Immunobiology xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect Immunobiology journal homepage: www.elsevier.com/locate/imbio Systemic sclerosis associated with moyamoya syndrome: A case report and literature review Haifeng Chen, Xinyu Jiang, Yitian Shi, Fenghong Yuan*, Zhigang Hu* The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi Children’s Hospital, Jiangsu, China A R T I C LE I N FO A B S T R A C T Keywords: Systemic sclerosis Moyamoya syndrome Retrospective studies Clinical characteristics Literature review Systemic sclerosis (SSc) associated with moyamoya syndrome (MMS) is a clinically rare disease. To further understand the clinical characteristics of SSc associated with MMS, we investigated and analyzed one case of SSc associated with MMS and conducted a literature review about this disease. Publications retrieved from MEDLINE and Wanfang databases were reviewed and discussed, and we found five well-described cases of SSc associated with MMS. The five patients had no family history of moyamoya disease, and the risk factors (cardiovascular disease) `were found in one of the five patients. The patients included in this study were more frequently female, and they often had limited or diffuse SSc. Unilateral involvement was frequently observed with clinical symptoms including hemiplegia, headache, loss of eyesight, and aphasia. The medical treatments included corticosteroids, immunosuppressive agents, antiplatelet agents, and anticoagulant therapy. The treatment with extraintracranial revascularization was an effective treatment strategy for MMD and MMS. Unilateral MMD was more likely to be associated with SSc. The efficacy of corticosteroids and immunosuppressive agents was uncertain. 1. Introduction 2. Data and methodology Systemic sclerosis (SSc) is an autoimmune disease characterized by microangiopathy and fibroblast dysfunction. Microvascular lesion in SSc is mainly characterized by non-inflammatory vascular endothelial hyperplasia, and it is a hallmark of SSc, although there is an ongoing debate on its presence in SSc. Macrovascular involvement-associated neurological complications and cerebral vasculopathy in SSc are rare and unusual, and moyamoya disease (MMD) is a rare, chronic progressive cerebrovascular occlusive disease that is characterized by a stenosis or occlusion in the terminal internal carotid artery and the proximal portion of the anterior and/or middle cerebral arteries, leading to the development of collateral vessels, as visualized by cerebral angiography. MMD includes idiopathic moyamoya disease and secondary moyamoya disease (named moyamoya syndrome, MMS). SSc associated with MMS is rarely reported worldwide. Herein, we present one case of SSc associated with MMS and review the other five cases reported in the literature. 2.1. Case report A 52-year-old woman was admitted to our Rheumatology Ward because of Raynaud’s phenomenon in January 2016. She had a history of digital tip ulcers. The skin of her fingers was tight and thick. The results of the laboratory test are shown in Table 1. She was diagnosed with SSc according to the ACR/EULAR criteria. The patient was thus prescribed oral prednisolone (10 mg/day) and antiplatelet agents. One month later, she withdrew from prednisolone therapy. In December 2016, the patient started having Wernicke’s aphasia and severe headache. However, no other focal neurologic findings, such as blurred vision, ataxia, or hemiparesis, were observed. She was normotensive, and other vital signs were within normal ranges. She had no other medical history, including that of hypertension and diabetes, smoking and ill pregnancy, or special family history. In February 2017, she was admitted to our hospital with a one-month history of headache and aphasia. Brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) scans showed a fresh cerebral infarction in the left temporal-parietal lobe, insula, and basal ganglia, an occlusive lesion in the left middle cerebral arteries (MCA), and collateral vascular supply from the left M1 (Fig. 1a–j). ⁎ Corresponding authors at: Department of Rheumatology & Immunology and Clinical laboratory, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi Children’s Hospital, Wuxi, 214023, China. E-mail addresses: yfh222222@163.com (F. Yuan), jswxhzg@163.com (Z. Hu). https://doi.org/10.1016/j.imbio.2019.11.017 Received 22 April 2019; Accepted 26 November 2019 0171-2985/ © 2019 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). Please cite this article as: Haifeng Chen, et al., Immunobiology, https://doi.org/10.1016/j.imbio.2019.11.017 Immunobiology xxx (xxxx) xxx–xxx H. Chen, et al. described cases of SSc associated with MMS. The five cases are detailed in Tables 2 and 3. Table 1 Clinical parameters of the patient at different time points. Variables 3 WBC (cells/mm ) Hemoglobin (g/dl) PLT (cells/mm3) ESR (mm/h) ANA Anti-ENAs RF ACL Echocardiography Lung CT Carotid artery ultrasound At admission in January 2016 At admission in February 2017 One month later 5900 11.8 183.0 9 1:160 ACA (+) Negative Negative Negative Negative Negative 5500 12.2 172.0 10 1:160 ACA (+) Negative Negative Negative Negative Negative 4300 10.2 133.0 18 ND ND ND ND ND ND ND 3. Discussion MMD, a rare chronic vasculopathy, usually affects the internal carotid and upstream arteries of the circle of Willis. Typical collateral circulation can be observed in imaging studies as “something hazy,” termed moyamoya in Japanese. The morbidity of moyamoya disease is low. Cerebral angiography is the standard method for the diagnosis of moyamoya disease and MMS. CTA or MRA can reveal abnormal findings, which are consistent with those by cerebral angiography, and may thus serve as an effective alternative. Because of the popularization of cerebrovascular non-invasive examination techniques such as CTA and MRA, the detectable rate of moyamoya disease has increased. This disease, firstly discovered in Japan in 1957, is mostly found in the yellow race. The highest incidence is observed in the Japanese population, followed by the Chinese and South Korean population. The proportion of males to females suffering from moyamoya disease is 1:1.8 to 1.9 in Japan and Korea (Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis and Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases, 2012; Ahn et al., 2014), but the proportion reported in China is 1:1.0–1.1 (Duan et al., 2012; Tang et al., 2017). The disease has a certain degree of family aggregation, and genetic factors may thus be involved. The proportion of Japanese patients with positive family history is about 10 %, and the proportion of family patients in China is 7.8 % (Zhang et al., 2016)· Although the exact pathophysiologic mechanism has not yet been elucidated, vessel occlusion in moyamoya disease may result from a combination of hyperplasia of smooth muscle cells and luminal thrombosis. The media are often attenuated with the irregular elastic lamina. Caspase-dependent apoptosis has been proposed as a contributory mechanism in the associated degradation of the arterial wall (Scott and Smith, 2009). Moyamoya disease associated with more than one underlying disease is called MMS. The underlying diseases or pathogenic factors are extensive, including autoimmune diseases (systemic lupus erythematosus, antiphospholipid antibody syndrome, nodular polyarteritis, and Sjogren syndrome). Few studies have examined the autoimmune disease combined with MMS; no more than 20 cases have ND: not detected; WBC: white blood cells; PLT: platelet; ESR: erythrocyte sedimentation rate; ANA: antinuclear Antibody; ENAs: extractable nuclear antigens; ACA: anti-cardiolipin antibodies; RF: rheumatoid factor; CT: computed tomography. Subsequently, whole-body MRA (WBMRA) was performed for further evaluation of this abnormal vasculature. The WBMRA result was similar to that of brain MRA. Thus, she was diagnosed with MMS. Methylprednisolone was administered at a dose of 40 mg per day for 5 days, and the dose was then reduced to 20 mg per day. She was also treated with antiplatelet, statin, and neuroprotective therapy. One month later, her headache was relieved, and her hearing, comprehension, and communication abilities were recovered. Informed consent was obtained from the patients prior to study participation. Wuxi People's Hospital Clinical New Technology and Research Ethics Committee approved this study (No.: kyl2016001). 2.2. Literature review We searched PubMed and Wanfang database from 1977 to July 2017 with the keywords including “moyamoya disease,” “moyamoya syndrome,” “systemic sclerosis,” “Scleroderma,” and “CREST Syndrome.” We also searched references in the articles found in the primary search to obtain pertinent articles. We found five well- Fig. 1. A 52-year-old woman with moyamoya syndrome and systemic sclerosis. (a) Axial T1-weighted MR image shows a large low-signal-intensity region in the left MCA territory, including the left temporal occipital lobes and the left insula. (b) Axial T2-weighted, (c) axial FLAIR, and (d) DWI images show hyperintensity. (e) Dark ADC map is consistent with reduced diffusivity. (f, g, h, i, and j) Axial different oblique MIP from a time of flight MRI angiogram shows occlusion in the left MCA. The responsible vessels in the left temporal occipital lobes and the left insula acute cerebral infarction were caused by the left middle cerebral artery occlusion; the left internal carotid artery was more delicate than the right one; and the distal left ICA was narrow. There is some collateral circulation (yellow arrow of g and h) around proximal segments of the left MCA.MR: magnetic resonance; MCA: middle cerebral artery; FLAIR: fluid-attenuated inversion recovery; DWI: diffusionweighted imaging; ADC: apparent diffusion coefficient; ICA: internal carotid artery (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article). 2 Past medical history for SSc 3 well controlled MMS Cerebrospinal fluid Therapy Prognosis MMS remission MRA/DSA: Left MCA occlusion, collateralization from the PCA and left external cerebral artery ND Somatic treatment Severe dizziness and headache No ND Cognitive impairment, vision loss, and left paresthesias MRA/DSA: right ICA stenosis with abnormal vascular network and right ACA and MCA stenosis ND Etanercept Methotrexate ND 4 (Wegner et al., 2016) No 54/F On admission Limited Raynaud's phenomenon (−), right hand, and digit swelling ANA (+) Anti-Scl-70 (+) 5 (Ahmad et al., 2018) MRA/DSA: Left MCA occlusion and bilateral ICA stenosis with prominent lenticulostriates ND Tissue plasminogen activator, antiplatelet, statin, and anti-hypertensive ND diabetes, hypertension, hyperlipidemia, and previous ischemic stroke Right hemiparesis and dysarthria 5 (Ahmad et al., 2018) arthritis, pulmonary fibrosis, and thickened skin ANA 1:2560 (+) Anti-topoisomerase (+) No 62/F On admission Diffuse Raynaud's phenomenon (−), 4 (Wegner et al., 2016) MMS: moyamoya syndrome; TIA: transient ischemic attack; MCA: middle cerebral arteries; PCA: posterior cerebral arteries; IC: internal carotids; CTX: cyclophosphamide; CTA: computed tomography angiography; MRA: magnetic resonance angiography; DSA: Digital subtraction angiography. CTA: Bilateral MCA stenosis with a right abnormal vascular network Negative Prednisolone Ciclosporin A Focal seizures, poor speech output, and decreasing vision MRA: Bilateral ICA stenosis and collateralization of the anterior circulation from the vertebral and basilar arteries ND Prednisolone 15 mg/d and CTX500 mg/m, phenytoin Improved hemiparesis and vision and worsening finger contractures TIA Images No No Cardiovascular risk factors Neurological signs 2 (Das et al., 2002) 1 (Terajima et al., 2001) Case Table 3 Clinical data of MMS. D-penicillamine and methylprednisolone xerostomia, arthritic pain, and thickened skin of the forearm ANA (+) Anti-Scl-70 (+) 48/F One year ago Limited Raynaud's phenomenon (+), 3 (Choi et al., 2012) 3 (Choi et al., 2012) No Autoantibody SSc: Systemic sclerosis; Scl-70: topoisomerase 1. fever, digital tip ulcers, and thickened skin ANA (+++) sclerodactyly, subcutaneous calcinosis, and thickened skin of the face ANA 1:1280 (+), ACA > 100 times normal Dexamethasone and cyclophosphamide 19/F Two years ago Diffuse Raynaud's phenomenon (−), 56/F On admission CREST Syndrome Raynaud's phenomenon (+), Age/sex diagnosis date Clinical types Signs /symptoms 2 (Das et al., 2002) 1 (Terajima et al., 2001) Case Table 2 Clinical features of the five SSc patients. H. Chen, et al. Immunobiology xxx (xxxx) xxx–xxx Immunobiology xxx (xxxx) xxx–xxx H. Chen, et al. with MMS is not clear, and multiple mechanisms, including vasculitis and endothelial hyperplasia, may be implicated in the pathogenesis. For patients with SSc with severe peripheral vascular disease, it is important to be aware of the possibility of cerebrovascular disease, and early cranial MRA screening is necessary. The efficacy of glucocorticoid, immunosuppressive, anticoagulant, or antithrombotic therapy for SSc combined with MMS is unclear. The clinical manifestations of moyamoya disease are progressive. Therefore, SSc combined with MMS should be followed up carefully. been reported, and all of them are from case reports. There are only 2 studies in China (Xue, 2006; Zhou and An, 2008). In this study, all the six cases were female, indicating a high incidence of SSc and moyamoya disease in females. The six patients had no family history of moyamoya disease, and the findings are different from those obtained from patients with idiopathic moyamoya disease. SSc is characterized by lumen stenosis occlusion induced by microvascular disease, intimal hyperplasia fibrosis, vascular destruction, and hyperplasia. However, whether SSc patients have macrovascular lesions remains unclear. Limited or diffuse SSc has been reported. Patients with SSc show a significant reduction in blood flow in the radial and ulnar arteries, as demonstrated by dual-energy ultrasound and angiography (Frerix et al., 2012). Doutrelon et al. demonstrated abnormal aorta and limb arteries in patients with SSc, such as hemodynamics, thickening of the vascular wall, and arterial occlusion (Doutrelon et al., 2016). Wegner et al. showed a case of moyamoya disease 18 years before SSc diagnosis (Wegner et al., 2016), suggesting that cerebrovascular moyamoya may be the first manifestations of SSc. However, moyamoya disease also occurs after the diagnosis of SSc, suggesting that SSc vascular lesions can trigger the pathogenesis of moyamoya disease (Terajima et al., 2001; Choi et al., 2012). One type of MMS is associated with intracranial atherosclerosis. In recent years, the relationship between SSc and arteriosclerosis has been a research hotspot. The risk of atherosclerosis is significantly higher in SSc patients than in healthy controls (Schiopu et al., 2014). The carotid intimamedia thickness is significantly increased in patients with SSc compared with those with other connective tissue diseases (CTD) or healthy controls, as demonstrated by two-dimensional ultrasound and color Doppler studies (Ciccone et al., 2015). However, cardiovascular risk factors, including diabetes, hypertension, hyperlipidemia, and previous ischemic stroke, were only found in one of the five reviewed cases. In our case, no atherosclerotic plaque was observed in the neck vascular color Doppler ultrasound scan; therefore, that type of MMS can be ruled out. Two in six cases had typical bilateral lesions of moyamoya disease. Studies also showed (Chen et al., 2016) a higher prevalence of unilateral vascular lesions in CTD patients with moyamoya disease. Unilateral vascular involvement of moyamoya disease may be more common in autoimmune diseases. Unilateral and bilateral vasculopathies of Moyamoya disease might have a different pathogenesis. Cerebral ischemia and intracranial hemorrhage are two major risk factors for this disease. The patients with cerebral ischemia had headache, which was obstinate and irresponsive to anesthetic medication. All cases reported had cerebral ischemia, with hemiplegia, headaches, decreased vision, and language barriers. To date, no definitive and effective drugs are available for moyamoya disease. Vasodilators, anti-platelet aggregation drugs, and anticoagulants may be beneficial for chronic ischemic moyamoya disease or MMS. However, long-term use of antiplatelet drugs may lead to the transformation from ischemic to hemorrhagic types. The immunosuppressive therapy is effective in (Systemic Lupus Erythematosus) SLE immune activity in systemic lupus erythematosus combined with MMS, but the efficacy of immunosuppressor in MMS is still unclear (Wang et al., 2013). In the five reviewed cases, two cases (Terajima et al., 2001; Das et al., 2002) were improved after the treatment with glucocorticoids and immunosuppressor, and one (Choi et al., 2012) only showed symptomatic improvement. The present patient in our study was treated with glucocorticoids and symptomatic therapy, and her symptoms improved. The inflammatory markers in the present patient were normal, suggesting that vascular lesions, rather than acute vasculitis, may be involved in the pathogenesis. We treated the SSc patient with anti-platelet drugs for the vascular disease, as well as the moderate dose of glucocorticoid for primary disease. Subsequently, her symptoms were gradually improved. 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