Eur J Clin Pharmacol (2014) 70:135–140 DOI 10.1007/s00228-013-1605-6

REVIEW ARTICLE

Putative effects of potentially anti-angiogenic drugs in rheumatic diseases Nicola Maruotti & Francesco Paolo Cantatore & Domenico Ribatti

Received: 2 September 2013 / Accepted: 15 October 2013 / Published online: 7 November 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract A role for angiogenesis has been described in several rheumatic diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic sclerosis, systemic lupus erythematosus, vasculitides, and osteoarthritis, leading to the possibility that angiogenesis inhibition may be an additional useful therapeutic arm. While the role of anti-angiogenic therapy in rheumatoid arthritis has received attention, it is conceivable that the inhibition of pathological angiogenesis may also be a useful therapeutical approach in other rheumatic diseases. Numerous compounds, such as, for example, various interleukins, antibodies directed against angiogenic factors, peptides, estrogen metabolites, disease-modifying antirheumatic drugs, have been found to have antiangiogenic properties. However, additional research is needed to obtain a clear understanding of the pathogenic mechanism of angiogenesis and the potential applications of anti-angiogenic therapy in rheumatic diseases.

Keywords Angiogenesis . Arthritis . Rheumatic disease . Therapy N. Maruotti : F. P. Cantatore Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia Medical School, Foggia, Italy D. Ribatti Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy F. P. Cantatore (*) Rheumatology Clinic “Mario Carrozzo”, “D’Avanzo” Hospital, Viale degli Aviatori, 1, 71100 Foggia, Italy e-mail: [email protected]

Introduction Angiogenesis, the formation of newly formed capillaries from pre-existing blood vessels, is involved in many biological processes, such as in wound healing and in the formation of granulation tissue. Pathological angiogenesis is due to an imbalance between positive and negative angiogenic factors, with a prevalence of positive regulators, or to a reduction of the expression of negative regulators [1]. Pathological angiogenesis is involved in numerous diseases, such as malignancies and inflammatory diseases. A key role for angiogenesis has been demonstrated in rheumatoid arthritis. In fact, in rheumatoid arthritis, important angiogenic mediators have been demonstrated in the synovium and tenosynovium (Table 1). Vascular endothelial growth factor (VEGF), produced in response to soluble mediators, such as growth factors and cytokines, and its receptors (VEGFRs) are responsible for angiogenesis regulation in rheumatoid joints [2]. Furthermore, other angiogenic mediators, such as tumor necrosis factor-α (TNF-α), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor, hepatocyte growth factor, transforming growth factor-β (TGF-β), angiogenin, platelet activating factor, soluble adhesion molecules, endothelial mediator (endoglin), and interleukin-1 (IL-1), IL-6, IL-8, IL-13, IL-15, IL-18, are involved in angiogenesis in rheumatoid arthritis [3]. Angiopoietins 1 and 2 (Ang1 and Ang2) and Tie receptor families are also important regulators of angiogenesis [4]. Ang1 is Tie2 agonistic, while Ang2 is both a Tie2 agonist and an antagonist [5]. The binding of Ang1 to Tie2 is responsible for the stabilization of newly formed vessels [3]. Tie2 expression has been demonstrated in the synovial lining and stromal cells in addition to blood vessels in rheumatoid synovial tissue [4]. Moreover, hypoxia, a condition which characterizes the rheumatoid joints, is responsible for inducing

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Table 1 Angiogenic factors in rheumatic diseases Factors

Role in angiogenesisa

Rheumatic diseasesb

Vascular endothelial growth factor Tumor necrosis factor-α Fibroblast growth factor-2 Platelet-derived growth factor Epidermal growth factor Insulin-like growth factor Hepatocyte growth factor Transforming growth factor-β Angiogenin Platelet activating factor Endoglin Interleukin-1 (IL-1) IL-6 IL-8 IL-13 IL-15 IL-18

↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑

RA RA RA RA RA RA RA RA RA RA RA RA RA RA RA RA RA

Angiopoietin 1 (Ang1) Ang2 Hypoxia-inducible factor-1α Monocyte chemoattractant protein-1 Soluble E-selectin Soluble VCAM-1 Endostatin Thrombospondin-1 (TSP-1) TSP-2

↑ ↑↓ ↑ ↑ ↑ ↑ ↓ ↓ ↓

RA RA RA

a

PSA PSA

AS

SS

SLE SLE

GCA GCA GCA GCA

BD

OA

TO

SLE

PSA

GCA

PSA

GCA GCA

KS

AAV

BD

SLE

GCA RA RA RA RA RA

↑ = stimulatory effect; ↓ = inhibitory effect

b

RA, Rheumatoid arthritis; PSA, psoriatic arthritis; SA, ankylosing spondylitis; SS, systemic sclerosis; SLE, systemic lupus erythematosus; GCA, giant cell arteritis; TO, thromboangiitis obliterans; KS, Kawasaki syndrome; AAV, ANCA associated vasculitides; BD, Behcet disease; OA, osteoarthritis

macrophage expression of hypoxia-inducible factor-1α (HIF1α). HIF-1α is involved in the upregulation of VEGF expression and in the post-transcriptional stabilization of VEGF mRNA [6]. Among the known angiogenic inhibitors, endostatin, thrombospondin-1 and -2 (TSP-1 and TSP-2) have been found in rheumatoid joints. The consequence of an imbalance between these inducers and inhibitors of angiogenesis is pathological angiogenesis, which maintains and perpetuates synovitis [2, 7]. A role for angiogenesis has also been described in other rheumatic diseases, including psoriatic arthritis, ankylosing spondylitis, systemic sclerosis, systemic lupus erythematosus, vasculitides, and osteoarthritis (Table 1). VEGF, IL-8, TNF-α, and TGF-β are thought to be involved in the pathogenesis of psoriatic arthritis [8]. An additional role for VEGF has been described in ankylosing spondylitis and systemic sclerosis [9, 10]. Moreover, even if systemic sclerosis is characterized by defective angiogenesis, several studies have found high levels of VEGF in patients affected by this disease [10]. More

recently, overexpression of the anti-angiogenic VEGF(165)b splice variant has been demonstrated in skin of patients affected by systemic sclerosis [11]. VEGF, EGF, FGF-2, and IL-18 have been detected in the sera of patients affected by systemic lupus erythematosus [9]. An additional role for angiogenesis has been described in the pathogenesis of numerous vasculitides, such as giant cell arteritis, thromboangiitis obliterans, Kawasaki syndrome, Churg–Strauss syndrome, Wegener granulomatosis, microscopic polyangiitis, and Behcet disease. Several angiogenic factors, including VEGF, FGF-2, TGF-β, monocyte chemoattractant protein-1, TNF-α, PDGF, IL-6, and IL-8 have been described in giant cell arteritis [12]. Overexpression of TNF-α has also been found in thromboangiitis obliterans [13]. Moreover, increased levels of TGF-β have been detected in both Kawasaki syndrome and in ANCA-associated vasculitides, such as Churg–Strauss syndrome, Wegener granulomatosis, and microscopic polyangiitis [9, 14]. Overexpression of IL-8 has been demonstrated in synovial fluids from Behcet

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disease patients, and increased VEGF levels have been found in blood serum, in oral aphthous lesions, and in the ocular inflammation [15]. Finally, VEGF has also been detected in the osteochondral junction and synovium from patients with osteoarthritis [16]. Given the role of angiogenesis in rheumatic diseases, angiogenesis inhibition may be considered to be a useful therapeutic arm against these diseases, and especially against rheumatoid arthritis. The focus of this review is the antiangiogenic strategies which have or may have a role in rheumatic diseases.

Disease-modifying anti-rheumatic drugs and other anti-rheumatic drugs Rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and systemic lupus erythematosus, are usually treated with methotrexate and biologics. Reduced VEGF production and reduced synovial vessel formation have been described in patients treated with methotrexate in combination with anti-TNF-α agents [3, 17]. ,Increased Ang2 expression and decreased Ang1 and Tie2 expression have also been seen in rheumatoid arthritis patients treated with anti-TNF-α agents [18]. In addition, Chen et al. reported the inhibition of Tie2 by a soluble Tie2 receptor transcript introduced via an adenoviral vector in mice with collagen-induced arthritis [19]. Sulfasalazine, usually used to treat a variety of diseases, including rheumatoid arthritis and sero-negative arthritis, plays a role in the inhibition of endothelial proliferation, as has been demonstrated in vitro [20]. Thalidomide is an immunomodulatory, anti-inflammatory and anti-angiogenic drug [21] used to treat cutaneous disorders in patients with systemic lupus erythematosus and mucocutaneous disease in those with Behcet’s disease [22, 23]. Animal studies have demonstrated that thalidomide is involved in the inhibition of VEGF- and FGF-2-mediated angiogenesis [21]. Moreover, thalidomide inhibits TNF-α, IL-5, IL-6, IL-8, and IL-12 production and increases the production of IL-2, IL-10, and interferon gamma, as demonstrated in studies using in vivo models [24]. The induction of cyclooxygenase-2 (COX-2) by different pro-inflammatory agents, growth factors, mitogens, endotoxins, and tumor agents indicates that this isoform is involved in many pathological disorders, such as inflammation [25, 26]. A role as angiogenic inhibitor has been hypothesized for COX-2 inhibitors, which are commonly used in the treatment of rheumatic diseases, including inflammatory arthritis, connectivities, and vasculitides. An upregulation of COX-2 activity has been demonstrated in the rheumatoid arthritis synovium; moreover, rofecoxib has been found to possess anti-angiogenic proprieties in vitro [27].

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Endogenous angiogenesis inhibitors Both endostatin and angiostatin work through the integrin αvβ3 which has been implicated in rheumatoid arthritis and osteoporosis [3]. This integrin is involved in bone resorption, angiogenesis, and inflammation, as demonstrated by its highly expression in activated macrophages, bone-resorbing osteoclats, angiogenic endothelial cells, and migrating smooth muscle cells [28]. Both molecules have demonstrated antiangiogenic activity in murine models of arthritis [29, 30]. Moreover, endostatin is responsible for decreasing joint VEGF and FGF-2 mRNA levels and inhibits synovial proliferation [2, 30]. A peptide derived from endostatin, E4, has demonstrated anti-fibrotic effects on existing fibrosis and fibrosis in human and mouse tissues triggered by TGF-β and bleomycin [31]. Thus, a possible therapeutic use has been hypothesized for E4 in fibro-proliferative disorders, such as systemic sclerosis [31]. Angiostatin is implicated in reducing synovial vessel formation in mouse models of collagen-induced arthritis [29]. Moreover, kallistatin, a serine proteinase inhibitor involved in angiogenesis and inflammation inhibition, as demonstrated by the suppression of rat ankle arthritis through the local injection of the kallistatin gene, has been found in the joints of patients with rheumatoid arthritis [32, 33]. TSP-1 and TSP-2 are produced by the macrophages and fibroblasts of patients with rheumatoid arthritis. Rico et al. reported that TSP1-derived peptide treatment was responsible for a reduction of both inflammation and angiogenesis in murine models of arthritis [34]. In human synovium-severe combined immunodeficiency mouse chimeras treated with TSP2-transfected fibroblasts obtained from synovial tissues of patients with active rheumatoid arthritis, overexpression of TSP-2 has been correlated to angiogenesis and inflammation suppression [7].

ILs and inhibition of VEGF The results of studies in which a gene therapy approach was used suggest that the transfer of genes which code for inflammatory inhibitors, such as IL-1 receptor antagonists, or for anti-inflammatory ILs, such as IL-4, IL-10, and IL-13, may induce an amelioration in rat adjuvant-induced arthritis [35, 36]. In two other studies, a direct role in angiogenesis inhibition has been demonstrated with IL-4 and IL-13 gene transfer [37, 38]. Anti-VEGF antibody or the soluble form of VEGFR1, both of which neutralize VEGF activity, or the use of VEGFR1 inhibitors, such as the VEGFR tyrosine kinase inhibitor PTK787/ZK222584 (vatalanib), have shown some therapeutic results in animal models of arthritis [3, 39]. Nevertheless, VEGF and VEGFR inhibition in vivo is limited by the

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presence of several side-effects, including hemorrhage, gastrointestinal perforation, and impaired wound healing [40].

Heat shock protein 90 inhibition Heat shock protein 90 (Hsp90) is a chaperone protein that is involved in the stabilization of several proteins [41]. Hsp90 inhibition plays a role in angiogenesis inhibition, as demonstrated in a Matrigel assay [42], and also induces HIF-1α degradation and reduces VEGF signaling in vitro [43]. Moreover, Hsp90 inhibition induces a reduction of nitric oxide production in human umbilical vein endothelial cells [44]. Nitric oxide is an important angiogenic and inflammatory factor that is responsible for the regulation of T cell functions under physiological conditions. Nevertheless, its overproduction is involved in alterations of T cell activation and the production of ILs. Several studies in patients with rheumatoid arthritis and systemic lupus erythematosus have demonstrated a state of increased nitric oxide synthesis [45]. Inhibitors of Hsp90 have already been used as an anti-cancer drug [46]. SNX-4414 is a small molecule inhibitor of Hsp90 which has been used with efficacy in rat collagen-induced arthritis and adjuvant-induced arthritis, following oral treatment [47].

2-Methoxyoestradiol The endogenous estrogen metabolite 2-methoxyoestradiol is an angiogenesis inhibitor in tumor models [48]. Its use in rheumatoid arthritis has been proposed because of the role of estrogen in reducing the severity of arthritis, as demonstrated during pregnancy and in murine models of arthritis [49].

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endothelin-1 antagonists, which are often used by patients affected by systemic sclerosis and primary pulmonary hypertension [3]. Vitaxin is a humanized monoclonal antibody directed against the vascular integrin αVβ3 and may inhibit synovial angiogenesis in animal models of arthritis [3]. Sphingosine-1-phosphate (S1P) is an activated sphingosine involved in angiogenesis [55]. High levels of S1P have been found in synovium isolated from patients with rheumatoid arthritis, where it is involved both in inducing inflammatory agents, such as IL-1 and TNF-α, and in favoring B cell production [56]. The fungal derivative FTY720 is an agonist for S1P receptors which have demonstrated a therapeutic effect in adjuvant-induced arthritis [57]. The fumagillin derivative AGM-1470/TNP-470 inhibits angiogenesis in murine models of arthritis [20]. Recently, a role for itraconazole, an antifungal drug, and bevacizumab, a recombinant humanized immunoglobulin G1 (IgG1) monoclonal antibody which binds to VEGF-A and its isoforms, has been hypothesized in rheumatoid arthritis [58]. Itraconazole has shown anti-angiogenic effects in non smallcell lung cancer in both murine models and in vitro assays using human umbilical vein endothelial cells [59]. A possible use in rheumatoid arthritis when other modalities have failed or as an adjuvant has been suggested because of its low cost and safety—even if large, randomized, clinical trials still have to be conducted to establish its efficacy, dosage, and duration of use [58]. On the other hand, the use of bevacizumab, which is currently used in the treatment of some types of neoplastic diseases, in rheumatoid arthritis has not yet been evaluated due to its cost and potential for causing adverse effects, such as gastrointestinal perforations, arterial thromboembolic events, and proteinuria [49, 58]. Concluding remarks

Chemotherapeutic agents Taxol is a chemotherapeutic agent involved in the inhibition of collagen-induced arthritis and synovial angiogenesis in rats [20]. Camptothecin (CPT) is a topoisomerase I inhibitor initially used in oncology [50]. Jackson et al. [51] demonstrated that CPT is involved in angiogenesis inhibition in vitro. More recently, CPT has been successfully used in collagen-induced arthritis in mice [52]. Nevertheless, its use in vivo is limited by numerous side-effects, including hypertransaminasemia, hematological alterations, and hemorrhagic renal cystitis [50]. Other anti-angiogenic agents Endothelin-1 is an endothelial factor involved in VEGF production and angiogenesis. Several studies have found increased levels of endothelin-1 in sera of patients with rheumatoid arthritis and systemic lupus erythematosus [53, 54]. Moreover, an anti-angiogenic effect has been hypothesized for

A great deal of research has focused on the role of angiogenesis in cancer, and in this context the inhibition of angiogenesis is considered to be an important area of development for efficacious treatment of this disease. The commonalities of cancer and some rheumatic diseases, such as rheumatoid arthritis, have often been described [60]. The emergence of angiogenesis as a key player in the pathogenesis of numerous rheumatic diseases may provide a basis for a rationale approach to the use and development of an anti-angiogenic therapy for these diseases. Even if studies mostly focus on the role of anti-angiogenic therapy in rheumatoid arthritis, it is conceivable that the inhibition of pathological angiogenesis may also be a useful therapeutical approach in other rheumatic diseases. Among the various compounds with anti-angiogenic properties, sulfasalazine, thalidomide, COX-2 inhibitors, and endothelin-1 antagonists are commonly used by clinicians to treat rheumatology due to their immunomodulatory and anti-

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inflammatory effects, or, in the case of endothelin-1 antagonists, for their role in decreasing pulmonary vascular resistance. However, the real impact of the anti-angiogenesis activities of these compounds is often not clearly understood as their effects have been demonstrated only in vitro or in animal models. On the contrary, in their prospective single-center study, Goedkoop et al. demonstrated that the association between methotrexate and infliximab was responsible for reducing both VEGF production and synovial vessel formation in their patient cohort affected by psoriatic arthritis [17]. An antiangiogenic role in rheumatoid arthritis has been only hypothesized for bevacizumab, taxol, and CPT, which are currently used in the oncology setting, and itraconazole, which is used to treat fungal infections. Also, the anti-angiogenic properties of all the other compounds mentioned in this review in treating rheumatic diseases remain a purely experimental concept, as these have only been studied in vitro or in animal models and are therefore a long way away from being used in rheumatic diseases. In consideration of the role of angiogenesis in the pathogenesis of many rheumatic diseases, further research and clinical trials are needed to demonstrate which compounds may have an effect on angiogenesis other than theoretical and clinical effects and to investigate the future potential applications of anti-angiogenic therapy in rheumatic diseases.

Competing interests None.

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Putative effects of potentially anti-angiogenic drugs in rheumatic diseases.

A role for angiogenesis has been described in several rheumatic diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis,...
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