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Erosive arthritis in hereditary amyloidosis.

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1145
EROSIVE ARTHRITIS IN HEREDITARY
AMYLOIDOSIS
STEVEN EYANSON and MERRILL D. BENSON
Nine patients from 2 distinct kindreds with familial amyloidosis had episodes of inflammatory arthritis
and radiographic evidence of joint erosions. Histologic
features from erosive lesions in both kindreds showed
proliferation of synovium with erosive bone and cartilage change. No large amyloid deposits were seen. This
study indicates that an erosive synovitis of unknown
cause may be a feature of some forms of hereditary
amyloidosis.
tion of patients with longstanding psoriasis (10). It is
n o t a clinical feature of secondary (AA type) amyloidosis and has not been described in hereditary amyloidosis. We describe 9 patients from 2 distinct kindreds
with amyloidosis who were found to have erosive
synovitis as a prominent feature of their disease.
These findings suggest that synovitis may be a part of
the clinical spectrum of hereditary amyloidosis.
Several kindreds of hereditary amyloidosis
have previously been described (1-4). Most of these
patients have some type of peripheral neuropathy as
well as varying amounts of other organ system involvement. Erosive synovitis has not previously been
noted as a feature of hereditary amyloidosis.
Arthritis associated with systemic amyloidosis
has previously been well described in patients with
immunoglobulin light chain-derived amyloid (5-9) and
recently has been described as an unusual complica-
PATIENTS AND METHODS
From the Division of Rheumatology, Indiana University
School of Medicine and the Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana.
Supported by the Richard L. Roudebush Veterans Administration Medical Center (MRIS 583-0888). United States Public
Health Service, National Cancer Institute (1 R01 CA22141). National Institute of Arthritis, Metabolism and Digestive Diseases (AM
20582), The Arthritis Foundation, and The Grace M. Showalter
Foundation.
Steven Eyanson, MD: Assistant Professor of Medicine,
Indiana University School of Medicine; Merrill D. Benson, MD:
Professor of Medicine, Indiana University School of Medicine and
Chief of Rheumatology, Richard L. Roudebush Veterans Administration Medical Center.
Address reprint requests to Merrill D. Benson, MD. Chief,
Rheumatology Section, Richard L. Roudebush Veterans Administration Medical Center, 1481 West 10th Street, Indianapolis, IN
46202.
Submitted for publication November 8, 1982; accepted in
revised form March 30. 1983.
Arthritis and Rheumatism, Vol. 26, No. 9 (September 1983)
Seven of the 9 patients studied are members of the
“Indiana kindred” of hereditary amyloidosis (2) (Table 1).
Five were male. One female (BC) had 2 brothers (RK and
CK) in the study group, and the other 4 members were their
cousins. Two of these (AD and CD) were also brothers. The
ages of the patients ranged from 50 to 72 years. Five of the 7
had the onset of their amyloidosis manifested as carpal
tunnel syndrome requiring surgery. The other 2 patients had
had symptoms of carpal tunnel syndrome but had not had
surgery. All but 1 had abnormal electromyographic changes
compatible with carpal tunnel syndrome and peripheral
neuropathy .
Other evidence of amyloidosis in this kindred was
the finding of fibrillar vitreous opacities in each patient.
Three of the patients had had vitrectomies with some
improvement in vision. Three of the patients had significant
cardiac involvement with symptomatic bradycardia and
electrocardiographic findings consistent with amyloid heart
disease. The youngest patient (MS), age 50, had a history of
decreased renal function and proteinuria which was related
to a longstanding history of hypertension. A renal biopsy
suggested that the process was not related to amyloidosis.
The 2 other patients studied (BG and JG) were from a
kindred of Swedish origin first described in 1977 (4). They
were brothers aged 47 and 50 years. Their onset of illness
was marked by progressive numbness and tingling in the feet
with progression of symptoms proximally. This kindred of
patients had evidence of renal involvement a s well as
electrocardiographic changes. One brother died in 1979 as a
result of the progression of his renal and cardiac disease.
1146
EYANSON AND BENSON
Table 1. Patients with hereditarv arnvloidosis*
Erosive changes
Patient
History of
joint swelling
History of
joint pain
on hand or wrist
Arthritis changes on
99”’te,chnetiurnmethylene
radiographs
diphosphonate scan
72lM
70lM
SOIF
50lM
571M
S3lM
S81F
+
+
+
+
+
+
5OlM
47lM
Agelsex
Kindred 1
CD
AD
LK
MS
RK
CK
BC
Kindred I1
BG
JG
*
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
ND
-
+
-
-
+
-
+
-
+
+
+ = positive result or history. - = normal or negative result or history. N D = not done.
Clinical assessment was done according to a formalized protocol for the study of amyloidosis. Serologic studies
included Westergren erythrocyte sedimentation rate, antinuclear antibody (ANA) test, sheep cell agglutination method
for rheumatoid factor test, serum complement levels, serum
A protein levels, serum immunoelectrophoresis, and complete blood profiles. Renal disease was assessed by creatinine clearance and intravenous pyelography. Chest radiographs, electrocardiograms, and echocardiograms were
performed. Biopsy specimens of skin and rectum were
stained with Congo red.
Because of the histories suggestive of an inflamrnatory arthritis, additional studies in these patients included
joint scans with 99mtechnetiummethylene diphosphonate
(wmTc MDP) and radiographic evaluation of the hands,
wrists, and other potentially involved joints. One patient had
a small knee effusion which was analyzed.
Biopsy material from 1 patient in each kindred (RK
and JG) was obtained from an interphalangeal joint and
studied histologically by routine methods and with Congo
red staining.
RESULTS
Articular features. Eight patients were found to
have a history of joint pain or swelling in addition to a
history of neuropathy. Most of the patients had noticed pain, swelling, and redness which was most
marked in the metacarpophalangeal (MCP) joints and
wrists. Some had also experienced pain in the proximal interphalangeal (PIP) joints. Morning stiffness of
more than 1 hour’s duration and clumsiness were
prominent features. In addition, most of the patients
complained of pain in the knees, ankles, and shoulders. At least 6 of the patients had been told by their
doctors that they had arthritis and 2 (BC and LK) had
been diagnosed as having rheumatoid arthritis. Salicylates and other nonsteroidal antiinflammatory drugs
had incompletely resolved symptoms in some patients.
Serum antinuclear antibodies and sheep cell
agglutination tests for rheumatoid factor were negative
in all patients. All had normal serum complement
levels and none showed serum protein electrophoresis
patterns suggestive of myeloma. Seven patients tested
for serum A protein (SAA) had normal levels. Serum
uric acid levels were less than 7.5 mg%. There were no
significant abnormalities noted in serum calcium,
phosphate, or cholesterol levels. One patient (JG) had
a synovial fluid analysis of knee fluid which showed
less than 100 white cells/mm3, normal mucin clot test
results, and no crystals. There were no free amyloid
bodies in the sediment.
Radiographic evidence in all patients showed
joint erosions with cystic changes in the hands and
wrists. There was no periarticular calcification. Radioisotopic joint scans with 9 9 m T ~MDP in 8 patients
indicated inflammation in areas suspected by clinical
history, examination, or radiographs. This included
the hands and wrists in all patients.
Patient RK. RK, a 57-year-old man from the
Indiana kindred, was evaluated for familial amyloidosis. His problems began with carpal tunnel symptoms
in 1960. This gradually progressed with muscle wasting in the hands until 1969, when bilateral carpal tunnel
release provided only partial relief of symptoms. Since
that time he has had progressive loss of muscle mass
and decreased sensation to pinprick and deep pain in
the lower and upper extremities. Other evidence of
amyloidosis included vitreous opacities which had
been surgically treated. In addition, the patient noted
problems with shortness of breath and swelling in the
lower extremities in 1979, and was found to have a low
cardiac ouput with a pulse rate of 28 beatshinute. A
cardiac pacemaker was placed, resulting in marked
improvement in these symptoms.
Articular symptoms began about 10 years ago
when RK noted fullness and stiffness in the wrists and
the MCP joints of the hands. He also noted redness in
these areas. The symptoms persisted despite local heat
therapy and the occasional use of aspirin. In 1972 he
HEREDITARY AMYLOID ARTHRITIS
Figure 1. Radiograph showing typical erosive changes that were
present in the metacarpophalangeal and proximal interphalangeal
joints of patients in the Indiana kindred (patient RK).
developed intense lower back pain and subsequently
underwent a laminectomy and spinal fusion for an
intervertebral disk herniation. This relieved most of
his back symptoms. The patient continued, however,
to have intermittent swelling and fullness of the digits
with little pain. General physical examination results
were unremarkable except for slightly irregular pupils
which reacted to light. There were vitreous opacities
bilaterally. There was 1 + pedal edema. A functioning
cardiac pacemaker was in place. Neurologically the
patient had no sensation to pain below the knees or in
the hands. He walked with a slapping gait and could
not extend or flex the ankles. There was no 2-point
discrimination at the fingers, but the forearm showed
normal 2-point discrimination.
Articular examination revealed 20" flexion contractures of all the PIP joints of the hands. There was
decreased ability to oppose the thumb secondary to
intrinsic muscle weakness. There were traumatic amputations of portions of the second, third, and fourth
fingers of the left hand. The wrists showed decreased
flexion and extension and the shoulders showed 3 +
crepitation with full range of motion. Knee examination findings were unremarkable. Examination of the
feet showed the first metatarsophalangeal joint to be
somewhat erythematous and swollen.
Laboratory evaluation included a normal complete blood count, negative serum antinuclear antibody test, and a negative sheep cell agglutination test
for rheumatoid factor. Serum SAA level was within
normal limits. Electrocardiogram showed a normal
paced rhythm, while chest roentgenogram findings
were consistent with biventricular hypertrophy. Biopsies of the skin and rectum showed amyloid deposits
when stained with Congo red. Radiographic examination of the hands (Figure 1) showed cystic areas and
1147
erosions of the PIP and MCP joints. The feet showed
some lack of usual mineral content but no erosions or
periosteal reactions were seen. The remaining radiographic survey showed no evidence of multiple myeloma.
A joint scan in this patient (Figure 2) showed
increased uptake of the MCP joints of the hands
bilaterally as well as an increased uptake in the right
ankle and right knee consistent with inflammatory
arthritis. Electromyographic changes shown in nerve
conduction studies of both upper and lower extremities were consistent with a polyneuropathy. Histologic evaluation of an erosive lesion from an MCP joint
showed a mildly proliferative response in the synovium within an erosion. Congo red stains showed
some deposition of amyloid in the synovium and in
blood vessels and connective tissues (Figure 3).
Patient JG. JG, a 50-year-old man from the
Swedish kindred, was first evaluated in 1972. He had a
10-month history of progressive neuropathy of the
hands and feet. In addition to the neuropathy, the
patient had experienced diffuse muscle weakness and
a history of deep ulcerations over the lower extrem-
Figure 2. Radioisotope (99m technetium methylene diphosphonate)
joint scan of patient R K . Note the inflammatory uptake at the
metacarpophalangeal joints.
1148
EYANSON AND BENSON
Figure 3. Histopathologic section of tissue from erosive area of a
metacarpophalangeal joint of patient RK, stained with Congo red.
There is a mildly proliferative synovium within the erosion. Modest
amyloid deposits are present in blood vessels and connective tissue
(arrows).
ities. Biopsies of the sural nerve, skin, and rectum
showed amyloid deposition when stained with Congo
red. The patient then experienced progressive neuropathy which led to confinement in a wheelchair. Laboratory evaluation showed a negative sheep cell agglutination test for rheumatoid factor and negative ANA.
Serum immunoelectrophoresis findings were normal.
On physical examination the patient exhibited prominences of the MCP and interphalangeal joints with
flexion contractures of the PIP joints. A profound
neuropathy of all extremities was present.
Histologic examination of a distal intei-phalangeal joint, performed after traumatic amputation of a
finger, showed proliferative synovium within an erosion of bone (Figure 4). There was very little amyloid
by Congo red staining and this was present only in
association with blood vessels or nerves.
toms in the fourth or fifth decade of life with progressive peripheral neuropathy starting in the lower extremities, causing sensory and motor loss in a
stocking-glove distribution. Varying amounts of renal,
cardiac, and gastrointestinal symptoms have been
seen. Autonomic dysfunction appears to be common.
Likewise, meningeal and central nervous system depositions of amyloidosis have been described.
Amyloid arthritis has been described primarily
in patients with immunoglobulin light chain-derived
amyloid (5-9), but not in patients with many forms of
secondary (AA type) amyloidosis (10,ll) nor in hereditary amyloidosis. Most previous reports of arthritis
associated with amyloidosis have dealt mainly with
generalized primary amyloidosis or amyloidosis associated with multiple myeloma (5-9). These patients
have had frequent
in shoulders, wrists,
knees, and small joints ofthe hands. There is usually a
short period of morning stiffness and the joints are
often swollen and red. Severe tenderness and redness,
however, are not featured in this disease. The shoulders may appear to be padded and subcutaneous
nodules are said to be common.
Rheumatoid factor is infrequently positive. Radiographic changes include soft tissue swelling and
rare erosions about the joints. There may be generalized osteoporosis. Reports of synovial fluid analyses
indicate that leukocyte counts are usually less than
10,000 cells with a median count of about 1,000 cells
(5,12,13). Free amyloid bodies, presumably detached
villi, have been reported in the sediment of some of
these fluids (13). Synovial biopsy shows amyloid deposition in the lining cell layers (5,10,14). Carpal tunnel
syndrome is frequently reported to be associated with
this form of amyloid arthritis (5,15).
DISCUSSION
Seven patients in this study were from the
“Indiana” or “Rukavina” kindred (2). This kindred
was first described in the 1950s and the members are
characterized by the development of carpal tunnel
syndrome in the fourth or fifth decades of life. They
have variable organ involvement with vitreous opacities, decreased sphincter tone, impotency, cardiac
involvement, and peripheral neuropathy. Nephropathy has not been a feature of the disease.
The remaining patients were brothers from a
kindred of Swedish origin first described in 1977 (4)This kindred is characterized by the onset of symp-
Figure 4. Histopathologic section from a distal interphalangeal joint
of patient JG. There is proliferation of the synovium into bone and
cartilage. No large deposits of amyloid were seen.
1149
HEREDITARY AMYLOID ARTHRITIS
Clinical arthropathy due to secondary forms of
amyloidosis appears to be very uncommon (5,lO).
While gross depositions of amyloid protein in the
synovial membrane are described in patients with
multiple myeloma and associated amyloidosis. these
are not usually described in those with secondary
amyloidosis.
Our patients presented with histories compatible with inflammatory arthritis including redness and
swelling of the joints, morning stiffness, and warmth
over the joints. Radiographs in all patients showed
evidence of erosive synovitis with cystic changes. The
one synovial fluid sample that was analyzed was
noninflammatory and did not contain free amyloid
bodies.
In each case in which tissue biopsies were
studied, there was a proliferative synovial response
with erosive change in areas previously identified
radiologically as erosions. There was not a marked
deposition of amyloid in the lining cell layers. This is in
contrast to synovial biopsies reported in myelomaassociated amyloid arthritis, in which there are large
deposits of amyloid and very little erosive change
(5,14). Crystals were not seen, though the tissues were
fixed in formalin.
Amyloid-associated arthritis is relatively uncommon in all forms of amyloidosis. The etiology of
amyloid arthritis and pathogenesis of the articular
changes remain unclear. The major constituent of
primary and myeloma-associated amyloid is derived
from immunoglobulin light chains which are synthesized exclusively by plasma cells (16). The amyloid of
one kindred with arthritis, reported here, is composed
of prealbumin which is synthesized by the liver (17). It
is unlikely that either of these proteins would be
synthesized aberrantly in articular structures. It is
more conceivable that articular deposition of amyloid
results from local chemical modification of the circulating precursors. Since amyloid fibrils usually are not
associated with inflammatory or proliferative reactions in the organs where they are deposited, some
other factor, possibly characteristic of synovial tissues, may be involved in the generation of erosive
disease.
Another possibility that must be considered in
familial amyloidosis is that there may be closely linked
genes coding for the dominantly inherited amyloid and
the arthritis. It is, however, unlikely that two separate
kindreds would have the same genetic linkage. Further
studies of these kindreds is needed to evaluate this
possibility. Now that this association of hereditary
amyloidosis and arthritis has been recognized, closer
evaluations of other affected kindreds may also serve
to answer some of these questions.
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