Clinics in Dermatology (2014) 32, 420–423
Chronic urticaria as a systemic disease Razvigor Darlenski, MD, PhD a,⁎, Jana Kazandjieva, MD b , Torsten Zuberbier, MD c , Nikolai Tsankov, MD, PhD, MSc a a
Department of Dermatology and Venereology, Tokuda Hospital-Sofia, 51B Nikola Vaptsarov Blvd., Bulgaria Department of Dermatology and Venereology, Medical Faculty, Medical University-Sofia, Bulgaria c Department of Dermatology, Venereology and Allergology, Charité University Clinic, Berlin, Germany b
Abstract Urticaria is one of the most common diseases seen in everyday dermatologic practice, characterized by the development of wheals, angioedema, or both. While acute urticaria is mostly related to allergic or pseudoallergic reaction to food, drugs, or infections, chronic urticaria is a more complex disease with different additional ethiopathologic mechanisms and evoking factors. While urticaria is an undisputed disease of the skin, growing evidence supports, like in other dermatologic diseases, the concept of urticaria as a systemic disease with clinical symptoms and signs predominantly presenting on the skin. In this review, we describe the evidence and association between chronic urticaria and a variety of disorders, such as autoimmune diseases, atopy, infections, metabolic conditions, and neoplastic disorders. Beyond the mechanistic association, the possible common underlying pathomechanisms, such as systemic immunologic processes, are discussed. © 2014 Elsevier Inc. All rights reserved.
Introduction A disease that affects a number of organs and tissues, or affects the body as a whole, can be regarded as a systemic one.1 Presuming this definition, a differentiation between disease association and true systemic involvement should be made. Urticaria, also known as hives, is an inflammatory disease, characterized by the development of wheals (hives), angioedema, or both.2 As different conditions, which may present with wheals or angioedema, eg, skin prick test, anaphylaxis, autoinflammatory syndromes, Muckle-Wells syndrome, Schnitzler’s syndrome, and Well’s syndrome, these are not the focus of this review and will not be addressed, herein. Chronic urticaria (CU) is defined as a duration of the disease for more than six weeks. The lifetime prevalence of ⁎ Corresponding author. Tel.: +359 890 545599. E-mail address: [email protected] (R. Darlenski). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.009
urticaria is 8.8% to 20% and 1.8% for CU in particular.3 CU seriously affects the quality of life of the patients and results in difficulties in relation to work, domestic activities, social life, home relationships, sexual life, hobbies, and holidays.4 It is the reason for sleep disturbances and impairs work and school productivity.5
Historical perspective Feng Yin Zheng is the name under which urticaria probably was first documented in the “The Yellow Emperor’s Inner Classic,” written about 1000 years B.C.E. 6 As with many diseases, it was considered as an imbalance between Yin and Yang. Hippocrates suggested that ingesting some foods like milk, as well as contact with nettle and mosquito bites, can induce an itching skin rash, named knido.7 It is accepted that the modern name of the disease dates back to the old Latin term urtica for nettle (Urtica urens), although the first use of the term urticaria
Chronic urticaria was in the 18th century in the book Synopsia Nosalogiae Methodica. In subsequent years, different subtypes of urticaria have been described. The modern understanding of the disease is related to the works of one man who, in 1877, discovered the mastocytes and the works of several researchers on histamine. 8 Milestones in the study of urticaria include the revealing of the role of IgE and the classification of the disease as a type 1 reaction.8 The concept of CU, as a systemic disease crossing the frontiers of the skin, is not a new one. In the midtwentieth century, different loci of infection or other concomitant disease were revealed by many researchers. An autoimmune nature was first suspected by the Swedish dermatologist Rorsman, and supported by the findings of Leznoff on the association of CU with thyroid autoimmunity.9 Today, autoimmune urticaria is accepted as one of the possible underlying causes in CSU. In the beginning of this century, the concept of chronic urticaria (CU) as a systemic disease has further developed.
Pathophysiology in the light of systemic involvement Patients with CSU present spontaneous appearance of wheals, angioedema, or both in unpredictable places of the integument without external triggers. The mast cell is the key player, although not the only one, in the pathogenesis of urticaria. Degranulation of these cells results in the release of mediators, above all histamine, responsible for the inflammatory changes, sensory nerve activation, and the local increase in permeability of capillaries and venules. Beyond histamine, leukotrienes, serine proteases, heparin, tryptase, and proinflammatory cytokines are involved in the pathogenesis of the disease. Histamine can modulate systemic inflammatory response and posses certain effects on cellmediated immunity, eg, on monocytes. 10 Subclinical inflammation, as also observed in obesity, stimulates mast cell reactivity by the secretion of adipocytokines, such as interleukin-9 (IL-9), IL-33, and stress molecules, including corticotropin-releasing hormone and neurotensin.11 Biologic markers of inflammation, namely C-reactive protein (CRP) and procalcitonin, are elevated in the sera of CU patients, suggesting possible enrolment in urticarial inflammation.12 CU can be regarded as a disease with systemic vascular inflammation, even in sites uninvolved with lesions. In support of this hypothesis, an increase in the soluble P-selectin in CU (as well as in dermographic urticaria) compared to healthy controls and rhinitis subjects.13 P-selectin, a cell adhesion molecule on the surfaces of activated endothelial cells, was observed immunohistologically even in nonlesional skin, suggesting subclinical inflammation in clinically healthy areas. Coagulation factors may enhance vascular permeability or induce mast cell degranulation. Tissue factor, an initiator of
421 the extrinsic cascade of blood coagulation, has been linked to systemic inflammation. Its activation results in signaling from the coagulant mediators (factors VIIa, Xa, and IIa), as well as from the fibrin mediate diverse intracellular activation and the production of proinflammatory mediators, including cytokines, adhesion molecules, and growth factors.14 Such coagulation-dependent or noncoagulationmediated actions suggest the role of the so-called coagulation-inflammation-thrombosis circuit. CU is characterized by elevated blood coagulation potential with all parameters of a global coagulation test correlating to the urticaria severity.15 Fibrin degradation products, D-dimer and serum CRP levels decreased in serum of CU patients as their disease improved, while they rose during CU exacerbation.16 The role of concomitant infections is mainly focused in the pathogenesis of acute urticaria. Infections and microbial carriage have a potential role in CU, namely Helicobacter pylori, Streptococcus spp., Yersinia enterocolitica, and the hepatitis C virus.17 The most commonly affected systems include ear-nose-throat (ENT), gastro-intestinal tract (GI), and dental. The most widely studied microorganism is H pylori. The rate of remission of CU, when H pylori was eradicated, was 61.5% in comparison to 33.6% without eradication (remission rate among control subjects without H pylori infection was 29.7%).17 It is suggested that among other factors, screening for H pylori infection and its eradication is reasonable in patients with CU.17,18 ENT infections, such as tonsillitis and sinusitis, have been found in about half of the patients with CU.19 Nasal carriage of Staphylococcus aureus was found in 53.2% of patients with CU, while this percentage reached just 13.3% in healthy controls.20 Although the list of reports for the association between different infections and CU is increasing, the efficacy of systemic antimicrobial agents has not been challenged in prospective controlled studies.
Clinical evidence for systemic involvement CNS effects of urticaria The link between skin and the mind and the role of neuroendocrino-immunologic regulation in both psychiatric and skin diseases has been considered in recent decades. Psychological stress is accepted as one of the provoking factors in CU.21 In addition, CU patients show difficulties in dealing with emotion arousal, suggesting an association between CU and alexithymia.22 The psychological profile of CU patients includes a neurotic personality trait.23 Psychiatric comorbidities were registered in 60% of the CU adult population; depression was the most common diagnosis.24 Similar results were revealed in the pediatric population, where 70% of the patients with CU (versus 30% of the controls) presented with a psychiatric comorbidity.25
422 The most common diagnoses included social anxiety disorder, separation anxiety disorder, and specific phobias. The authors also disclosed depression, trait anxiety, internalizing problems, and somatic complaints as major issues in these patients. No correlation was found with the duration and the severity of CU. A recent study observed psychiatric problems in 48% of patients with chronic spontaneous urticaria.26 Among all anxiety disorders, mostly phobias, followed by depression, and somatoform disorders, were the most common. The role of treating psychiatric comorbidities in CU remains to be elucidated.
Association between CU and other diseases CU can often be associated with multiple systemic disorders. Some of the evidence shows that these associations are not simply mechanistic, but they also possibly involve common pathogenic mechanism.
Atopic diathesis A study among more than 4000 children up to 2 years of age found an association between atopic dermatitis (AD) and other manifestations from the atopic spectrum.27 Urticaria was one of the most common concomitant diseases with a ratio of proportions of 2.04 (CI 1.80-2.31). In another study, history of childhood dermatitis was strongly associated with urticaria (odds ratio, 2.50).28 In a large cohort, prick tests revealed sensitization of ≥ 1 for type 1 allergens in 39.1% of patients with urticaria.3 The results were related to comorbidities, such as allergic rhinitis or oral allergy syndrome, but were never the underlying cause of CU, as proven by doubleblind, placebo-controlled provocation tests. Allergic skin disorders, such as AD and urticarial, are frequently associated with comorbidities, including allergic rhinitis and chronic rhinosinusitis.29 In addition to the high prevalence and coincidence, probable common or similar pathomechanisms could be involved. In a study among almost 4000 schoolchildren urticaria was disclosed as a significant risk factor for the development of allergic rhinitis.30
Autoimmune diseases Chronic autoimmune urticaria (CAU) is caused by antiFcεRI, and less frequently, by anti-IgE autoantibodies that lead to mast cell activation. Autoimmunity is a systemic process not limited to the skin, in accordance with understanding of urticaria as a systemic disease. Confirmation comes from the numerous associations between CU and autoimmune diseases.31
R. Darlenski et al. Autoantibodies against the alpha subunit of the high-affinity IgE receptor have been witnessed in the sera of 35% to 55% of patients with CU, an entity that was later classified as autoimmune urticaria.32,33 The specificity of autoantibodies responsible for the activation of the basophils (CU index) was evaluated in different diseases, demonstrating positivity in 33% of the cases with CU, 23% in systemic lupus erythematosus, 3.7% of patients with rheumatoid arthritis, and 15% of controls.34 These results suggest that the functional autoantibodies are not specific, although highly prevalent in CU. Recent data from following nearly 13,000 patients with CU found that women had a significantly higher incidence of rheumatoid arthritis, Sjögren syndrome, celiac disease, type I diabetes mellitus, and systemic lupus erythematosus.31 Positive rheumatoid factor and antinuclear antibodies were significantly more prevalent in patients with CU. The diagnosis of the autoimmune disorder was made mostly in the 10 years after the patient was diagnosed with CU. CU was observed in 4.3 of the cases amongst 46 studied patients with systemic sclerosis.35 Antithyroid antibodies are detectable in up to 30% in patients with CU, although their presence is neither associated with hormonal dysfunction of the gland, nor with the severity and the course of urticaria.36,37
Miscellaneous The metabolic syndrome (MS) is associated with CU according to a recent report.38 MS was observed in 29.8% of patients with CU, significantly higher compared with 17.8% in a matched control group. Patients with coexistence of both disorders had a higher mean urticaria activity score and serum levels of eosinophil cationic protein, tumor necrosis factor-α, and complements, and showed a higher rate of negative autologous serum skin tests in comparison to those without metabolic syndrome. Lower serum vitamin D levels were found in patients with CU.39 In analogy to other diseases, supplementation of vitamin D in subjects with urticarial skin lesions resulted in improvement of the symptoms.40
Conclusions Until recently, extensive testing of urticaria patients was the rule. Currently, the evidence is clear that extensive testing is not economic and the guidelines strongly recommend focusing the diagnostic procedures based on patient history. A growing body of evidence suggests that CU is often accompanied, as well as modulated, by a plethora of systemic diseases. That may open a new debate on the clinical relevance of administering laboratory investigations for the active screening of concomitant disorders. The question of predicting markers and the role of treating these comorbidities remains to be addressed in future controlled clinical trials.
Chronic urticaria
References 1. Dorland WAN, Anderson DM. Dorland’s Illustrated Medical Dictionary. 28th ed. Philadelphia: Elsevier Health Sciences; 1994: 489, 1653. 2. Zuberbier T, Asero R, Bindslev-Jensen C, et al. EAACI/GA(2) LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy. 2009;64:1417-1426. 3. Zuberbier T, Balke M, Worm M, et al. Epidemiology of urticaria: a representative cross-sectional population survey. Clin Exp Dermatol. 2010;35:869-873. 4. O’Donnell BF, Lawlor F, Simpson J, et al. The impact of chronic urticaria on the quality of life. Br J Dermatol. 1997;136:197-201. 5. Zuberbier T. Pharmacological rationale for the treatment of chronic urticaria with second-generation non-sedating antihistamines at higherthan-standard doses. J Eur Acad Dermatol Venereol. 2012;26:9-18. 6. Veith I. The Yellow Emperor’s Classic of Internal Medicine. Malaysia: Pelanduk Publications. 1992. 7. Juhlin L. The History of Urticaria and Angioedema. ESHDV Special Annual Lecture: Geneva, Switzerland. 2000. 8. Greaves M. History of urticaria. In: Zuberbier T, Grattan CEH, Maurer M, eds. Urticaria and Angiodema. Heidelberg Dordrecht London New York: Springer-Verlag; 2010. p. 1-7. 9. Leznoff A, Sussman GL. Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients. J Allergy Clin Immunol. 1989;84:66-71. 10. Soga F, Katoh N, Kishimoto S. Histamine prevents apoptosis in human monocytes. Clin Exp Allergy. 2007;37:323-330. 11. Sismanopoulos N, Delivanis DA, Mavrommati D, et al. Do mast cells link obesity and asthma? Allergy. 2013;68:8-15. 12. Kasperska-Zajac A, Grzanka A, Machura E, et al. Analysis of procalcitonin and CRP concentrations in serum of patients with chronic spontaneous urticaria. Inflamm Res. 2013;62:309-312. 13. Zuberbier T, Schadendorf D, Haas N, et al. Enhanced P-selectin expression in chronic and dermographic urticaria. Int Arch Allergy Immunol. 1997;114:86-89. 14. Chu AJ. Tissue factor, blood coagulation, and beyond: an overview. Int J Inflam. 2011;367:284. 15. Takeda T, Sakurai Y, Takahagi S, et al. Increase of coagulation potential in chronic spontaneous urticaria. Allergy. 2011;66:428-433. 16. Takahagi S, Mihara S, Iwamoto K, et al. Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria. Allergy. 2010;65:649-656. 17. Wedi B, Raap U, Wieczorek D, et al. Urticaria and infections. Allergy Asthma Clin Immunol. 2009;5:10. 18. Federman DG, Kirsner RS, Moriarty JP, et al. The effect of antibiotic therapy for patients infected with Helicobacter pylori who have chronic urticaria. J Am Acad Dermatol. 2003;49:861-864. 19. Buss YA, Garrelfs UC, Sticherling M. Chronic urticaria—which clinical parameters are pathogenetically relevant? A retrospective investigation of 339 patients. J Dtsch Dermatol Ges. 2007;5:22-29. 20. Ertam I, Biyikli SE, Yazkan FA, et al. The frequency of nasal carriage in chronic urticaria patients. J Eur Acad Dermatol Venereol. 2007;21:777-780. 21. Gupta MA, Gupta AK. Chronic idiopathic urticaria and post-traumatic stress disorder (PTSD): an under-recognized comorbidity. Clin Dermatol. 2012;30:351-354.
423 22. Barbosa F, Freitas J, Barbosa A. Alexithymia in chronic urticaria patients. Psychol Health Med. 2011;16:215-224. 23. Chung MC, Symons C, Gilliam J, et al. The relationship between posttraumatic stress disorder, psychiatric comorbidity, and personality traits among patients with chronic idiopathic urticaria. Compr Psychiatry. 2010;51:55-63. 24. Ozkan M, Oflaz SB, Kocaman N, et al. Psychiatric morbidity and quality of life in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2007;99:29-33. 25. Herguner S, Kilic G, Karakoc S, et al. Levels of depression, anxiety and behavioural problems and frequency of psychiatric disorders in children with chronic idiopathic urticaria. Br J Dermatol. 2011;164: 1342-1347. 26. Staubach P, Dechene M, Metz M, et al. High prevalence of mental disorders and emotional distress in patients with chronic spontaneous urticaria. Acta Derm Venereol. 2011;91:557-561. 27. Bohme M, Lannero E, Wickman M, et al. Atopic dermatitis and concomitant disease patterns in children up to two years of age. Acta Derm Venereol. 2002;82:98-103. 28. Bingefors K, Svensson A, Isacson D, et al. Self-reported lifetime prevalence of atopic dermatitis and co-morbidity with asthma and eczema in adulthood: a population-based cross-sectional survey. Acta Derm Venereol. 2012;93:438-441. 29. Olze H, Zuberbier T. Comorbidities between nose and skin allergy. Curr Opin Allergy Clin Immunol. 2011;11:457-463. 30. Sultesz M, Katona G, Hirschberg A, et al. Prevalence and risk factors for allergic rhinitis in primary schoolchildren in Budapest. Int J Pediatr Otorhinolaryngol. 2010;74:503-509. 31. Confino-Cohen R, Chodick G, Shalev V, et al. Chronic urticaria and autoimmunity: associations found in a large population study. J Allergy Clin Immunol. 2012;129:1307-1313. 32. Tong LJ, Balakrishnan G, Kochan JP, et al. Assessment of autoimmunity in patients with chronic urticaria. J Allergy Clin Immunol. 1997;99:461-465. 33. Hide M, Francis DM, Grattan CE, et al. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med. 1993;328:1599-1604. 34. Cho CB, Stutes SA, Altrich ML, et al. Autoantibodies in chronic idiopathic urticaria and nonurticarial systemic autoimmune disorders. Ann Allergy Asthma Immunol. 2013;110:29-33. 35. Ghosh SK, Bandyopadhyay D, Saha I, et al. Mucocutaneous and demographic features of systemic sclerosis: A profile of 46 patients from eastern India. Indian J Dermatol. 2012;57:201-205. 36. Wan KS, Wu CS. The essential role of anti-thyroid antibodies in chronic idiopathic urticaria. Endocr Res. 2013;38:85-88. 37. Nuzzo V, Tauchmanova L, Colasanti P, et al. Idiopathic chronic urticaria and thyroid autoimmunity: experience of a single center. Dermatoendocrinol. 2011;3:255-258. 38. Ye YM, Jin HJ, Hwang EK, et al. Co-existence of chronic urticaria and metabolic syndrome: clinical implications. Acta Derm Venereol. 2013;93:156-160. 39. Thorp WA, Goldner W, Meza J, et al. Reduced vitamin D levels in adult subjects with chronic urticaria. J Allergy Clin Immunol. 2010;126:413. [author reply 413-414]. 40. Goetz DW. Idiopathic itch, rash, and urticaria/angioedema merit serum vitamin D evaluation: a descriptive case series. W V Med J. 2011;107: 14-20.
Chronic urticaria as a systemic disease Razvigor Darlenski, MD, PhD a,⁎, Jana Kazandjieva, MD b , Torsten Zuberbier, MD c , Nikolai Tsankov, MD, PhD, MSc a a
Department of Dermatology and Venereology, Tokuda Hospital-Sofia, 51B Nikola Vaptsarov Blvd., Bulgaria Department of Dermatology and Venereology, Medical Faculty, Medical University-Sofia, Bulgaria c Department of Dermatology, Venereology and Allergology, Charité University Clinic, Berlin, Germany b
Abstract Urticaria is one of the most common diseases seen in everyday dermatologic practice, characterized by the development of wheals, angioedema, or both. While acute urticaria is mostly related to allergic or pseudoallergic reaction to food, drugs, or infections, chronic urticaria is a more complex disease with different additional ethiopathologic mechanisms and evoking factors. While urticaria is an undisputed disease of the skin, growing evidence supports, like in other dermatologic diseases, the concept of urticaria as a systemic disease with clinical symptoms and signs predominantly presenting on the skin. In this review, we describe the evidence and association between chronic urticaria and a variety of disorders, such as autoimmune diseases, atopy, infections, metabolic conditions, and neoplastic disorders. Beyond the mechanistic association, the possible common underlying pathomechanisms, such as systemic immunologic processes, are discussed. © 2014 Elsevier Inc. All rights reserved.
Introduction A disease that affects a number of organs and tissues, or affects the body as a whole, can be regarded as a systemic one.1 Presuming this definition, a differentiation between disease association and true systemic involvement should be made. Urticaria, also known as hives, is an inflammatory disease, characterized by the development of wheals (hives), angioedema, or both.2 As different conditions, which may present with wheals or angioedema, eg, skin prick test, anaphylaxis, autoinflammatory syndromes, Muckle-Wells syndrome, Schnitzler’s syndrome, and Well’s syndrome, these are not the focus of this review and will not be addressed, herein. Chronic urticaria (CU) is defined as a duration of the disease for more than six weeks. The lifetime prevalence of ⁎ Corresponding author. Tel.: +359 890 545599. E-mail address: [email protected] (R. Darlenski). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.009
urticaria is 8.8% to 20% and 1.8% for CU in particular.3 CU seriously affects the quality of life of the patients and results in difficulties in relation to work, domestic activities, social life, home relationships, sexual life, hobbies, and holidays.4 It is the reason for sleep disturbances and impairs work and school productivity.5
Historical perspective Feng Yin Zheng is the name under which urticaria probably was first documented in the “The Yellow Emperor’s Inner Classic,” written about 1000 years B.C.E. 6 As with many diseases, it was considered as an imbalance between Yin and Yang. Hippocrates suggested that ingesting some foods like milk, as well as contact with nettle and mosquito bites, can induce an itching skin rash, named knido.7 It is accepted that the modern name of the disease dates back to the old Latin term urtica for nettle (Urtica urens), although the first use of the term urticaria
Chronic urticaria was in the 18th century in the book Synopsia Nosalogiae Methodica. In subsequent years, different subtypes of urticaria have been described. The modern understanding of the disease is related to the works of one man who, in 1877, discovered the mastocytes and the works of several researchers on histamine. 8 Milestones in the study of urticaria include the revealing of the role of IgE and the classification of the disease as a type 1 reaction.8 The concept of CU, as a systemic disease crossing the frontiers of the skin, is not a new one. In the midtwentieth century, different loci of infection or other concomitant disease were revealed by many researchers. An autoimmune nature was first suspected by the Swedish dermatologist Rorsman, and supported by the findings of Leznoff on the association of CU with thyroid autoimmunity.9 Today, autoimmune urticaria is accepted as one of the possible underlying causes in CSU. In the beginning of this century, the concept of chronic urticaria (CU) as a systemic disease has further developed.
Pathophysiology in the light of systemic involvement Patients with CSU present spontaneous appearance of wheals, angioedema, or both in unpredictable places of the integument without external triggers. The mast cell is the key player, although not the only one, in the pathogenesis of urticaria. Degranulation of these cells results in the release of mediators, above all histamine, responsible for the inflammatory changes, sensory nerve activation, and the local increase in permeability of capillaries and venules. Beyond histamine, leukotrienes, serine proteases, heparin, tryptase, and proinflammatory cytokines are involved in the pathogenesis of the disease. Histamine can modulate systemic inflammatory response and posses certain effects on cellmediated immunity, eg, on monocytes. 10 Subclinical inflammation, as also observed in obesity, stimulates mast cell reactivity by the secretion of adipocytokines, such as interleukin-9 (IL-9), IL-33, and stress molecules, including corticotropin-releasing hormone and neurotensin.11 Biologic markers of inflammation, namely C-reactive protein (CRP) and procalcitonin, are elevated in the sera of CU patients, suggesting possible enrolment in urticarial inflammation.12 CU can be regarded as a disease with systemic vascular inflammation, even in sites uninvolved with lesions. In support of this hypothesis, an increase in the soluble P-selectin in CU (as well as in dermographic urticaria) compared to healthy controls and rhinitis subjects.13 P-selectin, a cell adhesion molecule on the surfaces of activated endothelial cells, was observed immunohistologically even in nonlesional skin, suggesting subclinical inflammation in clinically healthy areas. Coagulation factors may enhance vascular permeability or induce mast cell degranulation. Tissue factor, an initiator of
421 the extrinsic cascade of blood coagulation, has been linked to systemic inflammation. Its activation results in signaling from the coagulant mediators (factors VIIa, Xa, and IIa), as well as from the fibrin mediate diverse intracellular activation and the production of proinflammatory mediators, including cytokines, adhesion molecules, and growth factors.14 Such coagulation-dependent or noncoagulationmediated actions suggest the role of the so-called coagulation-inflammation-thrombosis circuit. CU is characterized by elevated blood coagulation potential with all parameters of a global coagulation test correlating to the urticaria severity.15 Fibrin degradation products, D-dimer and serum CRP levels decreased in serum of CU patients as their disease improved, while they rose during CU exacerbation.16 The role of concomitant infections is mainly focused in the pathogenesis of acute urticaria. Infections and microbial carriage have a potential role in CU, namely Helicobacter pylori, Streptococcus spp., Yersinia enterocolitica, and the hepatitis C virus.17 The most commonly affected systems include ear-nose-throat (ENT), gastro-intestinal tract (GI), and dental. The most widely studied microorganism is H pylori. The rate of remission of CU, when H pylori was eradicated, was 61.5% in comparison to 33.6% without eradication (remission rate among control subjects without H pylori infection was 29.7%).17 It is suggested that among other factors, screening for H pylori infection and its eradication is reasonable in patients with CU.17,18 ENT infections, such as tonsillitis and sinusitis, have been found in about half of the patients with CU.19 Nasal carriage of Staphylococcus aureus was found in 53.2% of patients with CU, while this percentage reached just 13.3% in healthy controls.20 Although the list of reports for the association between different infections and CU is increasing, the efficacy of systemic antimicrobial agents has not been challenged in prospective controlled studies.
Clinical evidence for systemic involvement CNS effects of urticaria The link between skin and the mind and the role of neuroendocrino-immunologic regulation in both psychiatric and skin diseases has been considered in recent decades. Psychological stress is accepted as one of the provoking factors in CU.21 In addition, CU patients show difficulties in dealing with emotion arousal, suggesting an association between CU and alexithymia.22 The psychological profile of CU patients includes a neurotic personality trait.23 Psychiatric comorbidities were registered in 60% of the CU adult population; depression was the most common diagnosis.24 Similar results were revealed in the pediatric population, where 70% of the patients with CU (versus 30% of the controls) presented with a psychiatric comorbidity.25
422 The most common diagnoses included social anxiety disorder, separation anxiety disorder, and specific phobias. The authors also disclosed depression, trait anxiety, internalizing problems, and somatic complaints as major issues in these patients. No correlation was found with the duration and the severity of CU. A recent study observed psychiatric problems in 48% of patients with chronic spontaneous urticaria.26 Among all anxiety disorders, mostly phobias, followed by depression, and somatoform disorders, were the most common. The role of treating psychiatric comorbidities in CU remains to be elucidated.
Association between CU and other diseases CU can often be associated with multiple systemic disorders. Some of the evidence shows that these associations are not simply mechanistic, but they also possibly involve common pathogenic mechanism.
Atopic diathesis A study among more than 4000 children up to 2 years of age found an association between atopic dermatitis (AD) and other manifestations from the atopic spectrum.27 Urticaria was one of the most common concomitant diseases with a ratio of proportions of 2.04 (CI 1.80-2.31). In another study, history of childhood dermatitis was strongly associated with urticaria (odds ratio, 2.50).28 In a large cohort, prick tests revealed sensitization of ≥ 1 for type 1 allergens in 39.1% of patients with urticaria.3 The results were related to comorbidities, such as allergic rhinitis or oral allergy syndrome, but were never the underlying cause of CU, as proven by doubleblind, placebo-controlled provocation tests. Allergic skin disorders, such as AD and urticarial, are frequently associated with comorbidities, including allergic rhinitis and chronic rhinosinusitis.29 In addition to the high prevalence and coincidence, probable common or similar pathomechanisms could be involved. In a study among almost 4000 schoolchildren urticaria was disclosed as a significant risk factor for the development of allergic rhinitis.30
Autoimmune diseases Chronic autoimmune urticaria (CAU) is caused by antiFcεRI, and less frequently, by anti-IgE autoantibodies that lead to mast cell activation. Autoimmunity is a systemic process not limited to the skin, in accordance with understanding of urticaria as a systemic disease. Confirmation comes from the numerous associations between CU and autoimmune diseases.31
R. Darlenski et al. Autoantibodies against the alpha subunit of the high-affinity IgE receptor have been witnessed in the sera of 35% to 55% of patients with CU, an entity that was later classified as autoimmune urticaria.32,33 The specificity of autoantibodies responsible for the activation of the basophils (CU index) was evaluated in different diseases, demonstrating positivity in 33% of the cases with CU, 23% in systemic lupus erythematosus, 3.7% of patients with rheumatoid arthritis, and 15% of controls.34 These results suggest that the functional autoantibodies are not specific, although highly prevalent in CU. Recent data from following nearly 13,000 patients with CU found that women had a significantly higher incidence of rheumatoid arthritis, Sjögren syndrome, celiac disease, type I diabetes mellitus, and systemic lupus erythematosus.31 Positive rheumatoid factor and antinuclear antibodies were significantly more prevalent in patients with CU. The diagnosis of the autoimmune disorder was made mostly in the 10 years after the patient was diagnosed with CU. CU was observed in 4.3 of the cases amongst 46 studied patients with systemic sclerosis.35 Antithyroid antibodies are detectable in up to 30% in patients with CU, although their presence is neither associated with hormonal dysfunction of the gland, nor with the severity and the course of urticaria.36,37
Miscellaneous The metabolic syndrome (MS) is associated with CU according to a recent report.38 MS was observed in 29.8% of patients with CU, significantly higher compared with 17.8% in a matched control group. Patients with coexistence of both disorders had a higher mean urticaria activity score and serum levels of eosinophil cationic protein, tumor necrosis factor-α, and complements, and showed a higher rate of negative autologous serum skin tests in comparison to those without metabolic syndrome. Lower serum vitamin D levels were found in patients with CU.39 In analogy to other diseases, supplementation of vitamin D in subjects with urticarial skin lesions resulted in improvement of the symptoms.40
Conclusions Until recently, extensive testing of urticaria patients was the rule. Currently, the evidence is clear that extensive testing is not economic and the guidelines strongly recommend focusing the diagnostic procedures based on patient history. A growing body of evidence suggests that CU is often accompanied, as well as modulated, by a plethora of systemic diseases. That may open a new debate on the clinical relevance of administering laboratory investigations for the active screening of concomitant disorders. The question of predicting markers and the role of treating these comorbidities remains to be addressed in future controlled clinical trials.
Chronic urticaria
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