Clin Rheumatol DOI 10.1007/s10067-014-2813-x
ORIGINAL ARTICLE
The fine line between Takayasu arteritis and giant cell arteritis Ari Polachek & Rachel Pauzner & David Levartovsky & Galia Rosen & Gideon Nesher & Gabriel Breuer & Marina Anouk & Uri Arad & Hagit Sarvagyl-Maman & Ilana Kaufman & Dan Caspi & Ori Elkayam
Received: 28 June 2014 / Revised: 21 October 2014 / Accepted: 23 October 2014 # International League of Associations for Rheumatology (ILAR) 2014
Abstract The objective of this study is to describe a series of patients above the age of 50 years with large vessel arteritis and vascular involvement typical of TAK. A retrospective review of 18 patients (median age 64 years) with emphasis on clinical characteristics, laboratory values, and vascular involvement by CT, MRI, or planar angiography. Five patients fulfilled the ACR criteria for GCA, five for TAK, three both GCA and TAK, while five patients did not fulfill the criteria for either disease. The dominant presenting symptoms were constitutional, while only a few patients had cranial or peripheral symptoms. Sixty-one percent had physical signs of vascular compromise. Temporal artery biopsy showed giant cell arteritis in six out of nine biopsies. Arterial involvement: 78 % had either involvement of the ascending aorta, the aortic arch, descending or/and abdominal aorta, 9 carotid, 12 subclavian, 5 axillary, 3 renal, 7 iliac, and 2 femoral arteries; 7 mesenteric or celiac trunk. All the patients were treated with prednisone and 50 % with steroid-sparing drug. Nine out of 15 patients (60 %) achieved remission after 1 year of follow-up. No substantial A. Polachek (*) : D. Levartovsky : M. Anouk : U. Arad : H. Sarvagyl-Maman : I. Kaufman : D. Caspi : O. Elkayam Department of Rheumatology, Tel Aviv Sourasky Medical Center, 6 Weizman st, Tel Aviv, 64239, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv, Israel e-mail: [email protected] R. Pauzner Department of Internal Medicine, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel G. Rosen Department of Radiology, Tel-Aviv Medical Center, Tel-Aviv, affiliated with Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel G. Nesher : G. Breuer Unit of rheumatology, Shaare Zedek Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel
differences in the distribution of vascular involvement, type of treatment, or outcome measures were observed between patients fulfilling criteria for GCA or TAK. Vascular involvement typical of TAK in patients above the age of 50 years with large vessel arteritis seems to be more frequent than previously assumed. Our findings support the assumption that TAK and GCA represent a spectrum of the same disease. Keywords Giant cell arteritis . Takayasu . Vasculitis
Introduction Ever since recent studies revealed a high rate of large vessel involvement patterns typical of Takayasu arteritis (TAK) in an older population that presented with a clinical picture of giant cell arteritis (GCA), the boundaries between those two most common types of large vessel arteritis (LVA) have been getting blurred [1–3]. The range of vessel involvement in GCA was reportedly between 33 and 67 % [2, 3]. The introduction of positron emission tomography (PET)-FDG has strengthened these observations by showing rates of involvement up to 83 % and by demonstrating that the subclavian artery and the aorta were the most implicated vessels [4]. Furthermore, systemic necropsy studies performed by Ostberg in 1972 revealed large vessel inflammation in 100 % of GCA patients [5]. The American College of Rheumatology (ACR) classification criteria clearly differentiates between TAK and GCA by several aspects [6, 7], specifically, age above 50 years in GCA and below 40 years in TAK, typical symptoms of new-onset headache in GCA, claudication of extremities in TAK, physical examination signs in GCA of tenderness or decreased pulsation of the temporal artery, compared to decreased brachial artery pulse, blood pressure differentiation between arms and bruit over the subclavian artery or aorta in TAK, elevated sedimentation rate in GCA with no mention of laboratory test
Clin Rheumatol
findings in TAK, temporal biopsy showing typical histological features in GCA, and an abnormal arteriogram showing narrowing or occlusion of the aorta or other large arteries in TAK. Other major differences relate to the predominant ethnicity: TAK seems to be more prevalent in Asian women, while GCA is more frequent in populations of Scandinavian descent [8–10]. The purpose of this study is to describe disease onset, course, and outcome of a series of patients above the age of 50 years who have clinical and angiographic findings of TAK.
Materials and methods Study population Patients above the age of 50 years who were diagnosed as having LVA involving extracranial arteries, particularly the aorta and its main tributaries, participated in this study which was approved by the Helsinki committee of each of the participating medical centers. Rheumatologists in the three centers were asked to localize in their database the records of patients complying with this requirement. The diagnosis of LVA was based on the findings on computerized tomographic angiography (CTA), magnetic resonance angiography (MRA), or intravenous angiography (IVA) that were read and confirmed by an expert radiologist. The patients were diagnosed between 1997 and 2012 and recruited from three rheumatologic centers in Israel. Their medical records were retrospectively reviewed in order to exclude similar diseases and other vasculitides or confounding conditions associated with secondary large vessel vasculitis that could mimic GCA or TAK, such as infectious diseases (e.g., Q fever, tuberculosis, syphilis) or other diseases (e.g., sarcoidosis, Behçet’s disease, Marfan’s syndrome, and fibrodysplasias). Clinical characteristics at disease onset The initially presenting clinical characteristics included constitutional symptoms (fatigue, fever, nausea, weight loss, night sweats), cranial symptoms (new-onset headache, jaw claudication, vision loss, blindness), peripheral symptoms (newonset hypertension, polymyalgia rheumatica symptoms, limb claudication, cerebrovascular accident, arthritis or arthralgia), and/or physical signs (abnormal blood pressure, pulses, arterial bruits, scalp tenderness, temporal artery tenderness).
Conservative and surgical treatment Details of conservative or surgical treatment administered throughout the course of disease were recorded. Outcome Outcome was analyzed according to the four parameters of improvement, remission, relapse, and major complications. Substantial improvement was determined by clinical and/or imaging evidence of decreased active vasculitis as estimated by the treating physician or radiologist, and ability to safely reduce glucocorticoid intake to 50 % of the starting dose at 6 months of treatment. Remission was defined as the absence of signs of active vasculitis (clinical signs, imaging signs if available and ESR ≤20 mm/h) and reduction of the glucocorticoid dose to 40 mm/ h attributable to active disease) requiring a sustained increase of the glucocorticoid dose to >10 mg prednisone per day for more than 4 weeks and/or escalation of glucocorticoid-sparing treatment. Myocardial infarction (MI), cerebrovascular accident (CVA), aortic dissection, aortic aneurysm, and aortic stenosis were considered as being major complications.
Results Fulfillment of ACR vasculitis classification criteria Eighteen patients were included in this cohort: five patients fulfilled the ACR criteria for GCA, five for TAK, and three for both GCA and TAK criteria, while five patients had clear large vessel involvement of large vessels without fulfilling the criteria for either diagnosis. Patient characteristics The age range at disease diagnosis was between 52 and 82 years (median, 64 years), with female predominance (16 patients, 89 %). The median latency period from the first symptom to diagnosis was 5.5 months. The follow-up ranged between 2 months to 15 years (median, 34 months).
Laboratory and imaging results Clinical presentation at disease onset Data on complete blood count, liver enzymes, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, as well as temporal artery biopsy, imaging evidence of large vessels by IVA, CTA, or MRA were retrieved from the patients’ medical files.
Constitutional symptoms, such as fatigue, fever, weight loss, night sweats, and nausea, were the most frequent complaints at disease onset, and 10 patients also had peripheral and/or cranial symptoms (Table 1). All 18 patients complained of
Clin Rheumatol Table 1 Clinical characteristics of the study population at diagnosis
Table 2 Laboratory values at diagnosis
No. of patients (%) Symptoms Constitutional Fever Nausea Weight loss Fatigue Night sweats Cranial New headache Jaw claudication Vision loss Blindness Peripheral New HTN Limb claudication TIA/CVA PMR symptoms Arthralgia/arthritis Signs of vascular involvement BP—asymmetry or not detectable Pulse—diminished or absent Arterial bruits Scalp tenderness Temporal artery tenderness
8 (44) 2 (11) 7 (39) 18 (100) 5 (28) 3 (17) 2 (11) 0 0 3 (17) 5 (28) 4 (22) 3 (17) 4 (22) 8 (44) 7 (39) 6 (34) 1 (6) 0
TIA transient ischemic accident, CVA cerebral vascular event, PMR polymyalgia rheumatica, BP blood pressure
fatigue. Eleven patients had fever and/or night sweats and/or weight loss. Cranial symptoms included new-onset headache or jaw claudication, which were reported by three patients, and none of the participants complained of vision loss. Nine patients (50 %) had one or more peripheral arterial symptoms. Physical examination at diagnosis Eight patients (44 %) had blood pressure asymmetry (of >10 mmHg difference between the two arms) or completely non-detectable blood pressure (Table 1). Seven patients (39 %) had diminished or absent pulses. Six patients (33 %) had arterial bruits. Only one patient had scalp tenderness, and there were no patients with temporal artery tenderness. Laboratory results at diagnosis Fourteen (78 %) patients had anemia (mainly normocytic), five (42 %) had mild leukocytosis and five had thrombocytosis (Table 2). All 18 patients had elevated acute phase reactants (APR), including a median ESR of 94 mm/h and a median CRP level of 70 mg/l. Six (33 %) patients had
Hemoglobin (g/dl) White blood count (K/μL) Platelets (K/μL) ESR (mm/h) CRP (mg/l) ALP (IU/l)
Range
Median
7.4–12.9 4.9–13.6 170–602 44–120 15–198 44–156
11 9.4 355 94 70 81
ESR erythrocyte sedimentation rate, CRP C-reactive protein, ALP alkaline phosphatase
elevated alkaline phosphatase (with a correspondent elevation of gamma glutamyl transferase). Only nine (50 %) patients underwent a temporal artery biopsy, and six of them (66 %) had positive results for GCA. Imaging findings at diagnosis CTA was the main imaging modality in 15 (83 %) patients. Two of the patients who had CTA also underwent an MRA. Two patients were evaluated by positron emission tomography (PET)-CT and one by ultrasonography plus IVA. Two patients had imaging evaluations of the upper body only (up to the abdominal aortic level). Vascular lesions compatible with arteritis were mainly observed in the upper body arteries, predominantly involving the aortic arch, the ascending and descending aortas, and the subclavian artery. Specifically, 14 patients (78 %) had involvement of the thoracic aorta (Fig. 1), nine (50 %) of the carotid arteries, 12 (67 %) of the subclavian arteries (Fig. 2), and five (28 %) of the axillary arteries. Nine out 16 (56 %) patients (who had abdominal imaging evaluations) had involvement of the abdominal aorta, and 15 of them had additional involvement of the thoracic aorta. Seven (44 %) of them had involvement of the mesenteric or celiac trunk, three (19 %) had involvement of the renal arteries, seven (44 %) of the iliac arteries, and two (13 %) of the femoral arteries (Table 3). During follow-up, a few patients had done repeated CTA. Among these patients, three developed aneurysms in the ascending and abdominal aorta. Treatment All the patients were started on treatment with prednisone, fifteen (82 %) at a dosage between 60 and 80 mg. In addition, five (28 %) patients were treated up front with steroid-sparing drugs (one with methotrexate, two with azathioprine, and one with cyclophosphamide). Four other patients (22 %) needed the addition of a steroid-sparing drug during the course of disease. At the end of follow-up, 12 (66 %) patients continued to be treated with prednisone, nine (75 %) at a dosage range of 5–10 mg/day and six (66 %) with steroid-sparing drugs
Clin Rheumatol Table 3 Distribution of vascular lesions (active vasculitis, stenosis, or aneurysms) No. of patients (%)
Fig. 1 Computed tomography showing thickening and enhancement of the descending aorta (arrow) in a 75-year-old woman
(methotrexate or azathioprine). Thirteen (72 %) patients were treated with low-dose aspirin as an oral platelet aggregation inhibitor. During follow-up, five (28 %) patients needed vascular surgical repair, mainly due to an aortic aneurysm. Outcome parameters Twelve out of the 17 (71 %) patients who completed at least 6 months of follow-up have improved. Nine out of the 15 (60 %) patients who completed at least 1 year of follow-up achieved remission. Three additional patients had a partial remission (clinical remission with persistently mildly elevated acute phase reactants). Three patients in the remission group relapsed (33 %). Five (28 %) patients had a major event (i.e.,
Fig. 2 Computed tomography angiography showing thickening and enhancement of both subclavian arteries (arrow) in a 70-year-old woman with a positive temporal biopsy for giant cell arteritis
Ascending and aortic arch Descending aorta Carotid Vertebral
13 (72) 12 (67) 9 (50) 1 (6)
Subclavian Axillary Abdominal aorta Mesenteric/celiac Renal Iliac Femoral
12 (67) 5 (28) 9 (56) 7 (44) 3 (19) 7 (44) 2 (13)
MI, CVA, aortic aneurysm, aortic regurgitation, and renal artery stenosis). During follow-up, five (28 %) patients needed vascular surgical repair—three due to an aortic aneurysm (in the ascending aorta), one due to renal artery stenosis (treated by stent insertion), and one needed surgery for treating a mesenteric event. Five (28 %) patients died, three due to vascular complications of their disease: one mesenteric event, one complication during aneurysm surgical repair, and a case of sepsis following aneurysm surgical repair.
A comparison between the patients who fulfilled the ACR criteria for GCA (five patients) and those who fulfilled the ACR criteria for TAK (five patients) The GCA patients were slightly older than the TAK patients (median age of 70 years vs. 64 years, respectively) (Table 4). The latency period from onset of first symptom to diagnosis was longer in the TAK patients (median of 6 vs. 3 months, respectively). The GCA group had more constitutional symptoms, while the TAK group had more peripheral symptoms and more vascular involvement signs on physical examination. The acute phase reactants were higher in the GCA group than in the TAK group: ESR of 104 vs. 84 mm/h and CRP of 110 vs. 57.5 mg/l, respectively. The hemoglobin level was 10.5 g/dl in both groups. The temporal biopsy was positive in all four GCA patients and negative in the two TAK patients who had undergone this procedure. The imaging evidence of vascular involvement in the upper body (ascending and descending aorta, carotid, axillary, and subclavian arteries) was similar in both groups; however, the GCA group had more vascular involvement in the lower body (abdominal aorta, mesenteric, celiac, renal, iliac, and femoral arteries). There were no differences in the pharmacologic or surgical treatment between these two groups, and their outcome measures were not substantially different.
Clin Rheumatol Table 4 A comparison of the patients who fulfilled the American College of Rheumatology criteria for giant cell arteritis (GCA) and for Takayasu arteritis (TAK)
Age (median), years Time from symptoms to diagnosis, months Symptoms, no. of patients Constitutional Fever Nausea Weight loss Fatigue Night sweats Cranial headache Jaw claudication Vision loss Blindness Peripheral New HTN Limb claudication TIA/CVA PMR symptoms Arthralgia/arthritis Signs of vascular involvement BP—asymmetry or not detectable Pulse—diminished or absent Arterial bruits Scalp tenderness Temporal artery tenderness Laboratory Hemoglobin (g/dl) ESR (mm/h) CRP (mg/l) Temporal biopsy Imaging results, no. of patients Upper body part Lower body part Prognosis Rate of remission Rate of relapse
GCA
TAK
70 3
64 6
3 2 1 5 2
2 0 2 5 1
1 1 0 0
0 0 0 0
0 0 1 0 1
2 2 3 1 2
0 0 1 1 0
4 4 3 0 0
10.5 104 110 4/4 patients
10.5 84 57.5 0/2 patients
5 5
5 1
40 % 20 %
40 % 25 %
ESR erythrocyte sedimentation rate, CRP C-reactive protein, TIA transient ischemic accident, CVA cerebral vascular event, PMR polymyalgia rheumatica, BP blood pressure
Discussion Our present study describes disease onset, course, and outcome of 18 patients above the age of 50 years who were diagnosed as having LVA. Thirteen of them (72 %) fulfilled the ACR criteria for either GCA or TAK or both, while five
did not meet the criteria of either, emphasizing the limitations of the current criteria. The diagnosis was established based on combinations of the clinical picture with imaging findings. Only four of the six (67 %) patients who underwent temporal artery biopsy demonstrated vasculitis, a percentage similar to that reported in previous studies [11, 12], indicating an ancillary but not mandatory role of this test. The relatively long duration of disease symptoms until diagnosis (median, 5.5 months) seems to be typical of GCA patients with large vessel involvement in comparison with those who have cranial disease (median, 8.1 vs 2.6 months, respectively in Barak et al. study) [12]. The dominant symptoms were constitutional in all (18) of our patients, while nine had primarily peripheral symptoms and signs and only three complained of symptoms related to impaired cranial blood flow. These rates of constitutional and peripheral symptoms and signs are supported by the reports of others [1, 2, 11]. The imaging findings revealed predominant involvement of the upper body arteries, in particular, the thoracic aorta and the subclavian arteries, confirming previous studies in GCA patients that reported a range of thoracic aortitis of 51–100 % and a range of subclavian arteritis of 43–74 % [1–5, 11, 13]. Axillary arteritis was detected in 28 % of our patients, similarly to the 17.5–50 % range of that involvement reported in other series [3, 4, 11, 13]. Also similar to the findings of previous studies, the abdominal aorta was the most involved vessel in the lower body, and it was usually accompanied by involvement of the thoracic aorta [3, 4, 11, 13]. In accordance with the EULAR recommendations on the management of LVA, all the patients in this study received treatment with high-dose glucocorticosteroids (GCS) [14, 15]. It is not clear if and when other immunosuppressive treatment should be added. The option of treatment with methotrexate, as a steroid sparing drug, was evaluated in a few prospective double blind studies that came to different conclusions [16–18]. Jover et al. showed a significantly reduced number of relapse and reduced cumulative GCS dose in the methotrexate-treated group [16]. In contrast, Hoffman et al. and Spiera et al. did not find such beneficial effects of this drug [17, 18]. Unlike previous studies with a low percentage of patients (27–36 %) treated with a platelet aggregation inhibitor [2, 11] 72 % of our patients received antiplatelet drugs. The 28 % rate of surgical vascular repair in our study was similar to the one of 33 % reported by Assie et al. [11]. The majority of our study sample showed improvement (72 %) or achieved remission (60 %), while 33 % had a relapse. Only a few studies had evaluated these outcome measures in patients with extracranial GCA patients. Our results are better than the range of remission between 37 and 44 % and the 51 % relapse reported in other series [4, 11]. This discrepancy might be explained by the early use of steroidsparing drugs in our series or, alternatively, by their use of different outcome measures and prognostic definitions that
Clin Rheumatol
relied on imaging modalities for follow-up, which was done in only a small portion of our study patients. Patients who fulfilled ACR criteria for GCA were slightly different from the patients who fulfilled ACR criteria for TAK. Our GCA patients were slightly older, had more constitutional and fewer peripheral symptoms as well as fewer signs of vascular involvement. In addition, our GCA patients had higher acute phase reactants and, although the rate of imaging vascular involvement of the upper body was similar between the TAK and GCA groups, the rate of involvement of the lower body was higher in the GCA group. No differences were found in the rate of cranial symptoms, other laboratory results, treatments, and the rate of the different outcome parameters. Maksimowicz-McKinnon et al. [19] compared 75 patients diagnosed as having TAK to 69 patients diagnosed as having GCA according to the ACR criteria. The mean age of each group was significantly dissimilar (26 years for the TAK patients versus 67 years for the GCA patients). Their GCA patients had significantly more cranial symptoms and higher APR, while signs and symptoms of vascular involvement were more frequent in the TAK group. The aorta was the predominantly involved vessel in our study in these two groups, but the TAK patients had significantly higher involvement of the carotid, subclavian, femoral, and mesenteric arteries than the GCA patients. GCA and TAK are classified as two different diseases [6, 7]. These distinctions are based on differences in age, ethnicity, symptoms, signs and vascular distribution and manifestations. Both our study and that of Maksimowicz-McKinnon et al. [19] have demonstrated a broad overlap in the signs, symptoms, laboratory results, vascular distribution, treatment, and outcome of GCA and TAK. The traditional age at TAK onset is under 40 years, yet Arnaud et al.’s study on TAK patients showed that 32 % of them had disease onset after the age of 40 years, 18 % after 50 years, and 5 % after 60 years [20]. This argument against traditional thinking was demonstrated in other cohorts as well [21–24]. In addition, while the ethnicity of patients with TAK is believed to typically be Asiatic, it was found to be primarily of white non-Asian women among patients in France, America, and Italy [20, 24–26]. On the other hand, the rate of involvement of extracranial arteries in GCA patients, which was estimated in the past to range between 3 and 18 % [27–30], was much higher in a few recent studies and reached rates between 45 and 83 % when advanced imaging modalities were used [1, 3, 4, 11]. Moreover, Grayson et al. found strong similarities as well as subtle differences in the distribution of arterial lesions between 145 TAK patients and 62 GCA patients [13]. This study has several limitations mainly derived from its small sample size and retrospective design. The retrospective design could cause physician bias in the evaluation and recording of the history details and physical findings, and consequently, these could lead to under-reporting of findings.
Only a few of our patients had imaging surveillance that could add another aspect of the response to treatment. Likewise, due to the retrospective design of the study, no clear guidelines were used to discriminate between atherosclerotic changes and vasculitic lesions. In addition, the estimation of LVA in this study and the numeric comparisons to other studies with unselected cohorts are not fully valid due to our selection of only older patients with these features. On the other hand, our findings confirm the observation that extracranial involvement typical of TAK in the elderly is probably more frequent than expected and should be searched more thoroughly. In conclusion, vascular involvement typical of TAK in patients above the age of 50 years who have LVA seems to be more frequent than previously assumed. This supports the need and the usefulness of imaging modalities in order to detect evidence of large-vessel inflammation and associated complications. In addition, the differences between the individuals who fulfill ACR criteria for each of the two disease entities are minor, and our findings support the likelihood that TAK and GCA might represent a part of the spectrum of the same disease. As such, a revision of the current classifications of TAK and GCA should be considered. Acknowledgment In the memory of Dr. Pauzner Rachel who was a dedicated and enthusiastic internist and rheumatologist, extremely devoted to her patients, especially interested in the field of Takayasu arteritis and antiphospholipid syndrome and who made a significant contribution to this article. Esther Eshkol is thanked for editorial assistance. This study has been approved by the appropriate ethics committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. This research received no specific funding. Conflict of interest The authors declare that they do not have any competing interests. Author’s contribution Ari Polachek recruited participants, collected and interpreted the data, and wrote and approved the final report. Rachel Pauzner, David Levartovsky, Galia Rosen, Gideon Nesher, Gabriel Breuer, Marina Anouk, Uri Arad, Hagit Sarvagyl-Maman, Ilana Kaufman, and Dan Caspi recruited patients and approved the final report. Ori Elkayam designed the study, recruited patients, interpreted the data, and wrote and approved the final report.
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ORIGINAL ARTICLE
The fine line between Takayasu arteritis and giant cell arteritis Ari Polachek & Rachel Pauzner & David Levartovsky & Galia Rosen & Gideon Nesher & Gabriel Breuer & Marina Anouk & Uri Arad & Hagit Sarvagyl-Maman & Ilana Kaufman & Dan Caspi & Ori Elkayam
Received: 28 June 2014 / Revised: 21 October 2014 / Accepted: 23 October 2014 # International League of Associations for Rheumatology (ILAR) 2014
Abstract The objective of this study is to describe a series of patients above the age of 50 years with large vessel arteritis and vascular involvement typical of TAK. A retrospective review of 18 patients (median age 64 years) with emphasis on clinical characteristics, laboratory values, and vascular involvement by CT, MRI, or planar angiography. Five patients fulfilled the ACR criteria for GCA, five for TAK, three both GCA and TAK, while five patients did not fulfill the criteria for either disease. The dominant presenting symptoms were constitutional, while only a few patients had cranial or peripheral symptoms. Sixty-one percent had physical signs of vascular compromise. Temporal artery biopsy showed giant cell arteritis in six out of nine biopsies. Arterial involvement: 78 % had either involvement of the ascending aorta, the aortic arch, descending or/and abdominal aorta, 9 carotid, 12 subclavian, 5 axillary, 3 renal, 7 iliac, and 2 femoral arteries; 7 mesenteric or celiac trunk. All the patients were treated with prednisone and 50 % with steroid-sparing drug. Nine out of 15 patients (60 %) achieved remission after 1 year of follow-up. No substantial A. Polachek (*) : D. Levartovsky : M. Anouk : U. Arad : H. Sarvagyl-Maman : I. Kaufman : D. Caspi : O. Elkayam Department of Rheumatology, Tel Aviv Sourasky Medical Center, 6 Weizman st, Tel Aviv, 64239, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv, Israel e-mail: [email protected] R. Pauzner Department of Internal Medicine, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel G. Rosen Department of Radiology, Tel-Aviv Medical Center, Tel-Aviv, affiliated with Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel G. Nesher : G. Breuer Unit of rheumatology, Shaare Zedek Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel
differences in the distribution of vascular involvement, type of treatment, or outcome measures were observed between patients fulfilling criteria for GCA or TAK. Vascular involvement typical of TAK in patients above the age of 50 years with large vessel arteritis seems to be more frequent than previously assumed. Our findings support the assumption that TAK and GCA represent a spectrum of the same disease. Keywords Giant cell arteritis . Takayasu . Vasculitis
Introduction Ever since recent studies revealed a high rate of large vessel involvement patterns typical of Takayasu arteritis (TAK) in an older population that presented with a clinical picture of giant cell arteritis (GCA), the boundaries between those two most common types of large vessel arteritis (LVA) have been getting blurred [1–3]. The range of vessel involvement in GCA was reportedly between 33 and 67 % [2, 3]. The introduction of positron emission tomography (PET)-FDG has strengthened these observations by showing rates of involvement up to 83 % and by demonstrating that the subclavian artery and the aorta were the most implicated vessels [4]. Furthermore, systemic necropsy studies performed by Ostberg in 1972 revealed large vessel inflammation in 100 % of GCA patients [5]. The American College of Rheumatology (ACR) classification criteria clearly differentiates between TAK and GCA by several aspects [6, 7], specifically, age above 50 years in GCA and below 40 years in TAK, typical symptoms of new-onset headache in GCA, claudication of extremities in TAK, physical examination signs in GCA of tenderness or decreased pulsation of the temporal artery, compared to decreased brachial artery pulse, blood pressure differentiation between arms and bruit over the subclavian artery or aorta in TAK, elevated sedimentation rate in GCA with no mention of laboratory test
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findings in TAK, temporal biopsy showing typical histological features in GCA, and an abnormal arteriogram showing narrowing or occlusion of the aorta or other large arteries in TAK. Other major differences relate to the predominant ethnicity: TAK seems to be more prevalent in Asian women, while GCA is more frequent in populations of Scandinavian descent [8–10]. The purpose of this study is to describe disease onset, course, and outcome of a series of patients above the age of 50 years who have clinical and angiographic findings of TAK.
Materials and methods Study population Patients above the age of 50 years who were diagnosed as having LVA involving extracranial arteries, particularly the aorta and its main tributaries, participated in this study which was approved by the Helsinki committee of each of the participating medical centers. Rheumatologists in the three centers were asked to localize in their database the records of patients complying with this requirement. The diagnosis of LVA was based on the findings on computerized tomographic angiography (CTA), magnetic resonance angiography (MRA), or intravenous angiography (IVA) that were read and confirmed by an expert radiologist. The patients were diagnosed between 1997 and 2012 and recruited from three rheumatologic centers in Israel. Their medical records were retrospectively reviewed in order to exclude similar diseases and other vasculitides or confounding conditions associated with secondary large vessel vasculitis that could mimic GCA or TAK, such as infectious diseases (e.g., Q fever, tuberculosis, syphilis) or other diseases (e.g., sarcoidosis, Behçet’s disease, Marfan’s syndrome, and fibrodysplasias). Clinical characteristics at disease onset The initially presenting clinical characteristics included constitutional symptoms (fatigue, fever, nausea, weight loss, night sweats), cranial symptoms (new-onset headache, jaw claudication, vision loss, blindness), peripheral symptoms (newonset hypertension, polymyalgia rheumatica symptoms, limb claudication, cerebrovascular accident, arthritis or arthralgia), and/or physical signs (abnormal blood pressure, pulses, arterial bruits, scalp tenderness, temporal artery tenderness).
Conservative and surgical treatment Details of conservative or surgical treatment administered throughout the course of disease were recorded. Outcome Outcome was analyzed according to the four parameters of improvement, remission, relapse, and major complications. Substantial improvement was determined by clinical and/or imaging evidence of decreased active vasculitis as estimated by the treating physician or radiologist, and ability to safely reduce glucocorticoid intake to 50 % of the starting dose at 6 months of treatment. Remission was defined as the absence of signs of active vasculitis (clinical signs, imaging signs if available and ESR ≤20 mm/h) and reduction of the glucocorticoid dose to 40 mm/ h attributable to active disease) requiring a sustained increase of the glucocorticoid dose to >10 mg prednisone per day for more than 4 weeks and/or escalation of glucocorticoid-sparing treatment. Myocardial infarction (MI), cerebrovascular accident (CVA), aortic dissection, aortic aneurysm, and aortic stenosis were considered as being major complications.
Results Fulfillment of ACR vasculitis classification criteria Eighteen patients were included in this cohort: five patients fulfilled the ACR criteria for GCA, five for TAK, and three for both GCA and TAK criteria, while five patients had clear large vessel involvement of large vessels without fulfilling the criteria for either diagnosis. Patient characteristics The age range at disease diagnosis was between 52 and 82 years (median, 64 years), with female predominance (16 patients, 89 %). The median latency period from the first symptom to diagnosis was 5.5 months. The follow-up ranged between 2 months to 15 years (median, 34 months).
Laboratory and imaging results Clinical presentation at disease onset Data on complete blood count, liver enzymes, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, as well as temporal artery biopsy, imaging evidence of large vessels by IVA, CTA, or MRA were retrieved from the patients’ medical files.
Constitutional symptoms, such as fatigue, fever, weight loss, night sweats, and nausea, were the most frequent complaints at disease onset, and 10 patients also had peripheral and/or cranial symptoms (Table 1). All 18 patients complained of
Clin Rheumatol Table 1 Clinical characteristics of the study population at diagnosis
Table 2 Laboratory values at diagnosis
No. of patients (%) Symptoms Constitutional Fever Nausea Weight loss Fatigue Night sweats Cranial New headache Jaw claudication Vision loss Blindness Peripheral New HTN Limb claudication TIA/CVA PMR symptoms Arthralgia/arthritis Signs of vascular involvement BP—asymmetry or not detectable Pulse—diminished or absent Arterial bruits Scalp tenderness Temporal artery tenderness
8 (44) 2 (11) 7 (39) 18 (100) 5 (28) 3 (17) 2 (11) 0 0 3 (17) 5 (28) 4 (22) 3 (17) 4 (22) 8 (44) 7 (39) 6 (34) 1 (6) 0
TIA transient ischemic accident, CVA cerebral vascular event, PMR polymyalgia rheumatica, BP blood pressure
fatigue. Eleven patients had fever and/or night sweats and/or weight loss. Cranial symptoms included new-onset headache or jaw claudication, which were reported by three patients, and none of the participants complained of vision loss. Nine patients (50 %) had one or more peripheral arterial symptoms. Physical examination at diagnosis Eight patients (44 %) had blood pressure asymmetry (of >10 mmHg difference between the two arms) or completely non-detectable blood pressure (Table 1). Seven patients (39 %) had diminished or absent pulses. Six patients (33 %) had arterial bruits. Only one patient had scalp tenderness, and there were no patients with temporal artery tenderness. Laboratory results at diagnosis Fourteen (78 %) patients had anemia (mainly normocytic), five (42 %) had mild leukocytosis and five had thrombocytosis (Table 2). All 18 patients had elevated acute phase reactants (APR), including a median ESR of 94 mm/h and a median CRP level of 70 mg/l. Six (33 %) patients had
Hemoglobin (g/dl) White blood count (K/μL) Platelets (K/μL) ESR (mm/h) CRP (mg/l) ALP (IU/l)
Range
Median
7.4–12.9 4.9–13.6 170–602 44–120 15–198 44–156
11 9.4 355 94 70 81
ESR erythrocyte sedimentation rate, CRP C-reactive protein, ALP alkaline phosphatase
elevated alkaline phosphatase (with a correspondent elevation of gamma glutamyl transferase). Only nine (50 %) patients underwent a temporal artery biopsy, and six of them (66 %) had positive results for GCA. Imaging findings at diagnosis CTA was the main imaging modality in 15 (83 %) patients. Two of the patients who had CTA also underwent an MRA. Two patients were evaluated by positron emission tomography (PET)-CT and one by ultrasonography plus IVA. Two patients had imaging evaluations of the upper body only (up to the abdominal aortic level). Vascular lesions compatible with arteritis were mainly observed in the upper body arteries, predominantly involving the aortic arch, the ascending and descending aortas, and the subclavian artery. Specifically, 14 patients (78 %) had involvement of the thoracic aorta (Fig. 1), nine (50 %) of the carotid arteries, 12 (67 %) of the subclavian arteries (Fig. 2), and five (28 %) of the axillary arteries. Nine out 16 (56 %) patients (who had abdominal imaging evaluations) had involvement of the abdominal aorta, and 15 of them had additional involvement of the thoracic aorta. Seven (44 %) of them had involvement of the mesenteric or celiac trunk, three (19 %) had involvement of the renal arteries, seven (44 %) of the iliac arteries, and two (13 %) of the femoral arteries (Table 3). During follow-up, a few patients had done repeated CTA. Among these patients, three developed aneurysms in the ascending and abdominal aorta. Treatment All the patients were started on treatment with prednisone, fifteen (82 %) at a dosage between 60 and 80 mg. In addition, five (28 %) patients were treated up front with steroid-sparing drugs (one with methotrexate, two with azathioprine, and one with cyclophosphamide). Four other patients (22 %) needed the addition of a steroid-sparing drug during the course of disease. At the end of follow-up, 12 (66 %) patients continued to be treated with prednisone, nine (75 %) at a dosage range of 5–10 mg/day and six (66 %) with steroid-sparing drugs
Clin Rheumatol Table 3 Distribution of vascular lesions (active vasculitis, stenosis, or aneurysms) No. of patients (%)
Fig. 1 Computed tomography showing thickening and enhancement of the descending aorta (arrow) in a 75-year-old woman
(methotrexate or azathioprine). Thirteen (72 %) patients were treated with low-dose aspirin as an oral platelet aggregation inhibitor. During follow-up, five (28 %) patients needed vascular surgical repair, mainly due to an aortic aneurysm. Outcome parameters Twelve out of the 17 (71 %) patients who completed at least 6 months of follow-up have improved. Nine out of the 15 (60 %) patients who completed at least 1 year of follow-up achieved remission. Three additional patients had a partial remission (clinical remission with persistently mildly elevated acute phase reactants). Three patients in the remission group relapsed (33 %). Five (28 %) patients had a major event (i.e.,
Fig. 2 Computed tomography angiography showing thickening and enhancement of both subclavian arteries (arrow) in a 70-year-old woman with a positive temporal biopsy for giant cell arteritis
Ascending and aortic arch Descending aorta Carotid Vertebral
13 (72) 12 (67) 9 (50) 1 (6)
Subclavian Axillary Abdominal aorta Mesenteric/celiac Renal Iliac Femoral
12 (67) 5 (28) 9 (56) 7 (44) 3 (19) 7 (44) 2 (13)
MI, CVA, aortic aneurysm, aortic regurgitation, and renal artery stenosis). During follow-up, five (28 %) patients needed vascular surgical repair—three due to an aortic aneurysm (in the ascending aorta), one due to renal artery stenosis (treated by stent insertion), and one needed surgery for treating a mesenteric event. Five (28 %) patients died, three due to vascular complications of their disease: one mesenteric event, one complication during aneurysm surgical repair, and a case of sepsis following aneurysm surgical repair.
A comparison between the patients who fulfilled the ACR criteria for GCA (five patients) and those who fulfilled the ACR criteria for TAK (five patients) The GCA patients were slightly older than the TAK patients (median age of 70 years vs. 64 years, respectively) (Table 4). The latency period from onset of first symptom to diagnosis was longer in the TAK patients (median of 6 vs. 3 months, respectively). The GCA group had more constitutional symptoms, while the TAK group had more peripheral symptoms and more vascular involvement signs on physical examination. The acute phase reactants were higher in the GCA group than in the TAK group: ESR of 104 vs. 84 mm/h and CRP of 110 vs. 57.5 mg/l, respectively. The hemoglobin level was 10.5 g/dl in both groups. The temporal biopsy was positive in all four GCA patients and negative in the two TAK patients who had undergone this procedure. The imaging evidence of vascular involvement in the upper body (ascending and descending aorta, carotid, axillary, and subclavian arteries) was similar in both groups; however, the GCA group had more vascular involvement in the lower body (abdominal aorta, mesenteric, celiac, renal, iliac, and femoral arteries). There were no differences in the pharmacologic or surgical treatment between these two groups, and their outcome measures were not substantially different.
Clin Rheumatol Table 4 A comparison of the patients who fulfilled the American College of Rheumatology criteria for giant cell arteritis (GCA) and for Takayasu arteritis (TAK)
Age (median), years Time from symptoms to diagnosis, months Symptoms, no. of patients Constitutional Fever Nausea Weight loss Fatigue Night sweats Cranial headache Jaw claudication Vision loss Blindness Peripheral New HTN Limb claudication TIA/CVA PMR symptoms Arthralgia/arthritis Signs of vascular involvement BP—asymmetry or not detectable Pulse—diminished or absent Arterial bruits Scalp tenderness Temporal artery tenderness Laboratory Hemoglobin (g/dl) ESR (mm/h) CRP (mg/l) Temporal biopsy Imaging results, no. of patients Upper body part Lower body part Prognosis Rate of remission Rate of relapse
GCA
TAK
70 3
64 6
3 2 1 5 2
2 0 2 5 1
1 1 0 0
0 0 0 0
0 0 1 0 1
2 2 3 1 2
0 0 1 1 0
4 4 3 0 0
10.5 104 110 4/4 patients
10.5 84 57.5 0/2 patients
5 5
5 1
40 % 20 %
40 % 25 %
ESR erythrocyte sedimentation rate, CRP C-reactive protein, TIA transient ischemic accident, CVA cerebral vascular event, PMR polymyalgia rheumatica, BP blood pressure
Discussion Our present study describes disease onset, course, and outcome of 18 patients above the age of 50 years who were diagnosed as having LVA. Thirteen of them (72 %) fulfilled the ACR criteria for either GCA or TAK or both, while five
did not meet the criteria of either, emphasizing the limitations of the current criteria. The diagnosis was established based on combinations of the clinical picture with imaging findings. Only four of the six (67 %) patients who underwent temporal artery biopsy demonstrated vasculitis, a percentage similar to that reported in previous studies [11, 12], indicating an ancillary but not mandatory role of this test. The relatively long duration of disease symptoms until diagnosis (median, 5.5 months) seems to be typical of GCA patients with large vessel involvement in comparison with those who have cranial disease (median, 8.1 vs 2.6 months, respectively in Barak et al. study) [12]. The dominant symptoms were constitutional in all (18) of our patients, while nine had primarily peripheral symptoms and signs and only three complained of symptoms related to impaired cranial blood flow. These rates of constitutional and peripheral symptoms and signs are supported by the reports of others [1, 2, 11]. The imaging findings revealed predominant involvement of the upper body arteries, in particular, the thoracic aorta and the subclavian arteries, confirming previous studies in GCA patients that reported a range of thoracic aortitis of 51–100 % and a range of subclavian arteritis of 43–74 % [1–5, 11, 13]. Axillary arteritis was detected in 28 % of our patients, similarly to the 17.5–50 % range of that involvement reported in other series [3, 4, 11, 13]. Also similar to the findings of previous studies, the abdominal aorta was the most involved vessel in the lower body, and it was usually accompanied by involvement of the thoracic aorta [3, 4, 11, 13]. In accordance with the EULAR recommendations on the management of LVA, all the patients in this study received treatment with high-dose glucocorticosteroids (GCS) [14, 15]. It is not clear if and when other immunosuppressive treatment should be added. The option of treatment with methotrexate, as a steroid sparing drug, was evaluated in a few prospective double blind studies that came to different conclusions [16–18]. Jover et al. showed a significantly reduced number of relapse and reduced cumulative GCS dose in the methotrexate-treated group [16]. In contrast, Hoffman et al. and Spiera et al. did not find such beneficial effects of this drug [17, 18]. Unlike previous studies with a low percentage of patients (27–36 %) treated with a platelet aggregation inhibitor [2, 11] 72 % of our patients received antiplatelet drugs. The 28 % rate of surgical vascular repair in our study was similar to the one of 33 % reported by Assie et al. [11]. The majority of our study sample showed improvement (72 %) or achieved remission (60 %), while 33 % had a relapse. Only a few studies had evaluated these outcome measures in patients with extracranial GCA patients. Our results are better than the range of remission between 37 and 44 % and the 51 % relapse reported in other series [4, 11]. This discrepancy might be explained by the early use of steroidsparing drugs in our series or, alternatively, by their use of different outcome measures and prognostic definitions that
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relied on imaging modalities for follow-up, which was done in only a small portion of our study patients. Patients who fulfilled ACR criteria for GCA were slightly different from the patients who fulfilled ACR criteria for TAK. Our GCA patients were slightly older, had more constitutional and fewer peripheral symptoms as well as fewer signs of vascular involvement. In addition, our GCA patients had higher acute phase reactants and, although the rate of imaging vascular involvement of the upper body was similar between the TAK and GCA groups, the rate of involvement of the lower body was higher in the GCA group. No differences were found in the rate of cranial symptoms, other laboratory results, treatments, and the rate of the different outcome parameters. Maksimowicz-McKinnon et al. [19] compared 75 patients diagnosed as having TAK to 69 patients diagnosed as having GCA according to the ACR criteria. The mean age of each group was significantly dissimilar (26 years for the TAK patients versus 67 years for the GCA patients). Their GCA patients had significantly more cranial symptoms and higher APR, while signs and symptoms of vascular involvement were more frequent in the TAK group. The aorta was the predominantly involved vessel in our study in these two groups, but the TAK patients had significantly higher involvement of the carotid, subclavian, femoral, and mesenteric arteries than the GCA patients. GCA and TAK are classified as two different diseases [6, 7]. These distinctions are based on differences in age, ethnicity, symptoms, signs and vascular distribution and manifestations. Both our study and that of Maksimowicz-McKinnon et al. [19] have demonstrated a broad overlap in the signs, symptoms, laboratory results, vascular distribution, treatment, and outcome of GCA and TAK. The traditional age at TAK onset is under 40 years, yet Arnaud et al.’s study on TAK patients showed that 32 % of them had disease onset after the age of 40 years, 18 % after 50 years, and 5 % after 60 years [20]. This argument against traditional thinking was demonstrated in other cohorts as well [21–24]. In addition, while the ethnicity of patients with TAK is believed to typically be Asiatic, it was found to be primarily of white non-Asian women among patients in France, America, and Italy [20, 24–26]. On the other hand, the rate of involvement of extracranial arteries in GCA patients, which was estimated in the past to range between 3 and 18 % [27–30], was much higher in a few recent studies and reached rates between 45 and 83 % when advanced imaging modalities were used [1, 3, 4, 11]. Moreover, Grayson et al. found strong similarities as well as subtle differences in the distribution of arterial lesions between 145 TAK patients and 62 GCA patients [13]. This study has several limitations mainly derived from its small sample size and retrospective design. The retrospective design could cause physician bias in the evaluation and recording of the history details and physical findings, and consequently, these could lead to under-reporting of findings.
Only a few of our patients had imaging surveillance that could add another aspect of the response to treatment. Likewise, due to the retrospective design of the study, no clear guidelines were used to discriminate between atherosclerotic changes and vasculitic lesions. In addition, the estimation of LVA in this study and the numeric comparisons to other studies with unselected cohorts are not fully valid due to our selection of only older patients with these features. On the other hand, our findings confirm the observation that extracranial involvement typical of TAK in the elderly is probably more frequent than expected and should be searched more thoroughly. In conclusion, vascular involvement typical of TAK in patients above the age of 50 years who have LVA seems to be more frequent than previously assumed. This supports the need and the usefulness of imaging modalities in order to detect evidence of large-vessel inflammation and associated complications. In addition, the differences between the individuals who fulfill ACR criteria for each of the two disease entities are minor, and our findings support the likelihood that TAK and GCA might represent a part of the spectrum of the same disease. As such, a revision of the current classifications of TAK and GCA should be considered. Acknowledgment In the memory of Dr. Pauzner Rachel who was a dedicated and enthusiastic internist and rheumatologist, extremely devoted to her patients, especially interested in the field of Takayasu arteritis and antiphospholipid syndrome and who made a significant contribution to this article. Esther Eshkol is thanked for editorial assistance. This study has been approved by the appropriate ethics committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. This research received no specific funding. Conflict of interest The authors declare that they do not have any competing interests. Author’s contribution Ari Polachek recruited participants, collected and interpreted the data, and wrote and approved the final report. Rachel Pauzner, David Levartovsky, Galia Rosen, Gideon Nesher, Gabriel Breuer, Marina Anouk, Uri Arad, Hagit Sarvagyl-Maman, Ilana Kaufman, and Dan Caspi recruited patients and approved the final report. Ori Elkayam designed the study, recruited patients, interpreted the data, and wrote and approved the final report.
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