E DI TO R IA L
BJD
British Journal of Dermatology
Chronic urticaria: an orphan disease for 125 years
The year 2013 was an important milestone in the history of British dermatology for two reasons. It was the 150th anniversary of the founding of St John’s Hospital for Diseases of the Skin, and it was also the 125th anniversary of the launch of the British Journal of Dermatology (BJD). Both of these have profoundly influenced my career. I was lucky to serve on the faculty of the former for 51 years in various capacities, interrupted only by 6 years’ training at Newcastle and, more recently, 7 years in the Far East. The BJD has unknowingly mentored my academic career by providing a platform for my better contributions to the dermatological literature, while counselling me to take on board flaws in the rest. A strength of both St John’s and the BJD is that they have adapted to change. They have facilitated the transition of British dermatology from a largely descriptive and observational discipline to an internationally acknowledged position at the forefront of biomedical science. This is owing, in part, to recognition of the skin as an accessible medium offering opportunities to solve the mysteries of the biology of healthy skin and the pathophysiology of skin diseases. It also acts as a surrogate investigative medium for tackling unsolved noncutaneous problems. Much groundbreaking research of this nature is being generated at St John’s in cutaneous inflammation, oncology, clinical pharmacology, molecular genetics and photobiology. Work on a more modest scale in cutaneous allergy, and specifically in chronic urticaria, in which I have been involved, has also flourished. My interest in urticaria was first stimulated when I was a registrar at St John’s in the early 1960s. Then, the limit of knowledge was that urticaria is mediated mainly if not entirely by histamine, and therefore routinely treated by antihistamines. My mentor was Sam Shuster, whose academic background was in physiology and pharmacology, and one of his interests was in mediators of inflammation. Sam opened my eyes to the potential of experimentation in the skin of human volunteers to help establish the relevance of proinflammatory mediators in specific inflammatory disorders. We carried out a detailed comparative study of the responses of human skin to three mediators: histamine, 5-hydroxytryptamine and the newly discovered bradykinin.1 Of these, histamine emerged as having the attributes of a mediator of short-lived inflammatory lesions such as acute urticaria. Histamine was known to be synthesized and stored in the skin in dermal mast cells, and manifests tachyphylaxis upon repeated intradermal injection,1 which argues against its involvement as a mediator of more sustained inflammatory reactions. At this time it was evident to both of us that enthusiasm and willingness to work hard
were no substitutes for the acquisition of formal training in research methodology, and I acquired a Medical Research Council 3-year research fellowship, which led to a postgraduate studentship supervised by Jack Mongar and Heinz Schild FRS in the pharmacology department, University College London. Given my interest in urticarial disorders, I was delighted to be offered the opportunity to work on the regulation of histamine secretion from mast cells and basophil leucocytes, and 3 years later I submitted a thesis entitled ‘The Role of the Basophil in Anaphylaxis’. I moved to Newcastle to complete my dermatological training under the guidance of Sam Shuster. There I had access to patients with chronic urticaria, including inducible (‘physical’) urticarias such as symptomatic dermographism and cold contact urticaria. As weals in these patients could be evoked at will, I and a Danish research fellow, the late Jorgen Sondergaard, were able to devise a dermal perfusion technique that enabled histamine to be recovered and measured directly from the patient’s lesional skin, and the time course of its release to be charted.2 Although we learned a great deal about the regulation of release of histamine from skin and its inhibition, this information was of limited value in addressing the greater clinical challenge of the cause and treatment of chronic spontaneous urticaria. Chronic urticaria affects 05–10% of the world population, and is, by general consensus, defined as the daily or almost daily occurrence of urticaria for > 6 weeks. Anyone who deals with these patients on a daily basis will appreciate that ‘chronic urticaria’ is an umbrella term encompassing entities that differ in morphology, histology, immunopathology and treatment. Inducible (‘physical’) urticarias (with the exception of delayed pressure urticaria) present with short-lived (< 30min) weals, which are generally unremarkable histologically, apart from vascular changes, and respond relatively well to H1-antihistamines. In contrast, the weals of chronic spontaneous urticaria individually persist for 12–18 h, have a significant perivascular infiltrate histologically and respond poorly to antihistamines in standard dosage,3 suggesting a more complex molecular pathogenesis and distinctive aetiology. Anne K. Black and I had, in the late 1970s, opened an urticaria clinic at St John’s Institute, which still flourishes to this day. Some years later the offer of a collaboration with Clive Grattan was very welcome and came at the right time. Clive had reported the presence in the serum of some patients with chronic spontaneous urticaria of a factor enabling passive transfer of wealing, which formed the basis of the autologous serum skin test.4 Earlier work of mine showed that basophil leucocytes in chronic spontaneous urticaria had reduced histamine releasability, suggesting basophil desensitization,
© 2014 British Association of Dermatologists
British Journal of Dermatology (2014) 170, pp1211–1213
DOI: 10.1111/bjd.13055
1211
1212 Editorial
possibly by a circulating factor.5 Could that transferable serum factor be an ‘urticaria mediator’? In order to test this hypothesis we needed financial and manpower resources. Our laboratories at St John’s (the Wellcome Laboratories for Skin Pharmacology), including a gas chromatography–mass spectrometry unit, had for some years been supported by the Medical Research Council’s programme grants, but these resources were earmarked for other research purposes that did not include urticaria. Funding for research on urticaria, as well as resources for running a service for these patients, is traditionally hard to come by, and remains so. Unlike psoriasis, skin cancer, eczema and hereditary mechanobullous disorders, urticaria is perceived as relatively trivial. In order to convince sceptical resource allocators, we acquired convincing quality-of-life data. These were obtained with the help of Brigid O‘Donnell. She used an internationally recognized quality-of-life instrument to establish that the degree of disability suffered by patients with chronic urticaria was comparable with that experienced by patients with severe coronary heart disease.6 I shall always be grateful to The Dunhill Trust for stepping in and supporting our hitherto unfashionable research on urticaria. With two Japanese investigators, Michihiro Hide and Naomasa Nimii, we were able to establish that Clive Grattan’s transferrable factor was an IgG or, rarely, IgM autoantibody that would release histamine from mast cells or basophil leucocytes by combining with and cross-linking the a-chain of adjacent high-affinity IgE receptors (FceR1) or, less commonly, IgE itself.7–9 Ruth Sabroe10 established that these autoantibodies are found in 35% of U.K. patients with chronic spontaneous urticaria, and similar figures have been published worldwide. These autoantibodies are histamine releasing, and are the cause of the urticaria. Otherwise similar but nonhistamine-releasing autoantibodies are found in immunobullous diseases and some connective tissue diseases.11 Autoimmune thyroid disease is frequently found in patients with chronic spontaneous urticaria. Recently, it has been proposed that antithyroid peroxidise IgE autoantibodies, when bound to mast cell or basophil leucocyte membranes, could cause ‘autoallergic’ degranulation, but although these autoantibodies are present in about 50% of patients with chronic spontaneous urticaria,12 they have not been demonstrated to be functional (histamine releasing). Can patients with chronic urticaria with functional autoantibodies directed against the high-affinity IgE receptor be deemed to have an autoimmune disease? Autoimmune disease caused by autoantibodies against receptors is well recognized. Examples include myasthenia gravis, in which the acetylcholine receptor is deactivated, and Graves disease, in which autoantibodies cause gain of function at the thyroid-stimulating hormone receptor. That anti-FceR1 autoantibodies cause mast cell and basophil leucocyte activation is akin to the latter. The forgoing developments have greatly influenced treatment of our patients. Those with a high Urticaria Activity Score and resistant to, or intolerant, of H1-antihistamines and montelukast will normally be considered for immunosuppressants British Journal of Dermatology (2014) 170, pp1211–1213
such as ciclosporin,13 methotrexate or mycophenolate mofetil. We have admitted highly selected patients with chronic spontaneous urticaria for intravenous immunoglobulin infusion or plasmapheresis.14,15 These treatments are generally suppressive rather than curative but are a welcome alternative to long-term systemic corticosteroids. Recently, research on chronic spontaneous urticaria has received a shot in the arm (or more precisely a subcutaneous injection) by the serendipitous discovery that the anti-IgE monoclonal antibody omalizumab is effective in inducing remission in even the most recalcitrant cases, with minimal risk of toxicity and only rare treatment failures.16 Like ciclosporin and other immunosuppressants it is not a ‘cure’. The licensing of omalizumab is at present restricted to allergic asthma, but there are grounds for believing its license will soon be extended to chronic spontaneous urticaria. It is believed to work by lowering serum IgE and thereby downregulating the expression of the high-affinity IgE receptor on the surface of dermal mast cells and basophils. That omalizumab causes more rapid remission in chronic urticaria than in allergic asthma raises the possibility of an alternative mode of action, and this is prompting intense research interest. The cause of urticaria in patients without evidence of autoimmunity is also the subject of research. Other unmet needs in chronic urticaria include laboratory diagnosis. This is currently dependent on the serum basophil histamine release test, which is commercially available but of only limited availability within the National Health Service. We hope that solutions to these problems will emerge and perhaps be published in the BJD before its 150th anniversary.
Conflicts of interest M.W.G. is a member of the advisory board of Genentech, which, in collaboration with Novartis, is negotiating an extension of the product licence of omalizumab to include chronic spontaneous urticaria. Cutaneous Allergy Clinic, St John’s Institute of Dermatology, St Thomas’ Hospital, Lambeth Palace Rd, London, SE1 7EH, U.K. E-mail: [email protected]
M.W. GREAVES
References 1 Greaves MW, Shuster S. Responses of skin blood vessels to bradykinin, histamine and 5-hydroxytryptamine. J Physiol 1967; 193:255–67. 2 Greaves MW, Sondergaard J. Pharmacological studies in cutaneous inflammation in man using an in vivo perfusion method. Br J Dermatol 1970; 82(Suppl. 6):82–5. 3 Greaves MW. Chronic idiopathic urticaria. Curr Opin Allergy Clin Immunol 2003; 3:363–8. 4 Grattan CEH, Wallington TB, Warin AP et al. A serological mediator in chronic idiopathic urticaria – a clinical immunological and histological evaluation. Br J Dermatol 1986; 114:583–90. © 2014 British Association of Dermatologists
Editorial 5 Greaves MW, Plummer VM, McLaughlan P, Stanworth DR. Serum and cell-bound IgE in chronic urticaria. Clin Allergy 1974; 4:265–71. 6 O’Donnell BF, Lawlor F, Simpson J et al. The impact of chronic urticaria on quality of life. Br J Dermatol 1997; 136:553–6. 7 Grattan CEH, Francis DM, Hide M, Greaves MW. Detection of circulating histamine releasing autoantibodies with functional properties of anti-IgE in chronic urticaria. Clin Exp Allergy 1991; 21:695–704. 8 Hide M, Francis DM, Grattan CEH et al. Autoantibodies against the high affinity IgE receptor as a cause for histamine release in chronic urticaria. N Eng J Med 1993; 328:1599–604. 9 Nimii N, Francis DM, Kermani F et al. Dermal mast cell activation by autoantibodies against the high affinity IgE receptor in chronic urticaria. J Invest Dermatol 1996; 106:1001–10. 10 Sabroe RA, Fiebiger E, Francis DM et al. Classification of anti-FceR1 and anti-IgE autoantibodies in chronic idiopathic urticaria and correlation with disease severity. J Allergy Clin Immunol 2002; 110:492–9.
© 2014 British Association of Dermatologists
1213
11 Fiebiger E, Hammerschmid F, Stingl G, Maurer D. Anti-FceR1a autoantibodies in autoimmune-mediated disorders. J Clin Invest 1998; 101:243–51. 12 Altrichter S, Peter H-J, Pisarevskala D et al. IgE-mediated autoallergy against thyroid peroxidise – a novel pathomechanism of chronic spontaneous urticaria? PLoS ONE 2011; 6:e14794. 13 Grattan CEH, O’Donnell BF, Francis DM et al. Randomized doubleblind study of cyclosporine in chronic idiopathic urticaria. Br J Dermatol 2000; 143:365–72. 14 Grattan CEH, Francis DM, Slater NGP et al. Plasmapheresis for severe unremitting chronic urticaria. Lancet 1992; 339:1078–80. 15 O’Donnell BF, Barr RM, Kobza Black AK et al. Intravenous immunoglobulin in autoimmune chronic urticaria. Br J Dermatol 1998; 138:101–6. 16 Maurer M, Rosen K, Hsie HJ et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Eng J Med 2013; 368:924–35.
British Journal of Dermatology (2014) 170, pp1211–1213
BJD
British Journal of Dermatology
Chronic urticaria: an orphan disease for 125 years
The year 2013 was an important milestone in the history of British dermatology for two reasons. It was the 150th anniversary of the founding of St John’s Hospital for Diseases of the Skin, and it was also the 125th anniversary of the launch of the British Journal of Dermatology (BJD). Both of these have profoundly influenced my career. I was lucky to serve on the faculty of the former for 51 years in various capacities, interrupted only by 6 years’ training at Newcastle and, more recently, 7 years in the Far East. The BJD has unknowingly mentored my academic career by providing a platform for my better contributions to the dermatological literature, while counselling me to take on board flaws in the rest. A strength of both St John’s and the BJD is that they have adapted to change. They have facilitated the transition of British dermatology from a largely descriptive and observational discipline to an internationally acknowledged position at the forefront of biomedical science. This is owing, in part, to recognition of the skin as an accessible medium offering opportunities to solve the mysteries of the biology of healthy skin and the pathophysiology of skin diseases. It also acts as a surrogate investigative medium for tackling unsolved noncutaneous problems. Much groundbreaking research of this nature is being generated at St John’s in cutaneous inflammation, oncology, clinical pharmacology, molecular genetics and photobiology. Work on a more modest scale in cutaneous allergy, and specifically in chronic urticaria, in which I have been involved, has also flourished. My interest in urticaria was first stimulated when I was a registrar at St John’s in the early 1960s. Then, the limit of knowledge was that urticaria is mediated mainly if not entirely by histamine, and therefore routinely treated by antihistamines. My mentor was Sam Shuster, whose academic background was in physiology and pharmacology, and one of his interests was in mediators of inflammation. Sam opened my eyes to the potential of experimentation in the skin of human volunteers to help establish the relevance of proinflammatory mediators in specific inflammatory disorders. We carried out a detailed comparative study of the responses of human skin to three mediators: histamine, 5-hydroxytryptamine and the newly discovered bradykinin.1 Of these, histamine emerged as having the attributes of a mediator of short-lived inflammatory lesions such as acute urticaria. Histamine was known to be synthesized and stored in the skin in dermal mast cells, and manifests tachyphylaxis upon repeated intradermal injection,1 which argues against its involvement as a mediator of more sustained inflammatory reactions. At this time it was evident to both of us that enthusiasm and willingness to work hard
were no substitutes for the acquisition of formal training in research methodology, and I acquired a Medical Research Council 3-year research fellowship, which led to a postgraduate studentship supervised by Jack Mongar and Heinz Schild FRS in the pharmacology department, University College London. Given my interest in urticarial disorders, I was delighted to be offered the opportunity to work on the regulation of histamine secretion from mast cells and basophil leucocytes, and 3 years later I submitted a thesis entitled ‘The Role of the Basophil in Anaphylaxis’. I moved to Newcastle to complete my dermatological training under the guidance of Sam Shuster. There I had access to patients with chronic urticaria, including inducible (‘physical’) urticarias such as symptomatic dermographism and cold contact urticaria. As weals in these patients could be evoked at will, I and a Danish research fellow, the late Jorgen Sondergaard, were able to devise a dermal perfusion technique that enabled histamine to be recovered and measured directly from the patient’s lesional skin, and the time course of its release to be charted.2 Although we learned a great deal about the regulation of release of histamine from skin and its inhibition, this information was of limited value in addressing the greater clinical challenge of the cause and treatment of chronic spontaneous urticaria. Chronic urticaria affects 05–10% of the world population, and is, by general consensus, defined as the daily or almost daily occurrence of urticaria for > 6 weeks. Anyone who deals with these patients on a daily basis will appreciate that ‘chronic urticaria’ is an umbrella term encompassing entities that differ in morphology, histology, immunopathology and treatment. Inducible (‘physical’) urticarias (with the exception of delayed pressure urticaria) present with short-lived (< 30min) weals, which are generally unremarkable histologically, apart from vascular changes, and respond relatively well to H1-antihistamines. In contrast, the weals of chronic spontaneous urticaria individually persist for 12–18 h, have a significant perivascular infiltrate histologically and respond poorly to antihistamines in standard dosage,3 suggesting a more complex molecular pathogenesis and distinctive aetiology. Anne K. Black and I had, in the late 1970s, opened an urticaria clinic at St John’s Institute, which still flourishes to this day. Some years later the offer of a collaboration with Clive Grattan was very welcome and came at the right time. Clive had reported the presence in the serum of some patients with chronic spontaneous urticaria of a factor enabling passive transfer of wealing, which formed the basis of the autologous serum skin test.4 Earlier work of mine showed that basophil leucocytes in chronic spontaneous urticaria had reduced histamine releasability, suggesting basophil desensitization,
© 2014 British Association of Dermatologists
British Journal of Dermatology (2014) 170, pp1211–1213
DOI: 10.1111/bjd.13055
1211
1212 Editorial
possibly by a circulating factor.5 Could that transferable serum factor be an ‘urticaria mediator’? In order to test this hypothesis we needed financial and manpower resources. Our laboratories at St John’s (the Wellcome Laboratories for Skin Pharmacology), including a gas chromatography–mass spectrometry unit, had for some years been supported by the Medical Research Council’s programme grants, but these resources were earmarked for other research purposes that did not include urticaria. Funding for research on urticaria, as well as resources for running a service for these patients, is traditionally hard to come by, and remains so. Unlike psoriasis, skin cancer, eczema and hereditary mechanobullous disorders, urticaria is perceived as relatively trivial. In order to convince sceptical resource allocators, we acquired convincing quality-of-life data. These were obtained with the help of Brigid O‘Donnell. She used an internationally recognized quality-of-life instrument to establish that the degree of disability suffered by patients with chronic urticaria was comparable with that experienced by patients with severe coronary heart disease.6 I shall always be grateful to The Dunhill Trust for stepping in and supporting our hitherto unfashionable research on urticaria. With two Japanese investigators, Michihiro Hide and Naomasa Nimii, we were able to establish that Clive Grattan’s transferrable factor was an IgG or, rarely, IgM autoantibody that would release histamine from mast cells or basophil leucocytes by combining with and cross-linking the a-chain of adjacent high-affinity IgE receptors (FceR1) or, less commonly, IgE itself.7–9 Ruth Sabroe10 established that these autoantibodies are found in 35% of U.K. patients with chronic spontaneous urticaria, and similar figures have been published worldwide. These autoantibodies are histamine releasing, and are the cause of the urticaria. Otherwise similar but nonhistamine-releasing autoantibodies are found in immunobullous diseases and some connective tissue diseases.11 Autoimmune thyroid disease is frequently found in patients with chronic spontaneous urticaria. Recently, it has been proposed that antithyroid peroxidise IgE autoantibodies, when bound to mast cell or basophil leucocyte membranes, could cause ‘autoallergic’ degranulation, but although these autoantibodies are present in about 50% of patients with chronic spontaneous urticaria,12 they have not been demonstrated to be functional (histamine releasing). Can patients with chronic urticaria with functional autoantibodies directed against the high-affinity IgE receptor be deemed to have an autoimmune disease? Autoimmune disease caused by autoantibodies against receptors is well recognized. Examples include myasthenia gravis, in which the acetylcholine receptor is deactivated, and Graves disease, in which autoantibodies cause gain of function at the thyroid-stimulating hormone receptor. That anti-FceR1 autoantibodies cause mast cell and basophil leucocyte activation is akin to the latter. The forgoing developments have greatly influenced treatment of our patients. Those with a high Urticaria Activity Score and resistant to, or intolerant, of H1-antihistamines and montelukast will normally be considered for immunosuppressants British Journal of Dermatology (2014) 170, pp1211–1213
such as ciclosporin,13 methotrexate or mycophenolate mofetil. We have admitted highly selected patients with chronic spontaneous urticaria for intravenous immunoglobulin infusion or plasmapheresis.14,15 These treatments are generally suppressive rather than curative but are a welcome alternative to long-term systemic corticosteroids. Recently, research on chronic spontaneous urticaria has received a shot in the arm (or more precisely a subcutaneous injection) by the serendipitous discovery that the anti-IgE monoclonal antibody omalizumab is effective in inducing remission in even the most recalcitrant cases, with minimal risk of toxicity and only rare treatment failures.16 Like ciclosporin and other immunosuppressants it is not a ‘cure’. The licensing of omalizumab is at present restricted to allergic asthma, but there are grounds for believing its license will soon be extended to chronic spontaneous urticaria. It is believed to work by lowering serum IgE and thereby downregulating the expression of the high-affinity IgE receptor on the surface of dermal mast cells and basophils. That omalizumab causes more rapid remission in chronic urticaria than in allergic asthma raises the possibility of an alternative mode of action, and this is prompting intense research interest. The cause of urticaria in patients without evidence of autoimmunity is also the subject of research. Other unmet needs in chronic urticaria include laboratory diagnosis. This is currently dependent on the serum basophil histamine release test, which is commercially available but of only limited availability within the National Health Service. We hope that solutions to these problems will emerge and perhaps be published in the BJD before its 150th anniversary.
Conflicts of interest M.W.G. is a member of the advisory board of Genentech, which, in collaboration with Novartis, is negotiating an extension of the product licence of omalizumab to include chronic spontaneous urticaria. Cutaneous Allergy Clinic, St John’s Institute of Dermatology, St Thomas’ Hospital, Lambeth Palace Rd, London, SE1 7EH, U.K. E-mail: [email protected]
M.W. GREAVES
References 1 Greaves MW, Shuster S. Responses of skin blood vessels to bradykinin, histamine and 5-hydroxytryptamine. J Physiol 1967; 193:255–67. 2 Greaves MW, Sondergaard J. Pharmacological studies in cutaneous inflammation in man using an in vivo perfusion method. Br J Dermatol 1970; 82(Suppl. 6):82–5. 3 Greaves MW. Chronic idiopathic urticaria. Curr Opin Allergy Clin Immunol 2003; 3:363–8. 4 Grattan CEH, Wallington TB, Warin AP et al. A serological mediator in chronic idiopathic urticaria – a clinical immunological and histological evaluation. Br J Dermatol 1986; 114:583–90. © 2014 British Association of Dermatologists
Editorial 5 Greaves MW, Plummer VM, McLaughlan P, Stanworth DR. Serum and cell-bound IgE in chronic urticaria. Clin Allergy 1974; 4:265–71. 6 O’Donnell BF, Lawlor F, Simpson J et al. The impact of chronic urticaria on quality of life. Br J Dermatol 1997; 136:553–6. 7 Grattan CEH, Francis DM, Hide M, Greaves MW. Detection of circulating histamine releasing autoantibodies with functional properties of anti-IgE in chronic urticaria. Clin Exp Allergy 1991; 21:695–704. 8 Hide M, Francis DM, Grattan CEH et al. Autoantibodies against the high affinity IgE receptor as a cause for histamine release in chronic urticaria. N Eng J Med 1993; 328:1599–604. 9 Nimii N, Francis DM, Kermani F et al. Dermal mast cell activation by autoantibodies against the high affinity IgE receptor in chronic urticaria. J Invest Dermatol 1996; 106:1001–10. 10 Sabroe RA, Fiebiger E, Francis DM et al. Classification of anti-FceR1 and anti-IgE autoantibodies in chronic idiopathic urticaria and correlation with disease severity. J Allergy Clin Immunol 2002; 110:492–9.
© 2014 British Association of Dermatologists
1213
11 Fiebiger E, Hammerschmid F, Stingl G, Maurer D. Anti-FceR1a autoantibodies in autoimmune-mediated disorders. J Clin Invest 1998; 101:243–51. 12 Altrichter S, Peter H-J, Pisarevskala D et al. IgE-mediated autoallergy against thyroid peroxidise – a novel pathomechanism of chronic spontaneous urticaria? PLoS ONE 2011; 6:e14794. 13 Grattan CEH, O’Donnell BF, Francis DM et al. Randomized doubleblind study of cyclosporine in chronic idiopathic urticaria. Br J Dermatol 2000; 143:365–72. 14 Grattan CEH, Francis DM, Slater NGP et al. Plasmapheresis for severe unremitting chronic urticaria. Lancet 1992; 339:1078–80. 15 O’Donnell BF, Barr RM, Kobza Black AK et al. Intravenous immunoglobulin in autoimmune chronic urticaria. Br J Dermatol 1998; 138:101–6. 16 Maurer M, Rosen K, Hsie HJ et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Eng J Med 2013; 368:924–35.
British Journal of Dermatology (2014) 170, pp1211–1213
