A young lady with inflammation of unknown origin

Open access

Abstract

Takayasu’s arteritis (TAK) is a systemic vasculitis mainly affecting the aorta and its first branches. The initial presentation can be very non-specific while its sequelae can be debilitating and fatal. Apart from clinical and biochemical tests, imaging studies remain pivotal for the diagnosis of this rare disease. Delay in treatment may result in vascular stenosis, leading to morbidity and mortality. We report a case of a young woman who presented with anemia with no obvious causes. Subsequently she developed ischemic symptoms and the diagnosis of TAK was established with magnetic resonance angiography (MRA). Our case illustrates the importance of recognition of the possibility of TAK in young women who presented with non-specific systemic upset and anemia of chronic inflammation. A high index of suspicion is needed and imaging studies should be considered early. The treatment of TAK will also be briefly reviewed.

1 Introduction

Anemia of chronic inflammation (ACI) is a condition in which anemia is associated with low iron concentration with adequate iron store. The pathogenesis of ACI is thought to be mediated by cytokines released during inflammation such as interleukin-1, interleukin-6, and tumor necrosis factor (TNF). This causes apoptosis of red cells precursors and down-regulation of erythropoietin receptors. Furthermore, hepcidin, an acute phase reactant, is produced in response to inflammation. Under its effect, iron carrier protein, ferroportin, is reduced, which inhibits iron absorption and utilization. These lead to shorted erythrocyte life span and reduced erythropoiesis, resulting in decreased hemoglobin level.

A long list of differential diagnoses should be considered in ACI, including malignancy, renal failure, chronic infections, and autoimmune diseases. Here we report a young woman who presented with anemia of chronic inflammation with no other apparent symptoms until she developed cerebrovascular symptoms, leading to an eventual diagnosis of TAK.

2 Case Report

A 31-year-old Asian woman was referred to general medical clinic with a presentation of anemia and raised C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR). She was a non-smoker, non-drinker, and enjoyed good past health. There was no family history of autoimmune conditions or premature cardiovascular mortality. She worked as a beauty consultant, was married, and had one healthy child.

She was first seen by private general practitioner with a chief complaint of oral ulcers for a few years. Apart from arthralgia there were no other symptoms. There was no arthritis, fever, skin rash, or malaise. Systemic enquiry was unremarkable. Physical examination was non-revealing. Blood tests showed normocytic normochromic anemia of 9.7 g/L (NR: 11.6–15.5 g/L) with raised CRP (9.8 mg/L; NR < 5 mg/L) and ESR (75 mm/h; NR 5–34 mm/h). Otherwise, her liver and renal function tests, platelet and leucocyte counts were normal; her autoimmune serologies including anti-nuclear antibody, anti-extractable nuclear antibody, rheumatoid factor, antineutrophil cytoplasmic antibody (ANCA) were all negative. She was then referred to our clinic for further work-up.

Upon our first assessment, she was asymptomatic. Her oral ulcers and arthralgia had already resolved. Physical examination was unremarkable with normal blood pressure, heart rate, and body temperature. Her urine dipsticks revealed no glucosuria or proteinuria. Repeated blood tests showed normochromic normocytic anemia of hemoglobin level 9.1 g/L with elevated CRP (15.6 mg/L) and ESR (82 mm/h). A repeat autoimmune panel remained negative. Her electrocardiogram showed normal sinus rhythm, and plain chest X-ray was unremarkable.

Regarding her anemia, iron profile revealed low-normal iron with normal ferritin levels. Upper and lower gastrointestinal endoscopies showed internal hemorrhoids only. There was no menorrhagia, while her fecal occult blood tests were negative when done thrice. Her vitamin B12, folate levels, and thyroid function tests were all normal, while CRP and ESR were persistently elevated. Gallium scan was done 1.5 years after initial presentation, which showed a gallium-avid thyroid nodule at the left lobe. There was no evidence of inflammatory or infective focus elsewhere. Left hemithyroidectomy was done by private surgeon showing a non-aggressive lesion. Despite so, her inflammatory markers were still elevated after surgery. She was reluctant to perform another gallium scan.

She was then followed up in our clinic and remained asymptomatic for another 1.5 years. Subsequently she complained of two episodes of sudden visual blurring on the left side, which spontaneous resolved within one month. A clinical diagnosis of amaurosis fugax was made by our neurologist. Repeated physical examination showed new bilateral carotid bruits. There were no other bruits detected. The rest of cardiovascular and neurological examination was non-revealing with normal blood pressure and electrocardiogram.

MRA of the brain was arranged, showing diffuse narrowing of bilateral common and internal carotid arteries. Carotid Doppler ultrasound also showed diffuse wall thickening with moderate stenosis over bilateral common carotid arteries. In light of persistently raised inflammatory markers, vascular symptoms and imaging findings, a diagnosis of TAK was made.

She was then started on high-dose prednisolone. She next sought second opinion from a private doctor, and was given daily pulse methylprednisolone for 3 days and then a dose of tocilizumab (TCZ). Eventually she came back to our clinic for further follow-up. Glucocorticoid was tapered off, methotrexate was added, and TCZ was continued. On follow-up computer tomography angiograms (CTA) performed yearly, and there were no interval changes.

3 Discussion

TAK is a rare, chronic, inflammatory disease affecting large and medium-sized arteries, including the aorta and its main branches. Patients typically present at young age (< 40 years old) and are of female predominance. The prevalence of this disease is reportedly higher in Asian countries such as Japan (40 per million of population) as compared with Europe or America (ranges from 0.9 to 33 per million of population). [1, 2, 17]

4 Clinical features

Initial symptoms of TAK can be non-specific. Constitutional symptoms such as fever, malaise, lethargy, and weight loss may precede vascular symptoms. Carotidynia is uncommon but may signify carotid artery involvement in earlier stage. Vascular symptoms such as limb claudication, hypertension, absence of pulse, and vascular bruits will then set in. Eventually, ischemic or stenotic complications, such as transient ischemic attack, stroke, and acute coronary syndrome, may occur [3].

Blood tests are often non-revealing in TAK [4]. Inflammatory markers such as CRP and ESR may be raised, but these are neither specific nor sensitive. Normochromic normocytic anemia may be noted, which signifies chronic inflammation. Autoimmune panels are usually unremarkable. While ANCA positivity is associated with various small vessel vasculitis, it is not associated with TAK.

Since initial symptoms can be non-specific and vascular complications occur late in the disease course, imaging evidence of vascular involvement becomes important in making a diagnosis early. Conventional angiography was generally considered as “gold standard” in the past. However, as it is invasive and lacks the power to detect early vascular changes, it is no longer indicated as first-line imaging technique [6]. MRA and CTA are shown to have high sensitivity and specificity in supporting a diagnosis of TAK [5] and they are now advocated as the first-line imaging technique for diagnosing TAK and monitoring of vascular complications in the latest EULAR guidelines in 2018 [6].

Advancements had been made in making diagnosis in an early phase using MRA. In the black-blood sequence of MRA, normal blood appears black. In such way, enhancement of blood vessel wall and mural thickness can be better demonstrated as compared with conventional MRA. In a placebo-controlled study in 2017, this sequence was done in 35 large vessel vasculitis patients with thoracic aorta involvement [7], concentric wall thickness and contrast enhancement over diseased segments was shown significantly more frequent in patients with underlying vasculitis when comparing with healthy individuals.

Other imaging techniques such as Doppler ultrasound had been reported useful in assessing the carotid arteries. Otherwise, fluorodeoxyglucose positron emission tomography (FDG-PET) had also been supported by a Japanese study for its role at initial diagnosis and monitoring of vascular activity in various causes of vascular inflammation [8]. In this study, with a cut-off standardized uptake value (SUV) at 2.1, the sensitivity and specificity of FDG-PET was 92.6% and 91.7% respectively during active TAK using MRA or CTA as the golden standard test. Otherwise, detection of TAK by gallium scan was only supported by case reports. The Numano’s angiographic classification of TAK is described in table 1. This classification was based on the anatomical distribution of vascular involvement. It was first proposed by Ueno et al. in 1967 and was modified by Hata et al. as Numano’s criteria in 1996 [18].

Table 1

Numano’s angiographic classification of TAK

TypeDescription
1Branches from aortic arch
2aAscending aorta, aortic arch, and its branches
2bAscending aorta, aortic arch, and its branches, descending thoracic aorta
3Thoracic descending aorta, abdominal aorta +/- renal arteries
4Abdominal aorta +/- renal arteries
5Combined features of 3 and 5

5 Classification criteria and disease activity assessment

Various classification criteria had been proposed for TAK. The 1990 American College of Rheumatology criteria, as described in table 2, had a sensitivity of 90.5% and specificity of 97.9% [9]. Another classification criteria published in 1996 was an updated version of the initial 1988 Ishikawa criteria, as listed in table 3. This criteria had a sensitivity of 92.5% and specificity of 95% [10]. These criteria may not be very useful in early phase of TAK where there is no vascular stenosis.

Table 2

1990 American College of Rheumatology criteria for TAK

Age 40 years old
Limb claudication symptoms
Decreased brachial pulse
Systolic blood pressure differences over bilateral arms of > 10 mmHg
Bruits over subclavian arteries or aorta
Angiographic evidence of narrowing/ occlusion of aorta, its primary branches or large arteries in the proximal upper or lower extremities
Presence of three out of the above six criteria is classified as positive.
Table 3

1996 Sharma-Modified Ishikawa criteria for TAK

Major criteriaLeft mid-subclavian artery lesion
Right mid-subclavian artery lesion
Characteristic symptoms for > 1 month
Minor criteriaErythrocyte sedimentation rate > 20

Carotidynia
Hypertension
Aortic regurgitation or annuloaortic ectasia
Pulmonary artery lesion
Left mid-common carotid artery lesion
Distal brachiocephalic trunk lesion
Descending thoracic aorta lesion
Abdominal aorta lesion
Coronary artery lesion
A patient is classified as having high probability of TAK in the presence of two major, one major with two minor or four minor criteria.

Disease activity of TAK is commonly measured by 1994 NIH criteria, which include several parameters, namely (1) systemic features, (2) raised inflammatory markers, (3) vascular ischemic symptoms, and (4) angiographic features. New onset or worsening of any two of the above reflects active disease [11]. Otherwise, the Birmingham Vasculitis Activity Score (BVAS) was a detailed and comprehensive documentation of disease activity and damage. Nonetheless BVAS was not designed specifically for TAK. Using BVAS as a template, a simplified version called the disease-extent index for TAK (DEI-TAK) was created and used in various studies. In 2010, the Indian Takayasu Clinical Activity Score (ITAS2010) was developed. It was a further simplified activity assessment tool, which focused on clinical features developed in recent three months. It was gaining popularity among recent studies. [3,19].

6 Treatment options

Pharmacological treatment is required in alleviation of symptoms and prevention of complications. Systemic glucocorticoid therapy is given in majority of cases as initial regime. However, only around 50% of cases will

respond to glucocorticoid therapy alone. In glucocorticoid-dependent or refractory cases, various medications including methotrexate, leflunomide, and azathioprine can be added as second-line or steroid-sparing agents as supported by small open-labelled studies. Mycophenalate mofetil and cyclophosphamide are also reasonable alternatives [12]. The remission rates do not differ among these agents.

Biologic agents have also been used in treating glucocorticoid-dependent or refractory cases of TAK. Anti-TNF agents including infliximab, etanercept, and adalimumab had been evaluated in a 2014 review [13]. In 120 patients treated with anti-TNF agents, overall response rate was of 70–90%, with 50% allowed steroid tapering. Yet, 40% of them experienced a relapse, especially for those who stopped biologic agents. Further studies are needed to establish optimal treatment duration.

So far, only one randomized controlled trial had been published regarding the treatment of TAK. The TAKT trial [14] was a placebo-controlled double-blinded study published in 2018 by Japanese investigators for the use of subcutaneous TCZ in treating relapsing TAK. In this study, 36 patients who relapsed within 12 weeks after initial glucocorticoid course was assigned 1:1 into receiving TCZ or placebo in addition to glucocorticoid augmentation. After a mean follow-up duration of 19 weeks, the time to relapse in the intention-to-treat analysis was not shown statistically significant between both groups. Despite so, the use of TCZ was supported by observational studies. In a multi-center retrospective study in France [15], the treatment response rate of TCZ in TAK was up to 89% and 6-month remission rate was 80%. When compared with age- and sex-matched TAK patients who were on steroid and non-biological agents only, those treated with TCZ showed a statistically significant better 3-year vascular events-free survival. In this study with 46 subjects, seven of them were being treated with TCZ as first-line agent after glucocorticoid. There was no difference in disease activity or event-free survival between subjects who used TCZ as initial or as subsequent treatment.

Furthermore, Rituximab had also been reported in treating TAK refractory to steroid and other agents. In a recent cases series, seven patients refractory to high-dose glucocorticoid therapy and conventional immunosuppressants and/or biologics were given Rituximab [16]. Only three of them responded. Thus, the use of this agent remained second or third-line in treating TAK.

7 Local situation in Hong Kong

Regarding situation of TAK in Hong Kong, a study was done involving 78 patients identified over 10 years [17]. The estimated point-prevalence was 1.1 in a million with male to female ratio of roughly 1 to 4. The mean age of presentation was 34.2 years old, which was older as compared with Caucasian studies. The commonest presentation was hypertension (62%), followed by vascular bruits (52%) and ischemic symptoms (38%). Only 12% of patients initially presented with constitutional symptoms, which was considered a relatively frequent initial presentation in other areas. Almost all patients received glucocorticoid therapy in Hong Kong, and 28% of them required additional agents, with methotrexate and azathioprine being the commonest drug of choice.

It was notable that in our locality, systemic upset was uncommon and most patients presented with vascular symptoms or complications. Surgical intervention was needed in relatively high portion (29%) of patients. The rarity of the disease and lack of symptoms during initial stage renders early detection and suspicion of TAK by primary care physician difficult, resulting in delayed referral and treatment.

8 Conclusion

This case illustrates the importance of considering Takayasu’s arteritis as a differential in a young woman with non-specific complaints and elevated inflammatory markers. With current advancement of imaging techniques and the use of newer agents, early diagnosis and prompt treatment may allow for better prognosis for these patients.

References

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    Gornik HL Creager MA. Aortitis. Circulation 2008;117:3039–51.

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    Terao C Yoshifuji H Mimori T. Recent advances in Takayasu arteritis. Int J Rheum Dis 2014;17:238–47

    • Crossref
    • PubMed
    • Export Citation
  • [3]

    Mason JC. Takayasu arteritis - advances in diagnosis and management. Nat Rev Rheumatol. 2010 Jul;6(7):406-15

    • Crossref
    • PubMed
    • Export Citation
  • [4]

    Eichhorn J Sima D Thiele B et al. Anti-endothelial cell antibodies in Takayasu arteritis. Circulation 1996;94:2396–401

    • Crossref
    • PubMed
    • Export Citation
  • [5]

    Barra L Kanji T Malette J et al. Imaging modalities for the diagnosis and disease activity assessment of Takayasu‘s arteritis: A systematic review and meta-analysis. Autoimmun Rev. 2018 Feb;17(2):175-187

    • Crossref
    • PubMed
    • Export Citation
  • [6]

    Dejaco C Ramiro S Duftner C et al. EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice. Ann Rheum Dis. 2018 May;77(5):636-643

    • Crossref
    • PubMed
    • Export Citation
  • [7]

    Treitl KM Maurus S Sommer NN et al. 3D-black-blood 3T-MRI for the diagnosis of thoracic large vessel vasculitis: A feasibility study. Eur Radiol. 2017 May;27(5):2119-2128.

    • Crossref
    • Export Citation
  • [8]

    Tezuka D Haraguchi G Ishihara T. Role of FDG PET-CT in Takayasu arteritis: sensitive detection of recurrences. JACC Cardiovasc Imaging. 2012 Apr;5(4):422-9.

    • Crossref
    • PubMed
    • Export Citation
  • [9]

    Arend WP Michel BA Bloch DA et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990;33:1129–34

  • [10]

    Sharma BK Jain S Suri S et al. Diagnostic criteria for Takayasu arteritis. Int J Cardiol 1996;54:S127–S133

    • Crossref
    • Export Citation
  • [11]

    Kerr GS Hallahan CW Giordano J et al. Takayasu arteritis. Ann Intern Med 1994;120:919–29

    • Crossref
    • PubMed
    • Export Citation
  • [12]

    Lillian Barra GraceYang Christian Pagnoux. Non-glucocorticoid drugs for the treatment of Takayasu‘s arteritis: A systematic review and meta-analysis. Autoimmunity Reviews Volume 17 Issue 7 July 2018 683-693.

    • Crossref
    • PubMed
    • Export Citation
  • [13]

    Clifford A Hoffman GS. Recent advances in the medical management of Takayasu arteritis: an update on use of biologic therapies. Curr Opin Rheumatol. 2014 Jan;26(1):7-15

    • Crossref
    • PubMed
    • Export Citation
  • [14]

    Nakaoka Y Isobe M Takei S et al. Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised double-blind placebo-controlled phase 3 trial in Japan (the TAKT study). Ann Rheum Dis. 2018 Mar;77(3):348-354

    • Crossref
    • PubMed
    • Export Citation
  • [15]

    Mekinian A Resche-Rigon M Comarmond C. Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients. J Autoimmun. 2018 Jul;91:55-60.

    • Crossref
    • PubMed
    • Export Citation
  • [16]

    Pazzola G Muratore F Pipitone N. Rituximab therapy for Takayasu arteritis: a seven patients experience and a review of the literature. Rheumatology (Oxford). 2017 Jul 18.

  • [17]

    Wong SPY Mok CC Lau CS et al. Clinical presentation treatment and outcome of Takayasu‘s arteritis in southern Chinese: a multicenter retrospective study. Rheumatol Int. 2018 Sep 4 [Epub ahead of print]

    • PubMed
    • Export Citation
  • [18]

    Hata A Noda M Moriwaki R et al. Angiographic findings of Takayasu arteritis: new classification. Int J Cardiol. 1996 Aug;54 Suppl:S155-63.

    • PubMed
    • Export Citation
  • [19]

    Alibaz-Oner F Direskeneli H. Update on Takayasu‘s arteritis. Presse Med. 2015 Jun;44(6 Pt 2):e259-65.

    • Crossref
    • PubMed
    • Export Citation

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  • [1]

    Gornik HL Creager MA. Aortitis. Circulation 2008;117:3039–51.

  • [2]

    Terao C Yoshifuji H Mimori T. Recent advances in Takayasu arteritis. Int J Rheum Dis 2014;17:238–47

    • Crossref
    • PubMed
    • Export Citation
  • [3]

    Mason JC. Takayasu arteritis - advances in diagnosis and management. Nat Rev Rheumatol. 2010 Jul;6(7):406-15

    • Crossref
    • PubMed
    • Export Citation
  • [4]

    Eichhorn J Sima D Thiele B et al. Anti-endothelial cell antibodies in Takayasu arteritis. Circulation 1996;94:2396–401

    • Crossref
    • PubMed
    • Export Citation
  • [5]

    Barra L Kanji T Malette J et al. Imaging modalities for the diagnosis and disease activity assessment of Takayasu‘s arteritis: A systematic review and meta-analysis. Autoimmun Rev. 2018 Feb;17(2):175-187

    • Crossref
    • PubMed
    • Export Citation
  • [6]

    Dejaco C Ramiro S Duftner C et al. EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice. Ann Rheum Dis. 2018 May;77(5):636-643

    • Crossref
    • PubMed
    • Export Citation
  • [7]

    Treitl KM Maurus S Sommer NN et al. 3D-black-blood 3T-MRI for the diagnosis of thoracic large vessel vasculitis: A feasibility study. Eur Radiol. 2017 May;27(5):2119-2128.

    • Crossref
    • Export Citation
  • [8]

    Tezuka D Haraguchi G Ishihara T. Role of FDG PET-CT in Takayasu arteritis: sensitive detection of recurrences. JACC Cardiovasc Imaging. 2012 Apr;5(4):422-9.

    • Crossref
    • PubMed
    • Export Citation
  • [9]

    Arend WP Michel BA Bloch DA et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990;33:1129–34

  • [10]

    Sharma BK Jain S Suri S et al. Diagnostic criteria for Takayasu arteritis. Int J Cardiol 1996;54:S127–S133

    • Crossref
    • Export Citation
  • [11]

    Kerr GS Hallahan CW Giordano J et al. Takayasu arteritis. Ann Intern Med 1994;120:919–29

    • Crossref
    • PubMed
    • Export Citation
  • [12]

    Lillian Barra GraceYang Christian Pagnoux. Non-glucocorticoid drugs for the treatment of Takayasu‘s arteritis: A systematic review and meta-analysis. Autoimmunity Reviews Volume 17 Issue 7 July 2018 683-693.

    • Crossref
    • PubMed
    • Export Citation
  • [13]

    Clifford A Hoffman GS. Recent advances in the medical management of Takayasu arteritis: an update on use of biologic therapies. Curr Opin Rheumatol. 2014 Jan;26(1):7-15

    • Crossref
    • PubMed
    • Export Citation
  • [14]

    Nakaoka Y Isobe M Takei S et al. Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised double-blind placebo-controlled phase 3 trial in Japan (the TAKT study). Ann Rheum Dis. 2018 Mar;77(3):348-354

    • Crossref
    • PubMed
    • Export Citation
  • [15]

    Mekinian A Resche-Rigon M Comarmond C. Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients. J Autoimmun. 2018 Jul;91:55-60.

    • Crossref
    • PubMed
    • Export Citation
  • [16]

    Pazzola G Muratore F Pipitone N. Rituximab therapy for Takayasu arteritis: a seven patients experience and a review of the literature. Rheumatology (Oxford). 2017 Jul 18.

  • [17]

    Wong SPY Mok CC Lau CS et al. Clinical presentation treatment and outcome of Takayasu‘s arteritis in southern Chinese: a multicenter retrospective study. Rheumatol Int. 2018 Sep 4 [Epub ahead of print]

    • PubMed
    • Export Citation
  • [18]

    Hata A Noda M Moriwaki R et al. Angiographic findings of Takayasu arteritis: new classification. Int J Cardiol. 1996 Aug;54 Suppl:S155-63.

    • PubMed
    • Export Citation
  • [19]

    Alibaz-Oner F Direskeneli H. Update on Takayasu‘s arteritis. Presse Med. 2015 Jun;44(6 Pt 2):e259-65.

    • Crossref
    • PubMed
    • Export Citation
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