Interleukin-6 (IL-6) is a pleiotropic cytokine with a wide range of biologic activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Recent accumulating evidence indicates a pathologic role for IL-6 in promoting proliferation of both smooth muscle and endothelial cells in the pulmonary arterioles, resulting in development of pulmonary arterial hypertension (PAH). Here, we describe a patient with mixed connective tissue disease and severe, refractory PAH. Her functional activity and hemodynamic parameters dramatically responded to tocilizumab, a humanized monoclonal antibody to human IL-6 receptor, which was aimed at treating multicentric Castleman's disease. It appears that IL-6 blockade may hold promise as an adjunct drug in treatment of PAH in idiopathic form as well as in association with connective tissue disease. 1. Introduction Pulmonary arterial hypertension (PAH) is a cause of significant morbidity and mortality in patients with connective tissue disease (CTD), especially in those with systemic sclerosis (SSc) or mixed connective tissue disease (MCTD) [1]. In fact, a survival study over the past 30 years in consecutive patients evaluated at the University of Pittsburgh has demonstrated that PAH became the primary cause of SSc-related deaths today [2]. PAH is characterized by increased pulmonary vascular resistance due to remodeling of the pulmonary arterioles. Left untreated, PAH leads irremediably to right ventricular hypertrophy, pressure overload and dilation, and impaired cardiac output, resulting in death [3]. Until recently, there was no effective therapy for PAH, a disease with a median survival estimated to be approximately one year following the diagnosis in patients with SSc [4]. However, in the past two decades, novel therapies have been developed, focusing on vasoactive substances derived from the pulmonary vascular endothelium [5]. These substances, such as endothelin-1, nitric oxide, and prostacyclin regulate smooth muscle cell tone and proliferation and were shown to be central to the pathogenesis of PAH [6]. Therefore, current therapeutic agents target these 3 essential biological pathways: the endothelin-1/endothelin receptor, nitric oxide/cGMP, and prostacyclin/cAMP pathways. Improvement of symptoms, functional activity, and quality of life and even prolongation of survival have been partially achieved with currently available therapies, but mostly in patients with idiopathic PAH [5]. Indeed, it has become clearer in the past few years that SSc patients with PAH have a strikingly divergent response to
References
[1]
R. Condliffe, D. G. Kiely, and D. G. Kiely, “Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era,” American Journal of Respiratory and Critical Care Medicine, vol. 179, no. 2, pp. 151–157, 2009.
[2]
V. D. Steen and T. A. Medsger, “Changes in causes of death in systemic sclerosis, 1972–2002,” Annals of the Rheumatic Diseases, vol. 66, no. 7, pp. 940–944, 2007.
[3]
K. M. Chin, N. H. S. Kim, and L. J. Rubin, “The right ventricle in pulmonary hypertension,” Coronary Artery Disease, vol. 16, no. 1, pp. 13–18, 2005.
[4]
E. T. Koh, P. Lee, D. D. Gladman, and M. Abu-Shakra, “Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients,” British Journal of Rheumatology, vol. 35, no. 10, pp. 989–993, 1996.
[5]
M. Humbert, O. Sitbon, and G. Simonneau, “Treatment of pulmonary arterial hypertension,” The New England Journal of Medicine, vol. 351, no. 14, pp. 1425–1473, 2004.
[6]
R. Budhiraja, R. M. Tuder, and P. M. Hassoun, “Endothelial dysfunction in pulmonary hypertension,” Circulation, vol. 109, no. 2, pp. 159–165, 2004.
[7]
S. M. Kawut, D. B. Taichman, C. L. Archer-Chicko, H. I. Palevsky, and S. E. Kimmel, “Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis,” Chest, vol. 123, no. 2, pp. 344–350, 2003.
[8]
M. R. Fisher, S. C. Mathai, and S. C. Mathai, “Clinical differences between idiopathic and scleroderma-related pulmonary hypertension,” Arthritis & Rheumatism, vol. 54, no. 9, pp. 3043–3050, 2006.
[9]
E. Hachulla, P. Carpentier, and P. Carpentier, “Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinérAIR-Sclérodermie study,” Rheumatology, vol. 48, no. 3, pp. 304–308, 2009.
[10]
E. Hachulla, D. Launay, A. Yaici, et al., “Pulmonary arterial hypertension associated with systemic sclerosis in patients with functional class II dyspnoea: mild symptoms but severe outcome,” Rheumatology, vol. 49, no. 5, pp. 940–944, 2010.
[11]
A. Dham and B. A. Peterson, “Castleman disease,” Current Opinion in Hematology, vol. 14, no. 4, pp. 354–359, 2007.
[12]
K. Yoshizaki, T. Matsuda, and T. Matsuda, “Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease,” Blood, vol. 74, no. 4, pp. 1360–1367, 1989.
[13]
A. Katsume, H. Saito, and H. Saito, “Anti-interleukin 6 (IL-6) receptor antibody suppresses Castleman's disease like symptoms emerged in IL-6 transgenic mice,” Cytokine, vol. 20, no. 6, pp. 304–311, 2002.
[14]
N. Nishimoto, Y. Kanakura, and Y. Kanakura, “Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease,” Blood, vol. 106, no. 8, pp. 2627–2632, 2005.
[15]
J. Soulier, L. Grollet, and L. Grollet, “Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease,” Blood, vol. 86, no. 4, pp. 1276–1280, 1995.
[16]
A. Gessain, A. Sudaka, and A. Sudaka, “Kaposi sarcoma-associated herpes-like virus (human herpesvirus type 8) DNA sequences in multicentric Castleman's disease: is there any relevant association in non-human immunodeficiency virus-infected patients?” Blood, vol. 87, no. 1, pp. 414–416, 1996.
[17]
T. M. Bull, C. D. Cool, and C. D. Cool, “Primary pulmonary hypertension, Castleman's disease and human herpesvirus-8,” European Respiratory Journal, vol. 22, no. 3, pp. 403–407, 2003.
[18]
D. Montani, L. Achouh, and L. Achouh, “Reversibility of pulmonary arterial hypertension in HIV/HHV8-associated Castleman's disease,” European Respiratory Journal, vol. 26, no. 5, pp. 969–972, 2005.
[19]
K. Taniguchi, C. Shimazaki, and C. Shimazaki, “Tocilizumab is effective for pulmonary hypertension associated with multicentric Castleman's disease,” International Journal of Hematology, vol. 90, no. 1, pp. 99–102, 2009.
[20]
S. A. Radkov, P. Kellam, and C. Boshoff, “The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms primary rat cells,” Nature Medicine, vol. 6, no. 10, pp. 1121–1127, 2000.
[21]
E. H.-Y. Cheng, J. Nicholas, D. S. Bellows, G. S. Hayward, H.-G. Guo, M. S. Reitz, and J. M. Hardwick, “A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 2, pp. 690–694, 1997.
[22]
C. D. Cool, P. R. Rai, and P. R. Rai, “Expression of human herpesvirus 8 in primary pulmonary hypertension,” The New England Journal of Medicine, vol. 349, no. 12, pp. 1113–1122, 2003.
[23]
M. Humbert, G. Monti, and G. Monti, “Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension,” American Journal of Respiratory and Critical Care Medicine, vol. 151, no. 5, pp. 1628–1631, 1995.
[24]
N. Selimovic, C.-H. Bergh, B. Andersson, E. Sakiniene, H. Carlsten, and B. Rundqvist, “Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension,” European Respiratory Journal, vol. 34, no. 3, pp. 662–668, 2009.
[25]
R. M. Tuder, M. Chacon, and M. Chacon, “Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis,” The Journal of Pathology, vol. 195, no. 3, pp. 367–374, 2001.
[26]
T. Yoshio, J.-I. Masuyama, and J.-I. Masuyama, “Association of interleukin 6 release from endothelial cells and pulmonary hypertension in SLE,” The Journal of Rheumatology, vol. 24, no. 3, pp. 489–495, 1997.
[27]
T. Nishimaki, S. Aotsuka, H. Kondo, K. Yamamoto, Y. Takasaki, M. Sumiya, and R. Yokohari, “Immunological analysis of pulmonary hypertension in connective tissue diseases,” The Journal of Rheumatology, vol. 26, no. 11, pp. 2357–2362, 1999.
[28]
P. Gourh, F. C. Arnett, and F. C. Arnett, “Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations,” Arthritis Research & Therapy, vol. 11, no. 5, p. R147, 2009.
[29]
P. Lesprit, B. Godeau, and B. Godeau, “Pulmonary hypertension in POEMS syndrome: a new feature mediated by cytokines,” American Journal of Respiratory and Critical Care Medicine, vol. 157, no. 3, pp. 907–911, 1998.
[30]
L. Savale, L. Tu, D. Rideau, M. Izziki, B. Maitre, S. Adnot, and S. Eddahibi, “Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice,” Respiratory Research, vol. 10, p. 6, 2009.
[31]
A. Bhargava, A. Kumar, N. Yuan, M. H. Gewitz, and R. Mathew, “Monocrotaline induces interleukin-6 mRNA expression in rat lungs,” Heart Disease, vol. 1, no. 3, pp. 126–132, 1999.
[32]
M. Miyata, M. Ito, T. Sasajima, H. Ohira, and R. Kasukawa, “Effect of a serotonin receptor antagonist on interleukin-6-induced pulmonary hypertension in rats,” Chest, vol. 119, no. 2, pp. 554–561, 2001.
[33]
T. Kishimoto, “IL-6: from its discovery to clinical applications,” International Immunology, vol. 22, no. 5, pp. 347–352, 2010.
[34]
G. G. Pietra, F. Capron, and F. Capron, “Pathologic assessment of vasculopathies in pulmonary hypertension,” Journal of the American College of Cardiology, vol. 43, no. 12, pp. 25S–32S, 2004.
[35]
R. M. Tuder, B. Groves, D. B. Badesch, and N. F. Voelkel, “Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension,” American Journal of Pathology, vol. 144, no. 2, pp. 275–285, 1994.
[36]
M. K. Steiner, O. L. Syrkina, N. Kolliputi, E. J. Mark, C. A. Hales, and A. B. Waxman, “Interleukin-6 overexpression induces pulmonary hypertension,” Circulation Research, vol. 104, no. 2, pp. 236–244, 2009.
[37]
J. S. Yao, W. Zhai, Y. Fan, M. T. Lawton, N. M. Barbaro, W. L. Young, and G.-Y. Yang, “Interleukin-6 upregulates expression of KDR and stimulates proliferation of human cerebrovascular smooth muscle cells,” Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 3, pp. 510–520, 2007.
[38]
C. D. Cool, D. Kennedy, N. F. Voelkel, and R. M. Tuder, “Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection,” Human Pathology, vol. 28, no. 4, pp. 434–442, 1997.
[39]
M. Rabinovitch, “Molecular pathogenesis of pulmonary arterial hypertension,” The Journal of Clinical Investigation, vol. 118, no. 7, pp. 2372–2379, 2008.
[40]
C. Atkinson, S. Stewart, P. D. Upton, R. Machado, J. R. Thomson, R. C. Trembath, and N. W. Morrell, “Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor,” Circulation, vol. 105, no. 14, pp. 1672–1678, 2002.
[41]
M. Brock, M. Trenkmann, and M. Trenkmann, “Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway,” Circulation Research, vol. 104, no. 10, pp. 1184–1191, 2009.
[42]
B. P. Lewis, C. B. Burge, and D. P. Bartel, “Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets,” Cell, vol. 120, no. 1, pp. 15–20, 2005.
[43]
H. Tagawa, K. Karube, S. Tsuzuki, K. Ohshima, and M. Seto, “Synergistic action of the microRNA-17 polycistron and Myc in aggressive cancer development,” Cancer Science, vol. 98, no. 9, pp. 1482–1490, 2007.
[44]
M. E. Yeager, G. R. Halley, H. A. Golpon, N. F. Voelkel, and R. M. Tuder, “Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension,” Circulation Research, vol. 88, no. 1, pp. E2–E11, 2001.
[45]
A. Papapetropoulos, D. Fulton, and D. Fulton, “Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway,” The Journal of Biological Chemistry, vol. 275, no. 13, pp. 9102–9105, 2000.
[46]
L. Kugathasan, J. B. Ray, Y. Deng, E. Rezaei, D. J. Dumont, and D. J. Stewart, “The angiopietin-1-Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice,” The Journal of Experimental Medicine, vol. 206, no. 10, pp. 2221–2234, 2009.
[47]
F. A. Masri, W. Xu, and W. Xu, “Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension,” American Journal of Physiology, vol. 293, no. 3, pp. L548–L554, 2007.
[48]
T. Imaizumi, H. Yoshida, and K. Satoh, “Regulation of CX3CL1/fractalkine expression in endothelial cells,” Journal of atherosclerosis and thrombosis, vol. 11, no. 1, pp. 15–21, 2004.
[49]
M. Hagen, K. Fagan, W. Steudel, M. Carr, K. Lane, D. M. Rodman, and J. West, “Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle,” American Journal of Physiology, vol. 292, no. 6, pp. L1473–L1479, 2007.
[50]
S. M. Golembeski, J. West, Y. Tada, and K. A. Fagan, “Interleukin-6 mild pulmonary hypertension and augments hypoxia-induced pulmonary hypertension in mice,” Chest, vol. 128, supplement 6, pp. 572S–573S, 2005.
[51]
L. Savale, M. Izikki, and L. Tu, “Attenuated hypoxic pulmonary hypertension in mice lacking the interleukin-6 gene,” American Journal of Respiratory and Critical Care Medicine, vol. 175, p. A42, 2007.
[52]
J. H. Newman, R. C. Trembath, and R. C. Trembath, “Genetic basis of pulmonary arterial hypertension: current understanding and future directions,” Journal of the American College of Cardiology, vol. 43, no. 12, pp. 33S–39S, 2004.
[53]
Y. Song, J. E. Jones, H. Beppu, J. F. Keaney Jr., J. Loscalzo, and Y.-Y. Zhang, “Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice,” Circulation, vol. 112, no. 4, pp. 553–562, 2005.
[54]
S. Sato, M. Hasegawa, and K. Takehara, “Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis,” Journal of Dermatological Science, vol. 27, no. 2, pp. 140–146, 2001.
[55]
K. Schmidt, L. Martinez-Gamboa, and L. Martinez-Gamboa, “Bronchoalveoloar lavage fluid cytokines and chemokines as markers and predictors for the outcome of interstitial lung disease in systemic sclerosis patients,” Arthritis Research & Therapy, vol. 11, no. 4, p. R111, 2009.
[56]
C. A. Feghali, K. L. Bost, D. W. Boulware, and L. S. Levy, “Mechanisms of pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts cultured from affected skin sites of patients with scleroderma,” The Journal of Rheumatology, vol. 19, no. 8, pp. 1207–1211, 1992.
[57]
B. Crestani, N. Seta, and N. Seta, “Interleukin 6 secretion by monocytes and alveolar macrophages in systemic sclerosis with lung involvement,” American Journal of Respiratory and Critical Care Medicine, vol. 149, no. 5, pp. 1260–1265, 1994.
[58]
R. T. Schermuly, E. Dony, and E. Dony, “Reversal of experimental pulmonary hypertension by PDGF inhibition,” The Journal of Clinical Investigation, vol. 115, no. 10, pp. 2811–2821, 2005.
[59]
H. A. Ghofrani, W. Seeger, and F. Grimminger, “Imatinib for the treatment of pulmonary arterial hypertension,” The New England Journal of Medicine, vol. 353, no. 13, pp. 1412–1413, 2005.
[60]
K. C. Patterson, A. Weissmann, T. Ahmadi, and H. W. Farber, “Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension,” Annals of Internal Medicine, vol. 145, no. 2, pp. 152–153, 2006.
[61]
R. Souza, O. Sitbon, F. Parent, G. Simonneau, and M. Humbert, “Long term imatinib treatment in pulmonary arterial hypertension,” Thorax, vol. 61, no. 8, p. 736, 2006.
