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Primary systemic amyloidosis presenting as giant cell arteritis and polymyalgia rheumatica.

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ARTHRITIS & RHEUMATISM Volume 37
Number 11, November 1994, pp 1621-1626
0 1994, American College of Rheumatology
1621
PRIMARY SYSTEMIC AMYLOIDOSIS PRESENTING AS
GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA
CARL0 SALVARANI, SHERINE E. GABRIEL, MORIE A. GERTZ, JOHANNES BJORNSSON,
CHIN-YANG LI, and GENE G. HUNDER
Primary systemic amyloidosis may present with
features suggesting a vasculitis, including giant cell
arteritis (GCA) and polymyalgia rheumatica (PMR). In
this report, we describe the clinical characteristics,
temporal artery biopsy findings, and the response of
vascular and musculoskeletal symptoms to corticosteroid therapy in 4 patients with primary systemic
amyloidosis who presented with manifestations of GCA
or PMR.
The presentation of most patients with primary
systemic amyloidosis is usually related to congestive
heart failure, nephrotic syndrome, carpal tunnel syndrome, peripheral neuropathy , or orthostatic hypotension (1,2). However, primary systemic amyloidosis
may present with features suggesting vasculitis. Jaw
claudication has been found in 9% of a group of
patients seen over an 11-year period (3), and case
reports have suggested that clinical features of polymyalgia rheumatica (PMR) andor giant cell arteritis
(GCA) may be the presenting manifestation of primary
systemic amyloidosis (3-9).
PATIENTS AND METHODS
We reviewed the medical records of all patients with
biopsy-proven amyloidosis (including senile, systemic, and
localized amyloidosis) and manifestations suggestive of
Car10 Salvarani, MD: Mayo Clinic and Foundation, Rochester, Minnesota (currently at Unit3 Reumatologica, 2^ Divisione de Medicine, Arcispedale S. Maria Nuova, Reggio Ernilia,
Italy); Sherine E. Gabriel, MD, MSc: Mayo Clinic and Foundation;
Morie A. Gertz, MD: Mayo Clinic and Foundation; Johannes
Bjomsson, MD: Mayo Clinic and Foundation; Chin-Yang Li, MD:
Mayo Clinic and Foundation; Gene G. Hunder, MD: Mayo Clinic
and Foundation.
Address reprint requests to Sherine E. Gabriel, MD, MSc,
Department of Health Sciences Research, Mayo Clinic, 200 First
Street SW, Rochester, MN 55905.
Submitted for publication February 22, 1994; accepted in
revised form June 5, 1994.
PMR andor GCA who were seen at the Mayo Clinic
between 1969 and 1992. All available tissue specimens from
autopsy or biopsy, including temporal artery specimens,
were reviewed. Where applicable, tissues were stained for
amyloid with alkaline Congo red and examined under polarized light, and with thioflavine T and examined under
fluorescent light. The diagnosis of primary systemic amyloidosis required the demonstration of amyloid on biopsy or
autopsy tissue, based on the typical apple-green birefringence of alkaline Congo red-stained sections viewed under
polarized light. We also employed the streptavidin-biotinimmunoperoxidase labeling method using antisera against
purified amyloid fibril proteins AL ( K and A light chains), AA
(protein A), ATTR (prealbumin, or transthyretin), and AB
(&-microglobulin) (10). The diagnoses of GCA and PMR
were confirmed when the American College of Rheumatology criteria and Chuang et a1 criteria, respectively, were
fulfilled (11,12).
RESULTS
We identified 13 patients with histologic evidence of amyloidosis and concurrent or preexisting
criteria for the diagnosis of GCA or PMR (Table 1). Of
these 13 patients, 12 patients had undergone temporal
artery biopsy. Tissue samples from the 5 patients
whose type of amyloidosis was uncertain were submitted to immunohistochemical staining for subtyping of
the amyloid deposits. Immunohistochemical staining
with antiserum to ATTR was positive in patients 5 and
6 and was considered diagnostic of senile systemic
amyloidosis (13), while patients 7-13 had localized
forms of amyloid deposits. No patients had a positive
family history of amyloid or amyloidosis from a secondary cause.
Four patients (patients 1 4 , Table 1) had primary systemic amyloidosis. In each of these patients,
immunoelectrophoresis of serum and/or urine revealed
the presence of a monoclonal (M) protein. Immuno-
SALVARANI ET AL
1622
Table 1. Characteristics of 13 patients with biopsy-proven amyloidosis who had manifestations of polymyalgia rheumatica or giant cell
arteritis
Patient
Classification of
amyloidosis
1
2
3
4
Primary systemic
Primary systemic
Primary systemic
Primary systemic
5
Senile systemic
6
Senile systemic
I
8
9
10
11
12
13
Serudurine
immunoelectrophoresis
result
Amyloid identification
Immunohistochemical
result
light chain
IgMA
A light chain
A light chain
Not done
Not done
Not done
Not done
Prealbumin
Negative
Prealbumin
Localized
Senile cardiac
Localized
Bone marrow, abdominal fat
Rectum, carpal tunnel, temporal artery
Bronchus, pleura, lymph node
Rectum, carpal tunnel, temporal
artery; intramural coronary arteries
at autopsy of heart
Carpal tunnel at autopsy (extensive
vascular type)
Temporal artery at autopsy (extensive
vascular type)
Carpal tunnel
Heart at autopsy
Orbit
Negative
Not done
Negative
Senile cardiac
Localized
Localized
Senile cardiac
Heart at autopsy
Breast
Seminal vesicle
Endomyocardial biopsy
Not done
Negative
Not done
Negative
Not done
Not done
Insufficient plasma cell
differentiation
Not done
Not done
Not done
Prealbumin
histochemical staining with antiserum to A light chain
was positive in patient 1. All 4 patients fulfilled the
criteria for primary systemic amyloidosis. The clinical
characteristics, the temporal artery biopsy findings,
and the response of pMR/GCA symptoms to corticosteroids among these 4 patients are shown in Table 2.
A more detailed description of these 4 cases is presented below.
IgGA
K
CASE REPORTS
Patient 1. This patient, a 74-year-old woman,
was examined because Of m r k e d aching and morning
stiffness in her shoulders and neck of 1-month duration. The erythrocyte sedimentation rate was 56 m d
hour. A diagnosis of PMR was made and she was
treated with prednisone, 15 mg/day. After 10 days of
Table 2. Characteristics of 4 Datients with AL and PMR or GCA*
Duration of PMlUGCA
symptoms at
Patient
diagnosis of AL
PMRIGCA symptoms and
laboratory parameters
Temporal artery
biopsy result
1
5 months
Aching and morning stiffness in shoulders Not done
and neck; ESR 56 mmhour
2
3 months
Aching and morning stiffness in shoulders Amyloid deposits
and neck; claudication of jaw and legs;
ESR 40 mmhour
3
28 months
4
5 months
New headache; scalp tenderness;
anorexia with weight loss; ESR 128
mmhour
Anorexia with weight loss; claudication
of jaw, arms, and legs; ESR 82 m d
hour; bruits over arms; abnormal
aortogram
Normal
Response to corticosteroid treatment
when AL diagnosed
Resolution of articular symptoms;
recurrence of aching and stiffness
when prednisone reduced
Resolution of aching and stiffness;
recurrence of aching and stiffness
when prednisone reduced;
persistence of claudications; no
change in pulses
-
Granulomatous arteritis Resolution of systemic symptoms;
improvement of arm claudication;
and amyloid deposits
no improvement of jaw and leg
claudication and pulses
* AL = primary systemic amyloidosis; PMR = polymyalgia rheurnatica; GCA = giant cell arteritis; ESR = erythrocyte sedimentation rate
(Westergren).
AMYLOIDOSIS PRESENTING AS GCA
1623
Figure 1. Temporal artery biopsy specimens from patient 2. A, Hematoxylin and eosin-stained section, showing intimal thickening but no
inflammation. B, Congo red-stained section under polarized light, showing amyloid deposits. (Original magnification x 250.)
therapy, the articular symptoms resolved completely.
One month later, she developed orthostatic hypotension. A diagnosis of idiopathic orthostatic hypotension
was made, and she was given 9a-fluorohydrocortisone,
0.1 mg/day. Three months later, while still taking
prednisone, she was hospitalized for fatigue, 8-kg
weight loss, and purpura involving the neck and face.
On examination, the liver and spleen were not
enlarged and there was no lymphadenopathy. Serum
immunoelectrophoresis showed a monoclonal IgGh
protein. A monoclonal free A protein and IgG monoclonal heavy-chain fragment were demonstrated in the
urine. Bone marrow biopsy revealed 5-10% plasma
cells with amyloid deposition in blood vessel walls.
Biopsy specimens were positive on immunohistochemical staining with antiserum to h light chain.
Subcutaneous fat aspirate was positive for amyloid.
No radiographic evidence of multiple myeloma was
found, and a diagnosis of primary systemic amyloidosis was made.
The patient was treated with cyclic melphalan
and prednisone (9 cycles) and with colchicine 1.2
mg/day. It was not possible to reduce the prednisone
dosage below 15 mg/day because of relapse of aching
and morning stiffness in the neck and shoulders.
Eleven months later, she developed congestive heart
failure. She died of refractory heart failure 15 months
after the diagnosis of amyloidosis. No autopsy was done.
Patient 2. This 66-year-old man was seen because of aching and morning stiffness in the shoulders
and neck of l-month duration. The erythrocyte sedimentation rate was 40 mmhour. The following month,
he developed bilateral carpal tunnel syndrome and jaw
claudication. PMR with GCA was suspected, and
bilateral temporal artery biopsy was performed. Sections were negative for arteritis but demonstrated
amyloid deposits (Figure 1). A rectal biopsy and tissue
obtained at surgical release of the left transverse
carpal ligament approximately 1 month later confirmed
thepresenceofamyloid. Serumandurineimmunoelectrophoresis showed a monoclonal K protein. The provisional diagnoses of PMR, possible GCA, and primary
systemic amyloidosis were made, and the patient was
treated with prednisone, 40 mg/day. Within 3 weeks of
steroid therapy, the aching and stiffness had completely resolved, but the jaw claudication persisted.
Four months later, the patient developed congestive heart failure, which was considered to be
secondary to amyloidosis. Colchicine therapy, 1.8
mg/day, was begun. The erythrocyte sedimentation
rate decreased to 25 mm/hour. One month later, he
developed intermittent calf claudication. Both popliteal posterior tibia1 and dorsalis pedis pulses were
markedly reduced. The prednisone dosage had been
tapered to 15 mg/day and after an additional 2 months,
was stopped. Two weeks later, when the aching and
morning stiffness in the shoulders and neck recurred,
prednisone was reinstituted at 10 mg/day. The symptoms resolved. Eight months following the diagnosis of
1624
primary systemic amyloidosis, the patient died of
refractory heart failure. No autopsy was done.
Patient 3. This patient, a 73-year-old man, was
seen because of new headache (dull pain in temporal
areas), scalp tenderness, malaise, and anorexia with a
6-kg weight loss over the previous 2-3 months. His
erythrocyte sedimentation rate was 128 mmhour.
GCA was suspected, but bilateral temporal artery
biopsies were negative for arteritis. Staining for amyloid (Congo red, thioflavine T) was also negative.
Corticosteroid therapy was not started. The symptoms
improved over the following 6 months.
One year later, the patient developed symptoms
of congestive heart failure, which responded to treatment with diuretics. Results of 2-dimensional sector
echocardiography performed at that time were compatible with mild cardiac amyloid involvement. After
an additional year, he was hospitalized for evaluation
of a right hilar mass with lower lobe infiltrate that had
been identified on chest radiographs. Physical examination revealed generalized lymphadenopathy and
hepatomegaly . A transbronchial biopsy from a right
lower lobe bronchus and a right axillary lymph node
biopsy yielded tissue positive for amyloid. Bone marrow biopsy revealed a normal percentage of plasma
cells (1%) and no evidence of amyloid deposition.
Serum immunoelectrophoresis revealed monoclonal
IgMh protein. A monoclonal A protein was demonstrated in the urine. A diagnosis of primary systemic
amyloidosis was made. Two years later, he developed
Bell’s palsy on the right side, which was considered to
be secondary to amyloidosis. Colchicine, 1.2 mg daily,
was started.
Seven months later, a thoracotomy with pleurectomy was performed because of refractory bilateral
pneumohydrothorax. Specimens from the right pleura
showed multiple nodular aggregates of amyloid. Over
the next weeks, he developed renal failure without
nephrotic syndrome. Thirty-one months after the diagnosis of primary systemic amyloidosis, the patient
died of refractory heart failure. No autopsy was done.
Patient 4. This 73-year-old man was admitted
for evaluation of bilateral carpal tunnel syndrome,
intermittent claudication of the arms, fatigue, anorexia, and a 7-kg weight loss over the previous 5
months. On examination, the right brachial pulse and
left radial pulse were absent. Bruits were audible over
the right and left brachial arteries. The erythrocyte
sedimentation rate was 82 mmhour. A monoclonal h
protein was found in the serum and the urine. Multiple
small lytic lesions typical of multiple myeloma were
SALVARANI ET AL
Figure 2. Temporal artery biopsy specimen from patient 4, showing
granulomatous giant cell arteritis. Thickened intima is at bottom,
media containing multinucleated giant cells in the center, and
adventitia with mononuclear cell infiltrationat the top. The lumen is
out of view below the figure (hematoxylin and eosin stained, original
magnification x 200).
detected on skeletal radiographs, and bone marrow
biopsy showed the presence of atypical plasma cells
(25%).
An aortogram showed changes consistent with
arteritis of aortic arch vessels. Bilateral temporal
artery biopsies demonstrated granulomatous arteritis
(Figure 2). In addition, amyloid deposits were seen in
the intima of the teqporal artery adjacent to the
inflammatory infiltrates qn hematoxylin and eosinstained sections. Congo red staining of the temporal
artery sections and of rectal biopsy sections confirmed
the presence of amyloid deposits. Histologic examination of specimens taken at carpal tunnel surgery
showed noninflammatory fibroligamentous tissue with
amyloid deposits.
The patient was diagnosed as having myelomaassociated amyloidosis and GCA with aortic arch
syndrome. He was treated with prednisone, 40 mgl
AMYLOIDOSIS PRESENTING AS GCA
day, and melphalan (in cycles). One month after
starting prednisone, the patient was able to work with
his arms over his head, whereas before prednisone
therapy, he had to intermittently rest his arms. The
erythrocyte sedimentation rate decreased to 44 mml
hour, but the leg claudication and pulses in the upper
extremities were unchanged.
Five months later, while taking 15 mg of prednisone per day, jaw claudication developed. One
month later, he died of heart failure. Postmortem
examination (heart only) revealed mild myocardial
interstitial amyloid deposits and moderate occlusive
coronary artery amyloid deposits.
DISCUSSION
In the 4 patients described above, manifestations of PMR and/or GCA appeared 4-28 months
before the diagnosis of primary systemic amyloidosis
was made. Our data confirm previous case reports that
primary systemic amyloidosis may present with a
clinical picture of either PMR or GCA or both (3,5,79). Moreover, we report, for the first time, a case of
primary systemic amyloidosis with coexistent GCA.
The proximal aching and morning stiffness in
patients 1 and 2 were typical of that seen in uncomplicated PMR, as was the response to corticosteroids.
Furthermore, when corticosteroids were reduced or
discontinued, the symptoms recurred. The symptoms
of uncomplicated PMR have been considered to be
due to proximal synovitis; however, the pathogenesis
of the symptoms in the cases reported herein is uncertain. Synovitis was not demonstrated. In patients 2, 3,
and 4, the diagnosis of GCA was considered because
of headache, scalp tenderness, and claudication as
well as the systemic symptoms. The claudication was
indistinguishable from that seen in GCA,except that
(unlike the musculoskeletal symptoms) it did not respond to corticosteroid therapy. The claudication in
patients 2 and 4 was likely related to amyloid deposits
in the arteries. Amyloid deposition in temporal artery
biopsy specimens was found in both patients.
Patient 4’s case is particularly unusual, in that
evidence of both amyloidosis and giant cell arteritis
was present on temporal artery biopsy. Moreover,
angiographic changes suggested large vessel vasculitis, and the claudication responded (partially) to corticosteroid therapy. His death was due to the amyloidosis.
A number of reported cases have indicated a
relationship between amyloidosis and PMR and GCA.
Ischemic vascular symptoms, such as jaw and limb
1625
claudication, which in some cases resembled GCA
symptoms, were believed to be related to amyloid
vasculopathy (3,7-9). In one series of patients with
primary systemic amyloidosis seen over an 1I-year
period, jaw claudication was noted in 9%; however,
the response to corticosteroid therapy was not described (3). There have been two case reports of
evidence of amyloid deposition in temporal artery
biopsy samples from patients with symptoms of GCA
(jaw claudication) that did not respond to corticosteroids (7,8). In those 2 patients, the amyloid deposits
were likely responsible for the GCA symptoms. Lafforgue et al described a patient with a clinical picture
of PMR and temporal artery biopsy evidence of massive light-chain amyloid deposits in the media (9). The
lack of response to corticosteroid therapy suggested to
those authors that the PMR symptoms may be the
result of vascular amyloidosis.
In two other cases, amyloidosis presented with
symptoms mimicking GCA and/or PMR (5,6). One
patient presented with pain in the shoulders and hips
associated with systemic symptoms and an elevated
erythrocyte sedimentation rate (145 mdhour) (6).
Temporal artery biopsy findings were negative, but
bone marrow biopsy revealed granulomatous giant cell
arteritis and amyloidosis. Corticosteroid therapy resulted in marked improvement of the articular symptoms and normalization of the erythrocyte sedimentation rate. Taillan et a1 described a patient with pain and
stiffness in the shoulders, headache, and systemic
symptoms (5). Temporal artery biopsy revealed amyloid deposition. After 6 days of corticosteroid therapy,
the articular symptoms resolved completely.
The possibility of secondary amyloidosis was
considered in a case reported by Dunea et a1 (4). Those
authors observed a patient in whom renal amyloidosis
developed 5 years after the onset of PMR. No cases of
secondary amyloidosis were identified in our series.
In conclusion, while coincidental association
cannot be excluded, our case series confirms previous
reports that primary systemic amyloidosis may
present with a clinical picture of PMR and/or GCA
(3-9). In particular, claudication seems to be connected with amyloid vasculopathy. We emphasize the
importance of appropriate staining of temporal artery
biopsy specimens for amyloidosis to ensure a correct
diagnosis, especially in patients with a monoclonal
band on immunoelectrophoresis or vascular ischemic
symptoms, or those who do not show a response to
corticosteroid therapy.
SALVARANI ET AL
1626
ACKNOWLEDGMENT
The authors wish to acknowledge Ms Lon Norby for
assistance in preparing the manuscript.
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