PRIMARY SYSTEMIC AMYLOIDOSIS PRESENTING AS GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA

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1 ARTHRITIS & RHEUMATISM Volume 37 Number 11, November 1994, pp , 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 Submitted for publication February 22, 1994; accepted in revised form June 5, PMR andor GCA who were seen at the Mayo Clinic between 1969 and 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 ( 1 1,12). 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 14, 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-

2 1622 SALVARANI ET AL Table 1. arteritis Characteristics of 13 patients with biopsy-proven amyloidosis who had manifestations of polymyalgia rheumatica or giant cell Serudurine Classification of immunoelectrophoresis Immunohistochemical Patient amyloidosis Amyloid identification result result 1 Primary systemic Bone marrow, abdominal fat IgGA A light chain 2 Primary systemic Rectum, carpal tunnel, temporal artery K light chain Not done 3 Primary systemic Bronchus, pleura, lymph node IgMA Not done 4 Primary systemic Rectum, carpal tunnel, temporal A light chain Not done artery; intramural coronary arteries at autopsy of heart 5 Senile systemic Carpal tunnel at autopsy (extensive Not done Preal bumin vascular type) 6 Senile systemic Temporal artery at autopsy (extensive Negative Prealbumin vascular type) I Localized Carpal tunnel Negative Not done 8 Senile cardiac Heart at autopsy Not done Not done 9 Localized Orbit Negative Insufficient plasma cell differentiation 10 Senile cardiac Heart at autopsy Not done Not done 11 Localized Breast Negative Not done 12 Localized Seminal vesicle Not done Not done 13 Senile cardiac Endom yocardial biopsy Negative 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. CASE REPORTS Patient 1. This patient, a 74-year-old woman, was examined because Of mrked 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 PMRIGCA symptoms and Temporal artery Response to corticosteroid treatment Patient diagnosis of AL laboratory parameters biopsy result when AL diagnosed 1 5 months Aching and morning stiffness in shoulders Not done Resolution of articular symptoms; and neck; ESR 56 mmhour recurrence of aching and stiffness when prednisone reduced 2 3 months Aching and morning stiffness in shoulders Amyloid deposits Resolution of aching and stiffness; and neck; claudication of jaw and legs; recurrence of aching and stiffness ESR 40 mmhour when prednisone reduced; persistence of claudications; no 3 28 months New headache; scalp tenderness; Normal change in pulses - anorexia with weight loss; ESR 128 mmhour 4 5 months Anorexia with weight loss; claudication Granulomatous arteritis Resolution of systemic symptoms; of jaw, arms, and legs; ESR 82 md and amyloid deposits improvement of arm claudication; hour; bruits over arms; abnormal no improvement of jaw and leg aortogram claudication and pulses * AL = primary systemic amyloidosis; PMR = polymyalgia rheurnatica; GCA = giant cell arteritis; ESR = erythrocyte sedimentation rate (Westergren).

3 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

4 1624 SALVARANI ET AL 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 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 infiltration at 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

5 AMYLOIDOSIS PRESENTING AS GCA 1625 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 (3,5,7-9). 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 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 1 I-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.

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