acetate
and lead citrate.
Other thin sections were examined unstained with the
EM 10 by using a 30 mmz Kevex Si (Li) dispersive x-ray detector interfaced with a multichannel analyzer and a computer system. Any crystals found were analyzed by using a
spot size of 0.5-3 pm diameter and 120 to 200-second analysis
times.
The globular material aspirated from the joints of patients 2 and 3 was air dried and examined by x-ray diffraction.
A Debye-Scherrer powder camera of 114.6 mm diameter using Chromium K alpha radiation with a vanadium filter was
used. Measurements were based on wave length 2.29092 A.
The specimen was exposed for 20 hours at 50 kV and 20
mamp.
CASE REPORTS
Patient 1. McJ was a 53-year-old black man, a
manual laborer, who presented to the emergency room
of Philadelphia VA Medical Center on August 19, 1977
with a 5-month history of episodes of pain and swelling
on the right second proximal interphalangeal (PIP)
joint. Mild swelling remained between painful episodes
32
Figure 1. Roentgenogram of patient 1 showing penarticular calcification, periosteal reaction, and bony erosion at right second PIP joint.
that subsided spontaneously or with low doses of aspirin. Four days before being seen he developed dramatically increased pain at the second PIP with swelling that
extended to the dorsum of the hand. He gave a history
of intermittent severe shoulder pain with no bouts in the
last 2 years, but denied any other diseases or specific
trauma to the finger. He was gifen colchicine 6 mg
orally over 12 hours with complete resolution of the
pain over 2 days.
On August 23, he returned and was noted to
have only slightly warm fluctuant swelling of the right
second PIP with minimal tenderness, slight limitation of
elbow extension, and otherwise normal findings of a
physical examination. There was no enlargement of
other finger joints, sclerodactyly, or muscle weakness.
Roentgenograms of the shoulders were normal, but the
hands revealed an arc of amorphous calcification on the
ulnar side of the right second PIP with marginal erosion
and periosteal reaction (Figure 1.) Hematocrit was 38%;
leukocyte count (WBC) was 6, 100/mm3with 5 1% polymorphonuclear leukocytes, 44% lymphocytes, 3% eosinophils, and 2% monocytes. Serum creatinine was 1.2
mg% and uric acid 7.7 mg%. Latex fixation for rheumatoid factor was negative. The fluctuant PIP joint was aspirated and yielded 1 cc of opaque gray-white, bloodtinged fluid. Examination of a wet smear revealed no birefringent crystals under compensated polarized light,
but large masses of shiny-appearing 2-lop chunks and
SCHUMACHER ET AL
globules as described with hydroxyapatite (4) were present. These stained brown with the Von Kossa stain. Differential cell count on a Wright’s stained smear of synovial fluid showed 50% large mononuclear cells, 25%
monocytes, 5% lymphocytes, 18% polymorphonuclears,
and 2% eosinophils. A Sudan stain was positive in the
large mononuclear cells, suggesting that they were
monocyte-derived phagocytic cells (7). Some shiny globules seen in these cells stained purple with Wright’s
stain. A leukocyte count was not possible. Electron microscopy confirmed the presence of tiny apatite-like
crystals of 100-250 A diameter. Synovial fluid culture
was negative.
The patient was given colchicine 0.5 mg orally
twice daily but discontinued this because he felt no further pain. He was seen once on October 21, 1977 when
bony enlargement and slight limitation of flexion was
noted at the right second PIP, but there was no soft tissue swelling. He was then lost to followup.
Patient 2. MR, a 50-year-old white woman, was
admitted to the Hospital of the University of Pennsylvania (HUP) in June 1976 with a 1-week history of arthritis of the second left proximal interphalangeal joint.
Since the age of 25 the patient had intermittent
pain, swelling, and warmth of elbows, wrists, and small
joints of her hands. The episodes characteristically involved one joint, although multiple joint attacks had
been noted, and subsided after 3 to 4 days. In 1951 and
1953 she received x-ray radiotherapy to elbows and
hands “for arthritis and calcium deposits,” which were
said to disappear after therapy.
In August 1959 she was admitted to HUP for
evaluation of recurrent pain and swelling of her upper
extremity joints. Her medication included high dose aspirin and dexamethasone 1.5 mg/day. She was hirsute
with moon facies. Her joint examination was negative
for inflammation or deformity. The hemoglobin was
12.6 gm%, WBC 9,900 per mm3, and erythrocyte sedimentation rate (ESR) (Wintrobe) 9 mm/hour. She had
a negative LE prep, rheumatoid latex fixation, serum
protein electrophoresis, and serologic test for syphilis.
Thyroid I3’I uptake was normal. Serum calcium, phosphorus, BUN, sugar, and 24-hour urinary calcium and
phosphate were normal. Roentgenograms of hands and
elbows revealed periarticular calcifications near metacarpophalangeal joints, wrists, and the right elbow. The
patient was said to have palindromic rheumatism and
gold sodium thiomalate therapy was initiated.
In August 1960 she was readmitted because of
recurrent joint pains despite the treatment with gold.
Gold was continued 25 mg weekly, and hydroxy-
EROSIVE ARTHRITIS
Figure 2. Wet preparation of synovial fluid from patient 2 showing
angular and globular dark or light appearing material with some
clumps. This is the typical light microscopic appearance of clumps of
apatite (4). Two erythrocytes are clearly circular. (Magnification X
33
for arthritis. She denied Raynaud’s phenomenon, serositis, alopecia, oral ulcerations, recent rashes, swallowing difficulty, or shortness of breath. Blood pressure was
155/88, pulse 76 per minute, temperature 99°F. Positive
physical findings included markedly erythematous, fluctuant, tender swelling of her second PIP with very limited range of motion. The right thumb IP was fused. A
small right knee effusion was present, but the joint was
nontender and had full range of motion.
Laboratory studies revealed hemoglobin 13.3
gm%, WBC 12,600/mm3 with 65% neutrophils, 11%
monocytes, and 24% lymphocytes. Westergren sedimentation rate was 2 mm/hour, antinuclear antibody was
negative, calcium 9.4 mg%. BUN 19 mg%, potassium
2.8 mEq/100 ml. Aspiration of the left second PIP joint
fluid revealed 1.0 cc of very viscous creamy white fluid.
loo.)
chloroquine 200 mg twice a day was started. In August
1963 she required readmission for excruciating right
wrist pain and swelling. Roentgenograms of the right
hand revealed soft tissue swelling with multiple areas of
soft tissue calcification. Swallowing function on cinefluorogram was normal. The patient gradually responded to a course of ACTH therapy and was discharged. Gold and hydroxychloroquine were
discontinued.
Without treatment except for ACTH at the time
of bouts, she had episodic arthritis with symptom-free
intervals up to 3 years. Acute episodes lasting several
days to weeks involved wrists, several metacarpophalangeal (MCP) and PIP joints, shoulders, and elbows. In
October 1969 she had a flare of the left third PIP joint
which was treated with an intraarticular injection and
intramuscular ACTH at home. She suffered intermittently from acute arthritic flares of the right thumb
interphalangeal (IP) joint and left second PIP, which
were treated with intraarticular steroids. In July 1975 a
right thumb IP fusion was performed for painful subluxation of the joint. Histologic examination of the joint
revealed thickened synovium with fibrosis, fragments of
dead bone, and amorphous debris staining positive with
the Von Kossa stain for calcium phosphate. She was
then free of joint symptoms until about 1 week prior to
admission when she noted acute onset of painful swelling of the second left PIP. Several days after an intraarticular steroid injection the joint flared again. Aspiration of the second left PIP revealed thick creamy white
fluid, and the patient was admitted with concern about
a possible septic arthritis. Family history was negative
Figure 3. Calcification and marked joint destruction of left second PIP
of patient 2, 1976. There is also a small periarticular calcification at
the DIP.
34
Figure 4. Small calcifications and bony erosions at MCP joints of patient 2, 1969.
A large amount of angular, globular or amorphous nonbirefringent material was present (Figure 2) which interfered with the determination of the joint fluid WBC.
Von Kossa stain was positive. Intermixed with the
above material were strongly negative and positive birefringent rodlike, chunky, and ovoid shaped crystals, not
resembling urate or calcium pyrophosphate (CPPD)
crystals. Electron microscopy identified apatite-like
needle and rod shaped crystals which were confirmed to
be apatite on x-ray diffraction (4). Calcium to phosphorus molar ratio by electron probe elemental analysis
was 1.64:l. Gram stain was negative for bacteria and
joint fluid cultures were negative. Right knee synovianalysis revealed 2 cc of straw-colored synovial fluid
with a good mucin clot and no cells or crystals. Hand
roentgenograms revealed marked periarticular calcification about the second PIP with destruction of the joint
space and adjacent bone (Figure 3). The second distal
interphalangeal (DIP) joint also had faint periarticular
calcification and irregular joint space narrowing. Calcifications were also found at other fingers, the hip greater
trochanters, and subacromial bursae. Review of 19651969 roentgenograms documented erosions at several
MCP joints with associated calcifications (Figure 4).
These still persisted and had worsened in the 1976
roentgenograms.
The patient was started on oral colchicine 0.6 mg
every hour until she developed gastrointestinal intolerance at the eleventh tablet; the colchicine dose then was
changed to 0.6 mg twice a day. During the initial 3-day
treatment with colchicine, the patient had a slow but
steady improvement in the left second PIP swelling. A
SCHUMACHER ET AL
second joint aspiration on the fourth hospital day still
revealed thick fluid that was brownish and culture-negative. The right knee effusion did not reappear and she
was discharged greatly improved. She was started on indomethacin 25 mg 4 times a day with continued resolution of the inflamed PIP. Further attacks have occurred
in a pattern similar to that established, but frequently
with possibly more rapid resolution after colchicine or
indomethacin therapy.
Patient 3. BB was a 54-year-old white man who
presented in July 1978 with 1% years of persistent
chronic pain and swelling in knees, elbows, shoulders,
and MCP joints. Ibuprofen and aspirin 3.2 gm/day
were of no help. He had been on chronic hemodialysis
for 2 years for renal failure secondary to polycystic kidney disease. Parathyroidectomy with single-gland forearm implantation had been done in February 1978 for
Figure 5. Calcifications at the left first, fourth, and fifth MCP joints,
ulnar side of the carpal-metacarpal area, and at several PIP joints in
patient 3. There is erosion most evident at the ulnar side of the distal
end of the fourth and fifth metacarpal bones.
EROSIVE ARTHRITIS
Figure 6. Apatite crystals from patient 3 with straight or slightly curved, dense needle shaped crystals of lW250A diameter. Crystals are
surrounded by finely granular material. (Electron micrograph magnification X 26,000.)
35
SCHUMACHER ET AL
36
secondary hyperparathyroidism; histologic examination
of the gland showed only hyperplasia. Carcinoma of the
prostate had been treated with local radiation I year
previously. Plasma studies in August 1978 revealed total
calcium 9.6 mg/100 ml, ionized calcium 3.6 mg/100 ml
(normal 3.74.50); phosphorus 5.9 mg/100 ml; parathyroid hormone level was 301 units per ml (normal
163-347).
On physical examination we identified multiple
deposits of a firm nodular substance around the first
and third right and first, fourth, and fifth left MCP
joints, within and adjacent to the elbows, adjacent to
the shoulders, and on the posterior chest wall. The
metacarpophalangeal joints and the knees were tender.
Roentgenograms revealed radiopaque material
in the MCP joints and in the other palpable deposits,
There were erosions in the MCP joints, especially on the
ulnar side (Figure 5) and at the lateral side of the femoral condyle of the right knee. Material aspirated from
the third right MCP joint, right elbow, and right shoulder confirmed the hydroxyapatite crystal deposition
with shiny globules (4) seen by light microscopy and
typical needles by electron microscopy (Figure 6) (4).
Electron probe analysis of material from MCP and
shoulder showed calcium :phosphorus molar ratios of
1.48: 1-1.69 : 1 which is very similar to identically handled known apatite (4). No birefringent crystals were
found. Therapy with indomethacin 25 mg 3 times a day
and naproxen 250 mg twice daily for 1 week was not
helpful. Injections of triamcinolone tebuate and I% procaine were given into the MCP joint, right shoulder, and
left knee without changing the deposits and slightly decreasing the discomfort for only 1 week. Further examinations have revealed increasing large deposits in the
first right and left metacarpophalangeal joints, and in
the right third and fourth MCP joints. Severe claudication recently developed in both legs.
DISCUSSION
The recent demonstration of hydroxyapatite
crystals with the synovial fluid (43) as well as in periarticular tissues (2) raised the possibility that they might
be associated with a wide spectrum of intraarticular diseases similar to gout or pseudogout. We first recognized
apatite crystals in acute arthritis mimicking acute gout
or pseudogout (4). The 3 patients reported here illustrate that apatite can also be associated with erosive and
destructive joint changes, as can chronic urate and
CPPD diseases (8). Mechanisms involved may well be
similar, because clumps of apatite are found phago-
cytized by leukocytes in some effusions (4) and can be
shown to be phagocytized in vitro (9) and to induce inflammation when injected into dog knees, much as do
urate and CPPD crystals (4).
The patients in this study were evaluated for
other causes of erosive arthritis and none were found.
Secondary hyperparathyroidism in patient 3 was considered a possible cause for joint erosions, but an elevated parathormone level was not found and there were
no typical subperiosteal erosions.
The possibility that calcifications adjacent to the
erosions were only secondary to bony erosion was considered very unlikely since 2 of the 3 patients also had
documented episodes of symptomatic periarticular calcifications in sites away from bone.
Patients 1 and 2 had no disease known to be associated with apatite crystal deposition. Patient 3 on
renal dialysis is another example of the recognized association of renal failure and dialysis with apatite deposition in periarticular (10) and intraarticular sites (4). We
have also previously reported a destructive arthritis associated with apatite crystals in patients with mixed collagen-vascular disease (11) and have seen other examples in scleroderma. In such patients, the etiology of
the erosion is not as clearly associated with crystal induced inflammation, but must be suspected since the socalled collagen diseases otherwise usually have few joint
erosions ( 12,13).
Intraarticular joint injections are a recognized
cause of periarticular calcifications (14,15) and may
contribute to more rapid joint destruction. Antecedent
injections given in patient 2 may have contributed to
her severe second PIP changes, but injections had not
been given at other sites with generally more subtle erosions and calcifications. The previous steroid injections
could have contributed some of the unidentified birefringent crystals in this patient; however, it should be
noted that apatite laden effusions may also occasionally
include some clumps with birefringence (4). No urate or
CPPD crystals were found in any of our 3 patients by
light or electron microscopy.
Diagnosis of apatite-associated arthritis and periarthritis can be suspected on roentgenograms or by examination of aspirated fluid for angular or irregular
nonbirefringent chunks, including some which are larger
than cells. Such clumps of apatite crystals stain with hematoxylin, and for calcium and phosphate with Von
Kossa stain (4). Identity of clumps as apatite can be
supported by electron microscopy (4) and electron
probe analysis, as described in the case reports. Apatite
is most definitively confirmed if sufficient numbers of
EROSIVE ARTHRITIS
37
crystals are present to be studied by x-ray diffraction 15.
This confirmation was performed in cases 2 and 3.
Treatment of acute episodes with colchicine or
indomethacin along with aspiration has seemed helpful
in 2 of our patients and in others reported (4,16), although many attacks also subside spontaneously. No effective long-term drug therapy is known, although continued administration of indomethacin may possibly be
helpful.
REFERENCES
1. Pinals RS, Short CL: Calcific periarthritis involving multiple sites. Arthritis Rheum 7:359-367,1964
2. McCarty DJ, Gatter RA: Recurrent acute inflammation
associated with focal apatite crystal deposition. Arthritis
Rheum 9:804-819, 1966
3. Schumacher HR, Schimmer B, Gordon GV, Bookspan
MA, Brogadir S, Dorwart BB: Articular manifestations of
polymyositis and dermatomyositis. Am J Med 67:287292, 1979
4. Schumacher HR, Somlyo AP, Tse RL, Maurer K: Arthritis associated with apatite crystals. Ann Intern Med
87:411416, 1977
5. Dieppe PA, Crocker P, Huskisson EC, Willoughby DA:
Apatite deposition disease-a new arthropathy. Lancet
1:266-269, 1976
6. Fam AG, Pritzker KPH, Stein JL, Houpt JB, Little AH:
Apatite associated arthropathy: a clinical study of 14 cases
and of 2 patients with calcific bursitis. J Rheumatol
6:461471. 1979
7. Traycoff RB, Pascual E, Schumacher HR: Mononuclear
cells in human synovial fluid: identification of lymphoblasts in rheumatoid arthritis. Arthritis Rheum 19:743748, 1976
8. Schumacher HR: Pathogenesis of crystal induced synovitis. Clin Rheum Dis 3:105-131, 1977
9. Maurer KH, Schumacher HR: Hydroxyapatite phagocytosis by human polymorphonuclear leukocytes. Ann
Rheum Dis 38:84-88, 1979
10. Moskowitz RW, Vertes V, Schwartz A, Marshall G: Crystal induced inflammation associated with chronic renal
failure treated with periodic hemodialysis. Am J Med
47:450-460, 1969
11. Reginato A, Schumacher HR: Synovial calcification in a
patient with collagen vascular disease: light and electron
microscopic studies. J Rheumatol4261-27 I, 1977
12. Labowitz R, Schumacher HR: The articular manifestations of systemic lupus erythematosus. Ann Intern Med
74:911-921, 1971
13. Schumacher HR: Joint involvement in progressive systemic sclerosis (scleroderma): a light and electron microscopic study of synovial membrane. Am J CLn Pathol
60593-600, 1973
14. Hardin JG, Greller JM, Andriopoulos N: Controlled
study of the long-term effects of “total hand” injection-a
preliminary report (abstract). Arthritis Rheum 19:800801, 1976
15. McCarty DJ: Treatment of rheumatoid joint inflammation with triamcinolone hexacetonide. Arthritis Rheum
15:157-173, 1972
Thompson
GR, Ting YM, Riggs GA, Fenn ME, Denning
16.
RM: Calcific tendinitis and soft tissue calcification resembling gout. JAMA 203:464-472, 1968
Practical Neurology, and Metabolism and Endocrinology
The University of Washington will hold a seminar in Practical Neurology and one in Metabolism
and Endocrinology February 21-28, 1981 in Hawaii. For further information contact Continuing
Medical Education, University of Washington, Seattle, WA 98195, or call (206) 543-1050.
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