REVIEW URRENT C OPINION
Diverse vascular lesions in systemic lupus erythematosus and clinical implications Ying Tan a,b,c,d,, Feng Yu a,b,c,d,, and Gang Liu a,b,c,d
Purpose of review Vascular injury is one of the typical symptoms of systemic lupus erythematosus (SLE), and may play a key role in the choice of treatment strategy and prediction of prognosis. In this review, diverse vascular lesions in SLE and their clinical significance are discussed. Recent findings The clinical features of vascular disease in SLE differ from organ to organ, and may be extreme with regard to renal vascular lesions. Vascular lesions in SLE may be of inflammatory or thrombotic origin, and immune system dysfunction is considered to be a predominant feature. Numerous lines of evidence suggest that the activation and injury of endothelial cells might play a key role in the pathogenesis. Summary Vascular lesions in SLE are mediated by a complex interaction between the immune system and other contributing factors. Different therapies developed for vascular lesions, both immunosuppressive and nonimmunosuppressive, should be selected based on the different clinical and pathological characteristics, and our future understanding of the different mechanisms involved. Keywords atherosclerosis, endothelial cells, systemic lupus erythematosus, thrombosis, vascular lesions
INTRODUCTION Vascular injury is one of the typical clinical features of systemic lupus erythematosus (SLE), which is considered to be a substantial contributor to morbidity and mortality. Previous studies showed that vascular events occurred in 26% of SLE patients during long-term follow-up and were predominantly because of atherothrombotic disease. Appel et al. [1] and D’Agati [2] provided a pathological classification for lupus vascular lesions (Table 1), whereas other clinical syndromes also included venous thrombosis, antiphospholipid syndrome (APS), atherosclerosis, etc. Vascular lesions in SLE may be of inflammatory or thrombotic origin [3], including cutaneous and visceral injuries, which might act as a key factor in the choice of treatment strategy and the prognosis [4 ]. Their clinical signs varied from organ to organ, with small-sized and medium-sized vessels mainly involved. Thus, the clinical manifestations, pathogenesis, and implications of vascular lesions in SLE are of great clinical significance, although there is still a lack of general agreement concerning the choice of therapeutic intervention because of the clinical and pathologenic complexity. In this review, diverse vascular &
www.co-nephrolhypertens.com
lesions in SLE are described, and the most recent hypothesis regarding the associated pathogenesis further discussed.
CLINICAL FEATURES OF VASCULAR LESIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS Vascular lesions in SLE include cutaneous and visceral injuries. Visceral vascular lesions can be life-threatening, and mostly involve the nervous
a
Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, cKey Laboratory of Renal Disease, Ministry of Health of China and dKey Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, PR China b
Correspondence to Gang Liu, MD, Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, PR China. Tel: +86 10 66551736; fax: +86 10 66551055; e-mail: liugang2003@ medmail.com.cn
Ying Tan and Feng Yu contributed equally to the writing of this article.
Curr Opin Nephrol Hypertens 2014, 23:218–223 DOI:10.1097/01.mnh.0000444812.65002.cb Volume 23 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Vascular lesions in systemic lupus erythematosus Tan et al.
KEY POINTS
likelihood of treatment with prednisone, cyclophosphamide, or hydroxychloroquine, contributed to accelerated atherosclerosis [8 ]. Coronary artery vasculitis was rarely reported in the literature, but aneurysms of coronary arteries may result from vasculitis. Interestingly, coronary aneurysm or coronary arteritis was found in some cases despite well controlled SLE activity [9]. &
Clinical features of vascular diseases of SLE differ from organ to organ. Renal vascular lesions appear to be an extreme form of vascular lesions in SLE. Activation and injury of endothelial cells might play a key role in the pathogenesis of vascular lesions in SLE. Different therapies developed for vascular lesions in SLE should be selected based on the different clinical and pathological characteristics and our future understanding of the different mechanisms involved.
system, coronary vascular system, and renal vascular system.
Nervous system involvement Neuropsychiatric SLE was mostly thought to be closely associated with vascular injury in the nervous system based on most histopathological studies [5]. Headache, cognitive dysfunction, acute confusion state, movement disorders, myelopathy, and psychiatric disorders are the common features of neuropsychiatric SLE. Ischemic stroke and transient ischemic attack account for over 80% of cerebrovascular disease cases. The European League Against Rheumatism (EULAR) group found that general SLE activity or damage, past or concurrent neuropsychiatric SLE, and persistently positive antiphospholipid antibodies in moderate-to-high titers were the most significant predictors for neuropsychiatric SLE [6]. Peripheral neuropathy occurs in 14% of SLE patients, and seems to be less frequent than central nervous system neuropathy [7]. Peripheral polyneuropathy and mononeuritis multiplex are the most common forms.
Coronary vascular involvement Coronary artery disease in SLE includes premature atherosclerosis, thrombosis, embolization, spasm, and vasculitis. Premature atherosclerosis is the most common cause of coronary artery disease in SLE patients, with a prevalence of 6–10%. Recent studies have indicated that autoimmunity, including high disease activity, longer disease duration, higher levels of SLE-associated damage, measurable levels of proinflammatory high-density lipoprotein (HDL), increased oxidative stress, high levels of homocysteine, adipose-derived hormone, and lower
Renal vascular lesions Vascular lesions are common in lupus nephritis. The renal vascular lesions in SLE include a series of features listed in Table 1. Renal vascular lesions consist of various types and more attention should be paid to these lesions and their adverse effects on the prognosis of the renal disease. The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) pathologic classifications of lupus nephritis specified the importance of vascular damage and indicated that these should be included in the summary diagnostic line [10]. The data from Peking University First Hospital showed that among 341 patients with pathologically diagnosed lupus nephritis, 279 patients (81.8%) with renal vascular lesions were identified and classified as following: 253 with vascular immune complex deposits (ICDs; 74.2%, 149 with uncomplicated vascular immune complexes), 82 with arteriosclerosis (24.0%), 60 with thrombotic microangiopathy (TMA; 17.6%), 13 with noninflammatory necrotic vasculopathy (NNV; 3.8%), and only 2 with true vasculitis (0.6%) [4 ]. A total of 105 patients (37.6%) presented with more than two types of vascular lesions. More importantly, the presence of vascular lesions was positively correlated with activity indices and chronicity indices, and the scores of renal vascular lesions were risk factors for renal outcome in the survival analysis [4 ]. The most common renal vascular lesion was vascular ICD. Our study also found that patients with vascular ICD presented with more active characteristics of renal disease compared with patients without this feature, and the renal outcome in the uncomplicated ICDs group was much poorer than other types, except for those with TMA, which had been thought to be clinically silent [1,2,4 ]. The pathogenesis of ICD in lupus nephritis is not yet clear. We found that the majority of cases had C1q (87%) and nearly half had IgG deposition (44.1%). Our further research showed that serum anti-C1q autoantibodies were closely associated with serum levels of C1q and glomerular deposition of C1q [11]. However, the intensity of glomerular C1q deposition was not associated with the intensity of vascular C1q deposition. The findings supported
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
&
www.co-nephrolhypertens.com
219
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal immunology and pathology Table 1. Pathological classification and descriptions of vascular lesions in lupus nephritis Pathological classification
Descriptions
Uncomplicated vascular immune complex deposits
On light microscopy, the extraglomerular arteries and arterioles with immune complex deposition usually appear normal, without thrombosis, necrosis, and inflammatory infiltration of the blood vessel walls. On immunofluorescence microscopy, the deposits may contain IgG, IgA, or IgM and various complement components. On electron microscopy, the granular electron-dense deposits were most commonly seen to be located beneath the vascular endothelium or within the basement membranes surrounding the medial myocytes.
Noninflammatory necrotic vasculopathy
On light microscopy, smudgy eosinophilic, fuchsinophilic material that stains focally positive for fibrin is seen to occupy the lumen and intima of arteries and arterioles, with frequent extension into the media. The endothelium is usually swollen or denuded, with occasional pyknotic nuclear fragments and smudgy degeneration of the medial myocytes. The elastic membrane of the interlobular arteries is usually disrupted, but there is no inflammatory infiltrate. On immunofluorescence microscopy, various staining patterns for IgG, IgM, IgA, complement components, and fibrin-related antigens are seen to be present in the blood vessel walls, extending to the lumen. Electron microscopy revealed massive confluent intraluminal and mural deposits of granular electron-dense material, with concomitant immune deposits, sometimes associated with tactoids of fibrillar fibrin and platelets.
Thrombotic microangiopathy
In the acute phase, there is marked luminal narrowing or total occlusion by intraluminal, subendothelial, or medial accumulation of eosinophilic, fuchsinophilic material with staining properties of fibrin, invariably associated with endothelial swelling, denudation, and sometimes fragmented and hemolyzed erythrocytes. Immunofluorescence microscopy and electron microscopy revealed an absence of discrete immune deposits. In the chronic phase, mucoid edema of the intima and the ‘‘onion skin’’ type of intimal fibroplasia may occur.
True vasculitis
On light microscopy, prominent inflammatory cell infiltration of the arterial wall by neutrophils and mononuclear leukocytes can be seen. This mural inflammation is accompanied in the acute phase by fibrinoid necrosis, usually most severe in the intima and to a lesser extent in the media. In some biopsies, rupture of the elastic lamellae is seen. On immunofluorescence microscopy, there is evidence of fibrin-related antigens sometimes associated with less intense staining for immunoglobulin and complement fractions.
Arteriosclerosis and arteriolosclerosis
This lesion was defined as fibrous thickening of the intima without necrosis, proliferation, or thrombosis. &
Adapted with permission [2,4 ]. Adaptations are themselves works protected by copyright. In order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
the hypothesis based on animal studies showing that anti-C1q autoantibodies deposited in glomeruli are only pathogenic in combination with glomerular C1q-containing immune complexes [12]. Although NNV is less common than ICD, it might have significant scientific implications for the following reasons: NNV was always combined with other renal vascular lesions, which might have contributed to the fact that this group presented with more severe clinical and pathological status; NNV might be a transition form from ICD to other severe vascular lesions; and most NNV is always combined with active proliferative lupus nephritis, and abundant ICDs in vascular walls consisted of immunoglobulins and complements, which strongly supports the roles of immunologic factors in the development of the lesion [1,4 ]. Another important vascular lesion was TMA, which presented with the most severe renal injury features and the poorest renal outcome. In fact, TMA in lupus nephritis consists of a group of diseases, including APS, thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP–HUS), scleroderma, malignant hypertension, etc. Our &
220
www.co-nephrolhypertens.com
study highlights the important status of complement overactivation via both classical and alternative pathways in the pathogenesis of renal lupus TMA [4 ,13 ], which is consistent with the previous reports [14,15]. Moreover, our study showed that serum ADAMTS-13 activity was significantly lower in patients with both lupus nephritis and TTP–HUS than in those with lupus nephritis (40 versus 69%, P ¼ 0.012), and the prevalence of ADAMTS-13 autoantibodies was significantly higher in the former group (86 versus 18%, P < 0.001). These findings suggest that ADAMTS-13 autoantibodies might play an important role in the pathogenesis of TTP–HUS associated with lupus nephritis [16]. The mechanism of renal arteriosclerosis is not yet clear. One interesting finding in our study (unpublished data) was that 70.7% of renal arteriosclerosis patients had combined ICD vascular lesions. More importantly, renal immunohistochemistry examination identified that arteriosclerosis and ICDs co-localized in the renal vessels of most patients. The arteriosclerosis scores were significantly higher in the group with combined arteriosclerosis and ICDs than that in pure &
&
Volume 23 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Vascular lesions in systemic lupus erythematosus Tan et al.
arteriosclerosis patients. Patients in the combination group presented with more severe renal injury and poorer renal outcomes compared with pure arteriosclerosis and no renal vascular injury group, although the levels of serum lipids were not significantly different. These findings support the hypothesis that renal ICD, rather than the traditional risk factors, might be associated with and contribute to the formation of renal arteriosclerosis in lupus nephritis [17,18,19 ]. On further analysis, we found that patients with combined renal arteriosclerosis and ICDs also presented with the worst cardiac structure and function, including the largest left atrium diameter, left ventricular enddiastolic diameter, left ventricular posterior wall thickness, and the highest pulmonary arterial systolic pressure. The scores of renal arteriosclerosis were positively correlated with left atrium diameter, interventricular septum, and left ventricular posterior wall thickness. Thus, renal arteriosclerosis might predict potent cardiovascular and renal risk in lupus nephritis patients combined with classical factors, and this needs further investigation. &&
Others Cutaneous lesions were the main clinical presentation of vascular lesions in SLE, making up 80–94% of the total cases [20]. Other organs, including the gastrointestinal tract [21], lung [22], and large vessels, can also be involved in SLE vascular injury.
PATHOGENESIS OF VASCULAR LESIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS Vascular lesions in SLE may be of inflammatory or thrombotic origin [3], and may appear alone or coexist in a patient. Atherosclerosis is also considered to be an inflammatory disease. The dysfunction of the immune system is considered to be the predominant feature of this disease. Numerous lines of evidence suggested that the activation and injury of endothelial cells might play a key role in the pathogenesis of vascular lesions in SLE. Endothelial dysfunction represents a state of deviation from normal to a vasoconstrictive, procoagulant, platelet-activating, and antifibrinolytic state. However, the precise mechanism of these diseases has not been fully elucidated. The most recent theory and hypothesis will be discussed in the following sections.
Vascular inflammation One well-accepted hypothesis for vascular lesions in SLE is that local deposition of immune complexes onto the vascular endothelium triggers an
inflammatory response involving activation of the complement cascade, possibly with the formation of C5b-9 membrane complement attack (MAC), and thus finally destroys the vascular basal membranes and inflammatory cell infiltrates. A recent study suggested that immune complex elicited proinflammatory responses in human endothelial cells and altered their function involving cellular signaling via the high-mobility group box 1 protein (HMGB1)–receptor for advanced glycation end products (RAGE) axis [23]. Briefly, immune complexes upregulated the cell-surface expression of RAGE, the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), increased the secretion of chemokines such as interleukin 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), the proinflammatory cytokines IL-6, and tumor necrosis factor-a (TNF-a), and also promoted the activation of the transcription factor NF-kB p65 in human endothelial cells. Various autoantibodies, such as antiendothelial cell antibodies (AECAs) [24], antiphospholipid antibodies, antidouble-stranded DNA antibodies, antioxLDL antibodies, and antiapolipoprotein A-I antibodies [25], could directly or indirectly affect the endothelial cells and cause chronic vessel wall damage as circulating or local immune complexes, and might contribute to the pathogenesis of atherosclerosis by causing injury to the endothelium and altering the metabolism of lipoproteins involved in atherogenesis. In addition to immune complexes and autoantibodies, the exposure of healthy endothelial cells to some cytokines, such as type I interferon (IFN) or TNF-a, from patients who had active SLE could result in the expression of nitric oxide synthase 2 and the generation of nitric oxide and adhesion molecules, and could also lead to the activation of the complement cascade. Furthermore, in-vitro and in-vivo studies have both shown that type I IFN could play a crucial role in cardiovascular disease development in SLE [26]. IFN leads to an imbalance of vascular damage and repair by inducing endothelial cell and endothelial progenitor cell (EPC) apoptosis, preventing the differentiation of EPCs and circulating angiogenic cells to mature endothelial cells, and by inducing transcriptional repression of angiogenic factors [27] through suppression of IL-1b pathways and upregulation of the inflammasome machinery and potentiation of IL-18 activation [28]. Moreover, IFN-a promoted the conversion of circulating angiogenic cells to dendritic cells. Meanwhile, IFN-a has the capacity to enhance foam cell formation [29] and activate platelets through changes in the megakaryocyte
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-nephrolhypertens.com
221
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal immunology and pathology
transcriptome [30]. Immunohistochemistry of renal biopsies from patients with lupus nephritis confirmed that IFN-a promoted an antiangiogenic signature through repression of vascular endothelial growth factor (VEGF)-A and induction of IL-1R antagonist, which correlated with decreased renal vascular density and vascular rarefaction [27]. IFN-b may promote atherosclerosis by promoting macrophage recruitment to arteries [31]. IFN-g is the prototypical TH1 cytokine, which could promote plaque instability by reducing collagen production and inhibiting the growth of smooth muscle cells and endothelial cells. IFN-g could also promote foam cell formation and plaque rupture [32]. The findings indicate that type I IFN could promote atherosclerosis and loss of renal function, and supported the use of therapeutic intervention blocking IFN-a in patients at high cardiovascular risk. In addition, endothelial cells were shed into the circulation, and membrane endothelial protein C receptor (EPCR) was lost. EPCR appears in the circulation in a soluble form (sEPCR), which could induce a procoagulant effect. Prothrombin fragment F1þ2 (a marker of thrombin generation) was generated, which was indirectly responsible for the release of sEPCR. The increased release of sEPCR coupled with higher thrombin generation indicated that less membrane-bound EPCR would be available in these individuals for efficient protein C activation [33].
b2GPI and thrombin might play a role in glomerular microthrombosis. SLE patients with these factors had more severe renal tissue injuries and poorer renal function than those without them. A large prospective study suggested that antiphospholipid antibody positivity during young adulthood was a risk factor for subsequent subclinical atherosclerosis and might play a role in the pathogenesis of atherosclerosis in SLE [37 ]. Moreover, the presence of antiphospholipid antibodies was associated with the HLA-DRB104 and HLA-DRB113 alleles, which were also associated with vascular events in SLE [38 ]. In brief, vascular lesions in SLE are mediated by a complex interaction between the immune system and other factors. The close associations between inflammatory cells, mediators, humoral activators, and endothelial injury, with subsequent alteration of endothelial adhesiveness and permeability to leukocytes and platelets, is key in the development of vascular injuries in SLE. Unfortunately, general agreements are still lacking regarding therapeutic approaches as a result of the clinical and pathologenic complexity of SLE vascular diseases. Corticosteroids are still considered to be the first-line medication in the treatment of vascular lesions of SLE, alone or in combination with other immunosuppressants. Use of nonimmunosuppressive therapies, such as smoking cessation, glycemic control, angiotensin-converting enzyme inhibitors, and statins use, was recommended for modifying the cardiovascular risk factors [39 ]. Treatment with plasmapheresis or plasma infusion is suggested for some special vascular lesions, such as TMA with ADAMTS-13 autoantibodies or low ADAMTS-13 activity [16]. However, the absence of clear causes limits the rational choice of therapy strategies. Thus, further explorations are warranted. &
&
&
Thrombotic noninflammatory vascular lesions The other category of vascular lesions is thrombotic injury in SLE. Mostly, antiphospholipid antibodies are considered to play a significant role in the development of the hypercoagulable state in SLE. Antiphospholipid antibodies are a heterogeneous group of antibodies directed against negatively charged phospholipids, phospholipid-binding proteins, and phospholipid–protein complexes with an estimated positivity in SLE ranging from 20 to 70%. Previous studies regarding the role of antiphospholipid antibodies in the development of vascular endothelial damage, arterial and venous thrombosis, proliferative heart valve lesions, and atherosclerosis in SLE suggested that they could induce proinflammatory, proadhesive, and procoagulant disorders. Recently, several studies have suggested that IgA antib2 glycoprotein I (b2GPI) is the most prevalent isotype in SLE, with a significant association with thrombotic events [34] and an increased prevalence of morbidities involving organs of mucosal immunity [35]. Zheng et al. [36] found that the lupus anticoagulant and antibodies against 222
www.co-nephrolhypertens.com
CONCLUSION Vascular lesions in SLE have various clinical features and pathogenesis. The evaluation of vascular lesions in the various involved organs, especially in the kidneys, is therefore important. The activation and dysfunction of endothelial cells, and the contribution of immune system dysfunction in the pathogenesis of vascular lesions in SLE, are the key important mechanisms to consider. Different therapies developed for vascular lesions in SLE, both immunosuppressive and nonimmunosuppressive, should be selected based on the different clinical and pathological characteristics. Additional therapies may emerge based on the understanding of different mechanisms in the future. Further investigation is required to gain new insights on several Volume 23 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Vascular lesions in systemic lupus erythematosus Tan et al.
still-unsolved issues regarding the physiopathological and therapeutic relevance of vascular lesions in SLE in the field of translational medicine. Acknowledgements None. Conflicts of interest There are no conflicts of interest. This work was supported by the grants of Chinese 973 project (No. 2012CB517700) and National Natural Science Foundation of China (No. 81100497).
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Appel GB, Pirani CL, D’Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol 1994; 4:1499–1515. 2. D’Agati VD. Renal disease in systemic lupus erythematosus, mixed connective tissue disease, Sjogren’s syndrome, and rheumatoid arthritis. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, editors. Heptinstall’s pathology of the kidney, 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. ; p. 530. 3. D’Cruz D. Vasculitis in systemic lupus erythematosus. Lupus 1998; 7:270– 274. 4. Wu LH, Yu F, Tan Y, et al. Inclusion of renal vascular lesions in the 2003 ISN/ & RPS system for classifying lupus nephritis improves renal outcome predictions. Kidney Int 2013; 83:715–723. This article focuses on the evaluation of different renal vascular lesions in lupus and suggests that renal vascular lesions could predict renal outcome. 5. Postal M, Costallat LT, Appenzeller S. Neuropsychiatric manifestations in systemic lupus erythematosus: epidemiology, pathophysiology and management. CNS Drugs 2011; 25:721–736. 6. Bertsias GK, Ioannidis JP, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 2010; 69:2074–2082. 7. Florica B, Aghdassi E, Su J, et al. Peripheral neuropathy in patients with systemic lupus erythematosus. Semin Arthritis Rheum 2011; 41:203–211. 8. Skaggs BJ, Hahn BH, McMahon M. Accelerated atherosclerosis in patients & with SLE – mechanisms and management. Nat Rev Rheumatol 2012; 8:214–223. An updated review of the pathogenesis and treatment of premature atherosclerosis in patients with SLE. 9. Suzuki H, Fujigaki Y, Mori M, et al. Giant coronary aneurysm in a patient with systemic lupus erythematosus. Intern Med 2009; 48:1407–1412. 10. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004; 65:521–530. 11. Tan Y, Song D, Wu LH, et al. Serum levels and renal deposition of C1q complement component and its antibodies reflect disease activity of lupus nephritis. BMC Nephrol 2013; 14:63. 12. Trouw LA, Groeneveld TW, Seelen MA, et al. Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest 2004; 114:679– 688. 13. Song D, Wu LH, Wang FM, et al. The spectrum of renal thrombotic micro& angiopathy in lupus nephritis. Arthritis Res Ther 2013; 15:R12. Evidence is provided on complement involvement in the pathogenesis of renal TMA in lupus nephritis. 14. Matheu MP, Beeton C, Parker I, et al. Imaging effector memory T cells in the ear after induction of adoptive DTH. J Vis Exp 2008; 18:907. 15. Shen Y, Chen XW, Sun CY, et al. Association between antibeta2 glycoprotein I antibodies and renal glomerular C4d deposition in lupus nephritis patients with glomerular microthrombosis: a prospective study of 155 cases. Lupus 2010; 19:1195–1203.
16. Yu F, Tan Y, Zhao MH. Lupus nephritis combined with renal injury due to thrombotic thrombocytopaenic purpura–haemolytic uraemic syndrome. Nephrol Dial Transplant 2010; 25:145–152. 17. Walport MJ. Complement. First of two parts. N Engl J Med 2001; 344:1058– 1066. 18. Walport MJ. Complement. Second of two parts. N Engl J Med 2001; 344:1140–1144. 19. Lewis MJ, Malik TH, Fossati-Jimack L, et al. Distinct roles for complement in && glomerulonephritis and atherosclerosis revealed in mice with a combination of lupus and hyperlipidemia. Arthritis Rheum 2012; 64:2707–2718. This animal study addresses the hypothesis that immune complex formation and systemic complement depletion are closely associated with accelerated atherosclerosis and renal inflammation in SLE. 20. Ramos-Casals M, Nardi N, Lagrutta M, et al. Vasculitis in systemic lupus erythematosus: prevalence and clinical characteristics in 670 patients. Medicine (Baltimore) 2006; 85:95–104. 21. Ebert EC, Hagspiel KD. Gastrointestinal and hepatic manifestations of systemic lupus erythematosus. J Clin Gastroenterol 2011; 45:436–441. 22. Torre O, Harari S. Pleural and pulmonary involvement in systemic lupus erythematosus. Presse Med 2011; 40:e19–e29. 23. Sun W, Jiao Y, Cui B, et al. Immune complexes activate human endothelium involving the cell-signaling HMGB1–RAGE axis in the pathogenesis of lupus vasculitis. Lab Invest 2013; 93:626–638. 24. Zhang JJ, Jiang L, Liu G, et al. Elevation of serum von Willebrand factor and antiendothelial cell antibodies in patients with immunoglobulin A nephropathy are associated with intrarenal arterial lesions. Nephrology (Carlton) 2008; 13:712–720. 25. Narshi CB, Giles IP, Rahman A. The endothelium: an interface between autoimmunity and atherosclerosis in systemic lupus erythematosus? Lupus 2011; 20:5–13. 26. Thacker SG, Zhao W, Smith CK, et al. Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis. Arthritis Rheum 2012; 64:2975–2985. 27. Thacker SG, Berthier CC, Mattinzoli D, et al. The detrimental effects of IFN-alpha on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. J Immunol 2010; 185:4457–4469. 28. Kahlenberg JM, Thacker SG, Berthier CC, et al. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus. J Immunol 2011; 187:6143–6156. 29. Li J, Fu Q, Cui H, et al. Interferon-alpha priming promotes lipid uptake and macrophage-derived foam cell formation: a novel link between interferonalpha and atherosclerosis in lupus. Arthritis Rheum 2011; 63:492–502. 30. Lood C, Amisten S, Gullstrand B, et al. Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. Blood 2010; 116:1951–1957. 31. Goossens P, Gijbels MJ, Zernecke A, et al. Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions. Cell Metab 2010; 12:142–153. 32. McLaren JE, Ramji DP. Interferon gamma: a master regulator of atherosclerosis. Cytokine Growth Factor Rev 2009; 20:125–135. 33. Clancy R, Ginzler EM. Endothelial function and its implications for cardiovascular and renal disease in systemic lupus erythematosus. Rheum Dis Clin North Am 2010; 36:145–160; ix–x. 34. Andreoli L, Fredi M, Nalli C, et al. Clinical significance of IgA anticardiolipin and IgA antibeta2 glycoprotein I antibodies. Curr Rheumatol Rep 2013; 15:343. 35. Sweiss NJ, Bo R, Kapadia R, et al. IgA antibeta2-glycoprotein I autoantibodies are associated with an increased risk of thromboembolic events in patients with systemic lupus erythematosus. PLoS One 2010; 5:e12280. 36. Zheng H, Chen Y, Ao W, et al. Antiphospholipid antibody profiles in lupus nephritis with glomerular microthrombosis: a prospective study of 124 cases. Arthritis Res Ther 2009; 11:R93. 37. Majka DS, Liu K, Pope RM, et al. Antiphospholipid antibodies and sub-clinical & atherosclerosis in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Inflamm Res 2013; 62:919–927. This study demonstrates the pathogenic role of antiphospholipid antibodies in subclinical atherosclerosis. 38. Lundstrom E, Gustafsson JT, Jonsen A, et al. HLA-DRB104/13 alleles are & associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus. Ann Rheum Dis 2013; 72:1018–1025. This study is the first to demonstrate the relationship between HLA-DRB1 alleles, antiphospholipid antibodies, and vascular events in SLE patients. 39. Griffin B, Lightstone L. Renoprotective strategies in lupus nephritis: beyond & immunosuppression. Lupus 2013; 22:1267–1273. An updated review which focuses on the treatment to prevent progression of chronic kidney disease beyond the use of steroids and immunosuppressants of lupus nephritis.
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-nephrolhypertens.com
223
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Diverse vascular lesions in systemic lupus erythematosus and clinical implications Ying Tan a,b,c,d,, Feng Yu a,b,c,d,, and Gang Liu a,b,c,d
Purpose of review Vascular injury is one of the typical symptoms of systemic lupus erythematosus (SLE), and may play a key role in the choice of treatment strategy and prediction of prognosis. In this review, diverse vascular lesions in SLE and their clinical significance are discussed. Recent findings The clinical features of vascular disease in SLE differ from organ to organ, and may be extreme with regard to renal vascular lesions. Vascular lesions in SLE may be of inflammatory or thrombotic origin, and immune system dysfunction is considered to be a predominant feature. Numerous lines of evidence suggest that the activation and injury of endothelial cells might play a key role in the pathogenesis. Summary Vascular lesions in SLE are mediated by a complex interaction between the immune system and other contributing factors. Different therapies developed for vascular lesions, both immunosuppressive and nonimmunosuppressive, should be selected based on the different clinical and pathological characteristics, and our future understanding of the different mechanisms involved. Keywords atherosclerosis, endothelial cells, systemic lupus erythematosus, thrombosis, vascular lesions
INTRODUCTION Vascular injury is one of the typical clinical features of systemic lupus erythematosus (SLE), which is considered to be a substantial contributor to morbidity and mortality. Previous studies showed that vascular events occurred in 26% of SLE patients during long-term follow-up and were predominantly because of atherothrombotic disease. Appel et al. [1] and D’Agati [2] provided a pathological classification for lupus vascular lesions (Table 1), whereas other clinical syndromes also included venous thrombosis, antiphospholipid syndrome (APS), atherosclerosis, etc. Vascular lesions in SLE may be of inflammatory or thrombotic origin [3], including cutaneous and visceral injuries, which might act as a key factor in the choice of treatment strategy and the prognosis [4 ]. Their clinical signs varied from organ to organ, with small-sized and medium-sized vessels mainly involved. Thus, the clinical manifestations, pathogenesis, and implications of vascular lesions in SLE are of great clinical significance, although there is still a lack of general agreement concerning the choice of therapeutic intervention because of the clinical and pathologenic complexity. In this review, diverse vascular &
www.co-nephrolhypertens.com
lesions in SLE are described, and the most recent hypothesis regarding the associated pathogenesis further discussed.
CLINICAL FEATURES OF VASCULAR LESIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS Vascular lesions in SLE include cutaneous and visceral injuries. Visceral vascular lesions can be life-threatening, and mostly involve the nervous
a
Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, cKey Laboratory of Renal Disease, Ministry of Health of China and dKey Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education, Beijing, PR China b
Correspondence to Gang Liu, MD, Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, PR China. Tel: +86 10 66551736; fax: +86 10 66551055; e-mail: liugang2003@ medmail.com.cn
Ying Tan and Feng Yu contributed equally to the writing of this article.
Curr Opin Nephrol Hypertens 2014, 23:218–223 DOI:10.1097/01.mnh.0000444812.65002.cb Volume 23 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Vascular lesions in systemic lupus erythematosus Tan et al.
KEY POINTS
likelihood of treatment with prednisone, cyclophosphamide, or hydroxychloroquine, contributed to accelerated atherosclerosis [8 ]. Coronary artery vasculitis was rarely reported in the literature, but aneurysms of coronary arteries may result from vasculitis. Interestingly, coronary aneurysm or coronary arteritis was found in some cases despite well controlled SLE activity [9]. &
Clinical features of vascular diseases of SLE differ from organ to organ. Renal vascular lesions appear to be an extreme form of vascular lesions in SLE. Activation and injury of endothelial cells might play a key role in the pathogenesis of vascular lesions in SLE. Different therapies developed for vascular lesions in SLE should be selected based on the different clinical and pathological characteristics and our future understanding of the different mechanisms involved.
system, coronary vascular system, and renal vascular system.
Nervous system involvement Neuropsychiatric SLE was mostly thought to be closely associated with vascular injury in the nervous system based on most histopathological studies [5]. Headache, cognitive dysfunction, acute confusion state, movement disorders, myelopathy, and psychiatric disorders are the common features of neuropsychiatric SLE. Ischemic stroke and transient ischemic attack account for over 80% of cerebrovascular disease cases. The European League Against Rheumatism (EULAR) group found that general SLE activity or damage, past or concurrent neuropsychiatric SLE, and persistently positive antiphospholipid antibodies in moderate-to-high titers were the most significant predictors for neuropsychiatric SLE [6]. Peripheral neuropathy occurs in 14% of SLE patients, and seems to be less frequent than central nervous system neuropathy [7]. Peripheral polyneuropathy and mononeuritis multiplex are the most common forms.
Coronary vascular involvement Coronary artery disease in SLE includes premature atherosclerosis, thrombosis, embolization, spasm, and vasculitis. Premature atherosclerosis is the most common cause of coronary artery disease in SLE patients, with a prevalence of 6–10%. Recent studies have indicated that autoimmunity, including high disease activity, longer disease duration, higher levels of SLE-associated damage, measurable levels of proinflammatory high-density lipoprotein (HDL), increased oxidative stress, high levels of homocysteine, adipose-derived hormone, and lower
Renal vascular lesions Vascular lesions are common in lupus nephritis. The renal vascular lesions in SLE include a series of features listed in Table 1. Renal vascular lesions consist of various types and more attention should be paid to these lesions and their adverse effects on the prognosis of the renal disease. The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) pathologic classifications of lupus nephritis specified the importance of vascular damage and indicated that these should be included in the summary diagnostic line [10]. The data from Peking University First Hospital showed that among 341 patients with pathologically diagnosed lupus nephritis, 279 patients (81.8%) with renal vascular lesions were identified and classified as following: 253 with vascular immune complex deposits (ICDs; 74.2%, 149 with uncomplicated vascular immune complexes), 82 with arteriosclerosis (24.0%), 60 with thrombotic microangiopathy (TMA; 17.6%), 13 with noninflammatory necrotic vasculopathy (NNV; 3.8%), and only 2 with true vasculitis (0.6%) [4 ]. A total of 105 patients (37.6%) presented with more than two types of vascular lesions. More importantly, the presence of vascular lesions was positively correlated with activity indices and chronicity indices, and the scores of renal vascular lesions were risk factors for renal outcome in the survival analysis [4 ]. The most common renal vascular lesion was vascular ICD. Our study also found that patients with vascular ICD presented with more active characteristics of renal disease compared with patients without this feature, and the renal outcome in the uncomplicated ICDs group was much poorer than other types, except for those with TMA, which had been thought to be clinically silent [1,2,4 ]. The pathogenesis of ICD in lupus nephritis is not yet clear. We found that the majority of cases had C1q (87%) and nearly half had IgG deposition (44.1%). Our further research showed that serum anti-C1q autoantibodies were closely associated with serum levels of C1q and glomerular deposition of C1q [11]. However, the intensity of glomerular C1q deposition was not associated with the intensity of vascular C1q deposition. The findings supported
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
&
www.co-nephrolhypertens.com
219
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal immunology and pathology Table 1. Pathological classification and descriptions of vascular lesions in lupus nephritis Pathological classification
Descriptions
Uncomplicated vascular immune complex deposits
On light microscopy, the extraglomerular arteries and arterioles with immune complex deposition usually appear normal, without thrombosis, necrosis, and inflammatory infiltration of the blood vessel walls. On immunofluorescence microscopy, the deposits may contain IgG, IgA, or IgM and various complement components. On electron microscopy, the granular electron-dense deposits were most commonly seen to be located beneath the vascular endothelium or within the basement membranes surrounding the medial myocytes.
Noninflammatory necrotic vasculopathy
On light microscopy, smudgy eosinophilic, fuchsinophilic material that stains focally positive for fibrin is seen to occupy the lumen and intima of arteries and arterioles, with frequent extension into the media. The endothelium is usually swollen or denuded, with occasional pyknotic nuclear fragments and smudgy degeneration of the medial myocytes. The elastic membrane of the interlobular arteries is usually disrupted, but there is no inflammatory infiltrate. On immunofluorescence microscopy, various staining patterns for IgG, IgM, IgA, complement components, and fibrin-related antigens are seen to be present in the blood vessel walls, extending to the lumen. Electron microscopy revealed massive confluent intraluminal and mural deposits of granular electron-dense material, with concomitant immune deposits, sometimes associated with tactoids of fibrillar fibrin and platelets.
Thrombotic microangiopathy
In the acute phase, there is marked luminal narrowing or total occlusion by intraluminal, subendothelial, or medial accumulation of eosinophilic, fuchsinophilic material with staining properties of fibrin, invariably associated with endothelial swelling, denudation, and sometimes fragmented and hemolyzed erythrocytes. Immunofluorescence microscopy and electron microscopy revealed an absence of discrete immune deposits. In the chronic phase, mucoid edema of the intima and the ‘‘onion skin’’ type of intimal fibroplasia may occur.
True vasculitis
On light microscopy, prominent inflammatory cell infiltration of the arterial wall by neutrophils and mononuclear leukocytes can be seen. This mural inflammation is accompanied in the acute phase by fibrinoid necrosis, usually most severe in the intima and to a lesser extent in the media. In some biopsies, rupture of the elastic lamellae is seen. On immunofluorescence microscopy, there is evidence of fibrin-related antigens sometimes associated with less intense staining for immunoglobulin and complement fractions.
Arteriosclerosis and arteriolosclerosis
This lesion was defined as fibrous thickening of the intima without necrosis, proliferation, or thrombosis. &
Adapted with permission [2,4 ]. Adaptations are themselves works protected by copyright. In order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
the hypothesis based on animal studies showing that anti-C1q autoantibodies deposited in glomeruli are only pathogenic in combination with glomerular C1q-containing immune complexes [12]. Although NNV is less common than ICD, it might have significant scientific implications for the following reasons: NNV was always combined with other renal vascular lesions, which might have contributed to the fact that this group presented with more severe clinical and pathological status; NNV might be a transition form from ICD to other severe vascular lesions; and most NNV is always combined with active proliferative lupus nephritis, and abundant ICDs in vascular walls consisted of immunoglobulins and complements, which strongly supports the roles of immunologic factors in the development of the lesion [1,4 ]. Another important vascular lesion was TMA, which presented with the most severe renal injury features and the poorest renal outcome. In fact, TMA in lupus nephritis consists of a group of diseases, including APS, thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP–HUS), scleroderma, malignant hypertension, etc. Our &
220
www.co-nephrolhypertens.com
study highlights the important status of complement overactivation via both classical and alternative pathways in the pathogenesis of renal lupus TMA [4 ,13 ], which is consistent with the previous reports [14,15]. Moreover, our study showed that serum ADAMTS-13 activity was significantly lower in patients with both lupus nephritis and TTP–HUS than in those with lupus nephritis (40 versus 69%, P ¼ 0.012), and the prevalence of ADAMTS-13 autoantibodies was significantly higher in the former group (86 versus 18%, P < 0.001). These findings suggest that ADAMTS-13 autoantibodies might play an important role in the pathogenesis of TTP–HUS associated with lupus nephritis [16]. The mechanism of renal arteriosclerosis is not yet clear. One interesting finding in our study (unpublished data) was that 70.7% of renal arteriosclerosis patients had combined ICD vascular lesions. More importantly, renal immunohistochemistry examination identified that arteriosclerosis and ICDs co-localized in the renal vessels of most patients. The arteriosclerosis scores were significantly higher in the group with combined arteriosclerosis and ICDs than that in pure &
&
Volume 23 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Vascular lesions in systemic lupus erythematosus Tan et al.
arteriosclerosis patients. Patients in the combination group presented with more severe renal injury and poorer renal outcomes compared with pure arteriosclerosis and no renal vascular injury group, although the levels of serum lipids were not significantly different. These findings support the hypothesis that renal ICD, rather than the traditional risk factors, might be associated with and contribute to the formation of renal arteriosclerosis in lupus nephritis [17,18,19 ]. On further analysis, we found that patients with combined renal arteriosclerosis and ICDs also presented with the worst cardiac structure and function, including the largest left atrium diameter, left ventricular enddiastolic diameter, left ventricular posterior wall thickness, and the highest pulmonary arterial systolic pressure. The scores of renal arteriosclerosis were positively correlated with left atrium diameter, interventricular septum, and left ventricular posterior wall thickness. Thus, renal arteriosclerosis might predict potent cardiovascular and renal risk in lupus nephritis patients combined with classical factors, and this needs further investigation. &&
Others Cutaneous lesions were the main clinical presentation of vascular lesions in SLE, making up 80–94% of the total cases [20]. Other organs, including the gastrointestinal tract [21], lung [22], and large vessels, can also be involved in SLE vascular injury.
PATHOGENESIS OF VASCULAR LESIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS Vascular lesions in SLE may be of inflammatory or thrombotic origin [3], and may appear alone or coexist in a patient. Atherosclerosis is also considered to be an inflammatory disease. The dysfunction of the immune system is considered to be the predominant feature of this disease. Numerous lines of evidence suggested that the activation and injury of endothelial cells might play a key role in the pathogenesis of vascular lesions in SLE. Endothelial dysfunction represents a state of deviation from normal to a vasoconstrictive, procoagulant, platelet-activating, and antifibrinolytic state. However, the precise mechanism of these diseases has not been fully elucidated. The most recent theory and hypothesis will be discussed in the following sections.
Vascular inflammation One well-accepted hypothesis for vascular lesions in SLE is that local deposition of immune complexes onto the vascular endothelium triggers an
inflammatory response involving activation of the complement cascade, possibly with the formation of C5b-9 membrane complement attack (MAC), and thus finally destroys the vascular basal membranes and inflammatory cell infiltrates. A recent study suggested that immune complex elicited proinflammatory responses in human endothelial cells and altered their function involving cellular signaling via the high-mobility group box 1 protein (HMGB1)–receptor for advanced glycation end products (RAGE) axis [23]. Briefly, immune complexes upregulated the cell-surface expression of RAGE, the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), increased the secretion of chemokines such as interleukin 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), the proinflammatory cytokines IL-6, and tumor necrosis factor-a (TNF-a), and also promoted the activation of the transcription factor NF-kB p65 in human endothelial cells. Various autoantibodies, such as antiendothelial cell antibodies (AECAs) [24], antiphospholipid antibodies, antidouble-stranded DNA antibodies, antioxLDL antibodies, and antiapolipoprotein A-I antibodies [25], could directly or indirectly affect the endothelial cells and cause chronic vessel wall damage as circulating or local immune complexes, and might contribute to the pathogenesis of atherosclerosis by causing injury to the endothelium and altering the metabolism of lipoproteins involved in atherogenesis. In addition to immune complexes and autoantibodies, the exposure of healthy endothelial cells to some cytokines, such as type I interferon (IFN) or TNF-a, from patients who had active SLE could result in the expression of nitric oxide synthase 2 and the generation of nitric oxide and adhesion molecules, and could also lead to the activation of the complement cascade. Furthermore, in-vitro and in-vivo studies have both shown that type I IFN could play a crucial role in cardiovascular disease development in SLE [26]. IFN leads to an imbalance of vascular damage and repair by inducing endothelial cell and endothelial progenitor cell (EPC) apoptosis, preventing the differentiation of EPCs and circulating angiogenic cells to mature endothelial cells, and by inducing transcriptional repression of angiogenic factors [27] through suppression of IL-1b pathways and upregulation of the inflammasome machinery and potentiation of IL-18 activation [28]. Moreover, IFN-a promoted the conversion of circulating angiogenic cells to dendritic cells. Meanwhile, IFN-a has the capacity to enhance foam cell formation [29] and activate platelets through changes in the megakaryocyte
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-nephrolhypertens.com
221
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Renal immunology and pathology
transcriptome [30]. Immunohistochemistry of renal biopsies from patients with lupus nephritis confirmed that IFN-a promoted an antiangiogenic signature through repression of vascular endothelial growth factor (VEGF)-A and induction of IL-1R antagonist, which correlated with decreased renal vascular density and vascular rarefaction [27]. IFN-b may promote atherosclerosis by promoting macrophage recruitment to arteries [31]. IFN-g is the prototypical TH1 cytokine, which could promote plaque instability by reducing collagen production and inhibiting the growth of smooth muscle cells and endothelial cells. IFN-g could also promote foam cell formation and plaque rupture [32]. The findings indicate that type I IFN could promote atherosclerosis and loss of renal function, and supported the use of therapeutic intervention blocking IFN-a in patients at high cardiovascular risk. In addition, endothelial cells were shed into the circulation, and membrane endothelial protein C receptor (EPCR) was lost. EPCR appears in the circulation in a soluble form (sEPCR), which could induce a procoagulant effect. Prothrombin fragment F1þ2 (a marker of thrombin generation) was generated, which was indirectly responsible for the release of sEPCR. The increased release of sEPCR coupled with higher thrombin generation indicated that less membrane-bound EPCR would be available in these individuals for efficient protein C activation [33].
b2GPI and thrombin might play a role in glomerular microthrombosis. SLE patients with these factors had more severe renal tissue injuries and poorer renal function than those without them. A large prospective study suggested that antiphospholipid antibody positivity during young adulthood was a risk factor for subsequent subclinical atherosclerosis and might play a role in the pathogenesis of atherosclerosis in SLE [37 ]. Moreover, the presence of antiphospholipid antibodies was associated with the HLA-DRB104 and HLA-DRB113 alleles, which were also associated with vascular events in SLE [38 ]. In brief, vascular lesions in SLE are mediated by a complex interaction between the immune system and other factors. The close associations between inflammatory cells, mediators, humoral activators, and endothelial injury, with subsequent alteration of endothelial adhesiveness and permeability to leukocytes and platelets, is key in the development of vascular injuries in SLE. Unfortunately, general agreements are still lacking regarding therapeutic approaches as a result of the clinical and pathologenic complexity of SLE vascular diseases. Corticosteroids are still considered to be the first-line medication in the treatment of vascular lesions of SLE, alone or in combination with other immunosuppressants. Use of nonimmunosuppressive therapies, such as smoking cessation, glycemic control, angiotensin-converting enzyme inhibitors, and statins use, was recommended for modifying the cardiovascular risk factors [39 ]. Treatment with plasmapheresis or plasma infusion is suggested for some special vascular lesions, such as TMA with ADAMTS-13 autoantibodies or low ADAMTS-13 activity [16]. However, the absence of clear causes limits the rational choice of therapy strategies. Thus, further explorations are warranted. &
&
&
Thrombotic noninflammatory vascular lesions The other category of vascular lesions is thrombotic injury in SLE. Mostly, antiphospholipid antibodies are considered to play a significant role in the development of the hypercoagulable state in SLE. Antiphospholipid antibodies are a heterogeneous group of antibodies directed against negatively charged phospholipids, phospholipid-binding proteins, and phospholipid–protein complexes with an estimated positivity in SLE ranging from 20 to 70%. Previous studies regarding the role of antiphospholipid antibodies in the development of vascular endothelial damage, arterial and venous thrombosis, proliferative heart valve lesions, and atherosclerosis in SLE suggested that they could induce proinflammatory, proadhesive, and procoagulant disorders. Recently, several studies have suggested that IgA antib2 glycoprotein I (b2GPI) is the most prevalent isotype in SLE, with a significant association with thrombotic events [34] and an increased prevalence of morbidities involving organs of mucosal immunity [35]. Zheng et al. [36] found that the lupus anticoagulant and antibodies against 222
www.co-nephrolhypertens.com
CONCLUSION Vascular lesions in SLE have various clinical features and pathogenesis. The evaluation of vascular lesions in the various involved organs, especially in the kidneys, is therefore important. The activation and dysfunction of endothelial cells, and the contribution of immune system dysfunction in the pathogenesis of vascular lesions in SLE, are the key important mechanisms to consider. Different therapies developed for vascular lesions in SLE, both immunosuppressive and nonimmunosuppressive, should be selected based on the different clinical and pathological characteristics. Additional therapies may emerge based on the understanding of different mechanisms in the future. Further investigation is required to gain new insights on several Volume 23 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Vascular lesions in systemic lupus erythematosus Tan et al.
still-unsolved issues regarding the physiopathological and therapeutic relevance of vascular lesions in SLE in the field of translational medicine. Acknowledgements None. Conflicts of interest There are no conflicts of interest. This work was supported by the grants of Chinese 973 project (No. 2012CB517700) and National Natural Science Foundation of China (No. 81100497).
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Appel GB, Pirani CL, D’Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol 1994; 4:1499–1515. 2. D’Agati VD. Renal disease in systemic lupus erythematosus, mixed connective tissue disease, Sjogren’s syndrome, and rheumatoid arthritis. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, editors. Heptinstall’s pathology of the kidney, 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. ; p. 530. 3. D’Cruz D. Vasculitis in systemic lupus erythematosus. Lupus 1998; 7:270– 274. 4. Wu LH, Yu F, Tan Y, et al. Inclusion of renal vascular lesions in the 2003 ISN/ & RPS system for classifying lupus nephritis improves renal outcome predictions. Kidney Int 2013; 83:715–723. This article focuses on the evaluation of different renal vascular lesions in lupus and suggests that renal vascular lesions could predict renal outcome. 5. Postal M, Costallat LT, Appenzeller S. Neuropsychiatric manifestations in systemic lupus erythematosus: epidemiology, pathophysiology and management. CNS Drugs 2011; 25:721–736. 6. Bertsias GK, Ioannidis JP, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 2010; 69:2074–2082. 7. Florica B, Aghdassi E, Su J, et al. Peripheral neuropathy in patients with systemic lupus erythematosus. Semin Arthritis Rheum 2011; 41:203–211. 8. Skaggs BJ, Hahn BH, McMahon M. Accelerated atherosclerosis in patients & with SLE – mechanisms and management. Nat Rev Rheumatol 2012; 8:214–223. An updated review of the pathogenesis and treatment of premature atherosclerosis in patients with SLE. 9. Suzuki H, Fujigaki Y, Mori M, et al. Giant coronary aneurysm in a patient with systemic lupus erythematosus. Intern Med 2009; 48:1407–1412. 10. Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004; 65:521–530. 11. Tan Y, Song D, Wu LH, et al. Serum levels and renal deposition of C1q complement component and its antibodies reflect disease activity of lupus nephritis. BMC Nephrol 2013; 14:63. 12. Trouw LA, Groeneveld TW, Seelen MA, et al. Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest 2004; 114:679– 688. 13. Song D, Wu LH, Wang FM, et al. The spectrum of renal thrombotic micro& angiopathy in lupus nephritis. Arthritis Res Ther 2013; 15:R12. Evidence is provided on complement involvement in the pathogenesis of renal TMA in lupus nephritis. 14. Matheu MP, Beeton C, Parker I, et al. Imaging effector memory T cells in the ear after induction of adoptive DTH. J Vis Exp 2008; 18:907. 15. Shen Y, Chen XW, Sun CY, et al. Association between antibeta2 glycoprotein I antibodies and renal glomerular C4d deposition in lupus nephritis patients with glomerular microthrombosis: a prospective study of 155 cases. Lupus 2010; 19:1195–1203.
16. Yu F, Tan Y, Zhao MH. Lupus nephritis combined with renal injury due to thrombotic thrombocytopaenic purpura–haemolytic uraemic syndrome. Nephrol Dial Transplant 2010; 25:145–152. 17. Walport MJ. Complement. First of two parts. N Engl J Med 2001; 344:1058– 1066. 18. Walport MJ. Complement. Second of two parts. N Engl J Med 2001; 344:1140–1144. 19. Lewis MJ, Malik TH, Fossati-Jimack L, et al. Distinct roles for complement in && glomerulonephritis and atherosclerosis revealed in mice with a combination of lupus and hyperlipidemia. Arthritis Rheum 2012; 64:2707–2718. This animal study addresses the hypothesis that immune complex formation and systemic complement depletion are closely associated with accelerated atherosclerosis and renal inflammation in SLE. 20. Ramos-Casals M, Nardi N, Lagrutta M, et al. Vasculitis in systemic lupus erythematosus: prevalence and clinical characteristics in 670 patients. Medicine (Baltimore) 2006; 85:95–104. 21. Ebert EC, Hagspiel KD. Gastrointestinal and hepatic manifestations of systemic lupus erythematosus. J Clin Gastroenterol 2011; 45:436–441. 22. Torre O, Harari S. Pleural and pulmonary involvement in systemic lupus erythematosus. Presse Med 2011; 40:e19–e29. 23. Sun W, Jiao Y, Cui B, et al. Immune complexes activate human endothelium involving the cell-signaling HMGB1–RAGE axis in the pathogenesis of lupus vasculitis. Lab Invest 2013; 93:626–638. 24. Zhang JJ, Jiang L, Liu G, et al. Elevation of serum von Willebrand factor and antiendothelial cell antibodies in patients with immunoglobulin A nephropathy are associated with intrarenal arterial lesions. Nephrology (Carlton) 2008; 13:712–720. 25. Narshi CB, Giles IP, Rahman A. The endothelium: an interface between autoimmunity and atherosclerosis in systemic lupus erythematosus? Lupus 2011; 20:5–13. 26. Thacker SG, Zhao W, Smith CK, et al. Type I interferons modulate vascular function, repair, thrombosis, and plaque progression in murine models of lupus and atherosclerosis. Arthritis Rheum 2012; 64:2975–2985. 27. Thacker SG, Berthier CC, Mattinzoli D, et al. The detrimental effects of IFN-alpha on vasculogenesis in lupus are mediated by repression of IL-1 pathways: potential role in atherogenesis and renal vascular rarefaction. J Immunol 2010; 185:4457–4469. 28. Kahlenberg JM, Thacker SG, Berthier CC, et al. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus. J Immunol 2011; 187:6143–6156. 29. Li J, Fu Q, Cui H, et al. Interferon-alpha priming promotes lipid uptake and macrophage-derived foam cell formation: a novel link between interferonalpha and atherosclerosis in lupus. Arthritis Rheum 2011; 63:492–502. 30. Lood C, Amisten S, Gullstrand B, et al. Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. Blood 2010; 116:1951–1957. 31. Goossens P, Gijbels MJ, Zernecke A, et al. Myeloid type I interferon signaling promotes atherosclerosis by stimulating macrophage recruitment to lesions. Cell Metab 2010; 12:142–153. 32. McLaren JE, Ramji DP. Interferon gamma: a master regulator of atherosclerosis. Cytokine Growth Factor Rev 2009; 20:125–135. 33. Clancy R, Ginzler EM. Endothelial function and its implications for cardiovascular and renal disease in systemic lupus erythematosus. Rheum Dis Clin North Am 2010; 36:145–160; ix–x. 34. Andreoli L, Fredi M, Nalli C, et al. Clinical significance of IgA anticardiolipin and IgA antibeta2 glycoprotein I antibodies. Curr Rheumatol Rep 2013; 15:343. 35. Sweiss NJ, Bo R, Kapadia R, et al. IgA antibeta2-glycoprotein I autoantibodies are associated with an increased risk of thromboembolic events in patients with systemic lupus erythematosus. PLoS One 2010; 5:e12280. 36. Zheng H, Chen Y, Ao W, et al. Antiphospholipid antibody profiles in lupus nephritis with glomerular microthrombosis: a prospective study of 124 cases. Arthritis Res Ther 2009; 11:R93. 37. Majka DS, Liu K, Pope RM, et al. Antiphospholipid antibodies and sub-clinical & atherosclerosis in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Inflamm Res 2013; 62:919–927. This study demonstrates the pathogenic role of antiphospholipid antibodies in subclinical atherosclerosis. 38. Lundstrom E, Gustafsson JT, Jonsen A, et al. HLA-DRB104/13 alleles are & associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus. Ann Rheum Dis 2013; 72:1018–1025. This study is the first to demonstrate the relationship between HLA-DRB1 alleles, antiphospholipid antibodies, and vascular events in SLE patients. 39. Griffin B, Lightstone L. Renoprotective strategies in lupus nephritis: beyond & immunosuppression. Lupus 2013; 22:1267–1273. An updated review which focuses on the treatment to prevent progression of chronic kidney disease beyond the use of steroids and immunosuppressants of lupus nephritis.
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-nephrolhypertens.com
223
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
