1) The document outlines an overview of chronic spontaneous urticaria (CSU), including its epidemiology, clinical presentation, natural history, and pathogenesis. 2) CSU affects approximately 0.5-1% of the general population and is more common in adults than children, with a peak age of onset between 20-40 years. 3) The pathogenesis of CSU is not fully understood but is believed to involve inappropriate activation of mast cells and basophils by autoantibodies, leading to the release of inflammatory mediators that cause wheals and angioedema.

1. Lalita Tearprasert; M.D.
8 July 2016
Chronic Spontaneous Urticaria
(CSU)
Part
1

2. Outline
Part 1
• Overview of Urticaria
• Diagnosis & Classification of Urticaria
• Chronic Spontaneous urticaria (CSU)
- Epidemiology
- Clinical presentation
- Natural history
- Pathogenesis
- Prognostic factors
Part 2
• Investigation & Management
(To be continued)
2

3. Overview of Urticaria
3

4. Urticaria
• 20% of the population experience an episode of
urticaria in their lifetime
• 1% of the general population : Chronic urticaria
• Manifests as wheals and/or angioedema
Sarbjit S. Saini. Middleton's 8th edition.
Fine LM. Bernstein JA. Curr Allergy Asthma Rep (2015) 15: 30.
4

5. Wheal
• Characterized by 3 features
1.) Superficial swelling of dermis and erythema papule/ plague
2.) Itching/burning sensation
3.) Transient nature with the skin returning to normal
within 1–24 hours
Sarbjit S. Saini. Middleton's 8th edition.
C Vestergaard and M Deleuran. Ther Adv Chronic Dis 2015, Vol. 6(6) 304 –313.
Angioedema
- Sudden erythematous or skin-colored swelling
of the lower dermis and subcutis
- Sometimes pain rather than itching
- Frequent involvement below the mucous membrane
- May last up to 3 days
5

6. Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2009.
6
Wheals and angioedema are not always urticaria

7. Patients should be investigated thoroughly for
urticarial vasculitis >> may be need skin biopsy
- presenting with wheals lasting for > 24 hours
- leave hyperpigmentation, or lesions which burn
Sarbjit S. Saini. Middleton's 8th edition.
Fine LM. Bernstein JA. Curr Allergy Asthma Rep (2015) 15: 30.
7

8. Histopathology
Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2009.
8

9. Diagnosis & Classification
9

10. 10
First step in diagnosis is a thorough history
Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2009.

11. Approach
Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2009.
11

12. Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2009.
Approach
12

13. Classification
Sarbjit S. Saini. Middleton's 8th edition.
Moolani Y, et al. F1000Research 2016, 5(F1000 Faculty Rev):177.
Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2014.
Based on duration and the presence of triggering factors
Old term : CIU
Old term : Physical Urticaria
80%
20%
13

14. Moolani Y, et al. F1000Research 2016, 5(F1000 Faculty Rev):177.
Choi SH and Baek HS. Korean J Pediatr 2015;58(5):159-164.
Associated with the onset, most cases are idiopathic
Trigger factors
14

15. Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2014.
15

16. Some guidelines and experts identify a subset
of patients on the basis of serologic evidence of a
presumed autoimmune etiology
- Chronic autoimmune urticaria (CAU)
: 30% to 40%
- Chronic spontaneous urticaria (CSU)
: remaining 60% to 70%
Sarbjit S. Saini. Middleton's 8th edition.
16

17. Chronic Spontaneous urticaria
(CSU)
17

18. Epidemiology
• 0.5–1.0% of the population
• Age: All age groups can develop a CSU
More common in adults > children
• Sex : Women > Men
• Peak age is between 20 and 40 years
in most studies
Maurer et al. Allergy 66 (2011) 317–330.
Sarbjit S. Saini. Middleton's 8th edition.
18

19. N=450
K. Kulthanan et al. Journal of Dermatology 2007; 34: 294–301.
Thailand
• Retrospective
• Dermatology of Siriraj hospital
• During 2000-2004
• Mean age 34 years
(range 15-80 years)
• N = 450
19

20. Lee XH, et al. Asia Pac Allergy 2016;6:16-28.
Choi SH and Baek HS. Korean J Pediatr 2015;58(5):159-164.
• Different prevalence in children
- around 0.1–0.3% in United Kingdom
- up to 13% in Thailand
- 18% Spanish (< 14 yr.)
• No sex difference was found in children
• Twice as frequent in female
Children
20

21. Coexpression with allergic disease
21
Zazzali JL. Ann Allergy Asthma Immunol 2012;108:98-102.
• In one insurance claims study
• 6,019 patients who had claims consistent with CIU
• Mean age was 36 years
- allergic rhinitis 48%
- asthma 21%
- atopic dermatitis in 8%
• 98 patients
• Chinese with median age 4 years 7 months
Lee XH, et al. Asia Pac Allergy 2016;6:16-28.

22. • 33–67% of all patients with chronic spontaneous
urticaria exhibit wheals and angioedema
• 29–65% exhibit only wheals
Maurer et al. Allergy 66 (2011) 317–330.
Clinical presentation
22

23. 23
• Children 4–15 yr of age
• Siriraj Hospital
• 32 children (34.0%) had underlying allergic diseases
- asthma 12.8%
- allergic rhinitis 14.9%
- atopic dermatitis 2.1%
- food allergy 16%
• 43 children (45.7%) had family history of atopy
• 48 children (51.1%) had CU with angioedema
Jirapongsananuruk et al. Pediatr Allergy Immunol 2010: 21: 508–514.

24. Severity
24
Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2014.

25. Natural history
• Most self-limited, average duration is 2 - 5 years
• Rates of spontaneous remission at 1 year of approximately
30% to 50% in no trigger or underlying disorder patients
• Persist beyond 5 years in nearly 20%
Sarbjit S. Saini. Middleton's 8th edition.
• Some studies suggest that in both adults and children,
there is a 30–50 % remission rate in CU within the first
3 years after onset of symptoms
Fine LM. Bernstein JA. Curr Allergy Asthma Rep (2015) 15: 30.
25

26. Maurer et al. Allergy 66 (2011) 317–330.
Most patients suffer from
chronic spontaneous urticaria for > 1 year
26

27. K. Kulthanan et al. Journal of Dermatology 2007; 34: 294–301.
CIU CAU
27

28. • Pediatric allergy clinic, Siriraj Hospital
• From March 2003 - March 2009
• Children 4 - 15 years of age, 92 children
• 40% of the patients : Chronic autoimmune urticaria (CAU)
• Investigation : CBC, ESR, ANA, CH50 level, thyroid studies,
ASST, SPT, food challenges, and stool examination for parasites
• Remission : symptoms did not recur for at least 12 months
without medication
Chansakulporn et al. J Am Acad Dermatol. October 2014.
28

29. Chansakulporn et al. J Am Acad Dermatol. October 2014.
Remission of CU in children
1 yr. = 18.5%
3 yr. = 54%
5 yr. = 67.7%
29

30. Remission of CAU VS non-CAU in children
Chansakulporn et al. J Am Acad Dermatol. October 2014.
CAU
1 yr. = 18.9%
3 yr. = 63.1%
5 yr. = 72.1%
non-CAU
1 yr. = 18.2%
3 yr. = 62.5%
5 yr. = 64.9%
30

31. Pathogenesis
31

32. • Remains unknown
• Mast cells and basophils play an important role
(Both cells in CSU patients have unique features
from healthy donors)
• Eosinophils are also present in CSU skin biopsies
• Endothelial cells indirectly demonstrated
by an increase of vasoactive peptides in skin
and plasma
Ferrer Clin Transl Allergy (2015) 5:30.
Lajos Kemeny. Hindawi Publishing Corporation Dermatology Research and Practice Volume 2014.
Chronic urticaria is initiated by inappropriate activation
and degranulation of dermal mast cells
32

33. Th1 or Th2 phenotype
• CSU : perivascular infiltrate surrounding small venules with a
predominance of CD4+ T lymphocyte cells along with
neutrophils, mast cell basophils, and eosinophils
• Cellular infiltration resembles that seen in the allergic late-phase
response but is different when examined closely
• The T lymphocytes are a combination of Th1 and Th 2 subtypes
(Th1 >> IFN-gamma, Th2 >> IL-4, IL-5) and neutrophils and
monocytes are more prominent in the lesions of
chronic urticaria than in the late-phase response
33
Ferrer Clin Transl Allergy (2015) 5:30.
Sarbjit S. Saini. Middleton's 8th edition.
Ferrer and Kaplan. Allergy, Asthma, and Clinical Immunology, Volume 3, Number 1, 2007.

34. • Central event in the development of the lesions in urticaria
& histamine levels are elevated in biopsied skin
• Cutaneous mast cell is the primary effector cell in most patterns of
urticaria
• Mast cell number in patients with CU is not increased
- Total serum tryptase level is only slightly elevated
• Heightened histamine presence in CU skin lesions could be
explained by either enhanced quantitative release of histamine
from skin mast cells or blood basophil infiltration of CU skin tissues
Mast cell
Sarbjit S. Saini. Middleton's 8th edition.
C. E. H. Grattan. Aetiopathogenesis of Urticaria.
34

35. 1.)
2.)
3.)
4.)
http://drrajivdesaimd.com.
35

36. 36
Mediators from mast cell
• Platelet activating factor
• Neuropeptides
• Arachidonic acid metabolites
such as PGD2, LTC4,
LTD4, and LTE4
• Serotonin
• Anaphylatoxins : C3a and C5a
Asero et al. Curr Treat Options Allergy (2015) 2:287–293.

37. Basophil
• In 1962, Rorsman found some patients with chronic urticaria
have basopenia
• CSU basophils are different not only in number but also in function
• Chronic urticaria basophils have several specific features
that distinguish from the basophils of healthy or atopic donors
- Hyporesponsive to anti-IgE, C5a
- Response normally to bradykinin, MCP-1, PAF
- Hyperresponsive to autologous serum in either
CIU and CAU
Ferrer Clin Transl Allergy (2015) 5:30.
Ferrer and Kaplan. Allergy, Asthma, and Clinical Immunology, Volume 3, Number 1, 2007.
37

38. • CU serum contained IgG anti-FcεRIα autoantibodies of IgE leading to a
dose-dependent histamine release from blood basophils of healthy adults.
This serum activity was termed histamine-releasing activity (HRA)
• 2 basophil phenotypes by blood basophil IgE receptor responses
1. CIU responders (CIU-Rs) : histamine degranulation profile similar
to that of normal subjects
2. CIU nonresponders (CIU-NRs) : do not degranulate to
IgE receptor activation
- elevated levels of the IgE receptor regulating inhibitory
phosphatases, SHIP-1 and SHIP-2
• Increased surface FcεRI expression in the basophils of patients suffering
from CSU
Sarbjit S. Saini. Middleton's 8th edition.
A. P. Kaplan & M. Greaves.Clinical & Experimental Allergy, 2009 (39) 777–787.
38

39. Ferrer Clin Transl Allergy (2015) 5:30.
Sarbjit S. Saini. Middleton's 8th edition.
Asero et al. Curr Treat Options Allergy (2015) 2:287–293.
Eosinophil
• Most abundant cells in CSU skin biopsies
• Eosinophil degranulation can cause secondary
degranulation of basophils as a result of the release of
eosinophil major basic protein (MBP)
• Eosinophils might be in turn activated and recruited by
mediators, cytokines, chemokines, or other as yet unknown
factors released by mast cells
39

40. • Several theories regarding the pathogenesis,
none has been conclusively established
- Abnormalities in skin mast cells and basophils
- Autoimmune theory
- Chronic infections
- Coagulation cascade
Sarbjit S. Saini. Middleton's 8th edition.
Asero et al. Curr Treat Options Allergy (2015) 2:287–293.
al explanation of the immunology underlyin
40

41. Autoimmune theory
• Autoimmune origin is the most accepted hypothesis
advanced to explain inappropriate activation
• CAU found 30% - 40% of patients with CIU
• Confirmed this concept
- Higher prevalence of thyroid autoantibodies
- Positive autologous serum skin test (ASST)
- Subsequent identification of IgG antibody directed to the
alpha subunit of the IgE receptor
Lajos Kemeny. Hindawi Publishing Corporation Dermatology Research and Practice Volume 2014.
41

42. Sarbjit S. Saini. Middleton's 8th edition.
42

43. • In 1983, Leznoff et al. first reported on the association
between CU and autoimmune thyroid disease
- 15% prevalence of autoimmune thyroid antibodies
in patients suffering from CSU but with a normal thyroid
function
• In 1989, Leznoff et al. report that patients with CIU have
an increased frequency of Hashimoto thyroiditis
• Thyroid antibody determination can be a useful tool as an
indirect marker for autoimmunity
Mark Boguniewicz, M.D. Allergy Asthma Proc 29:433–438, 2008.
Asero et al. Curr Treat Options Allergy (2015) 2:287–293.
Thyroid autoimmunity
43

44. • Hashimoto's thyroiditis and less commonly
Graves' disease show a positive association with CIU
• Thyroid disease and chronic urticaria are frequently
associated but there is no evidence that the thyroid
autoantibodies are pathogenic in the context of chronic
urticaria
• No convincing evidence that treating the underlying thyroid
dysfunction alters the course of the accompanying urticaria
A. P. Kaplan & M. Greaves.Clinical & Experimental Allergy, 2009 (39) 777–787.
44

45. " ASST test "
• In 1986, Grattan reported that the serum from 12 patients suffe
Asero et al. Curr Treat Options Allergy (2015) 2:287–293.
45

46. • In 1993, Hide M. and co-workers demonstrated
for the first time the functional autoantibodies in CSU
• IgG subclass distribution of anti-FceRIa is an important
determinant of functional activity (can activated complement)
• Pathogenic autoAb : IgG1 and/or IgG3
(IgG3 primarily, IgG1 frequently)
• IgG4 occasionally
• IgG2 is typically inactive
Asero et al. Curr Treat Options Allergy (2015) 2:287–293.
Soundararajan et al. J Allergy Clin Immunol 2005;115:815-21.
46

47. Sarbjit S. Saini. Middleton's 8th edition.
Lajos Kemeny. Hindawi Publishing Corporation Dermatology Research and Practice Volume 2014.
Ag cross-linking IgE
IgG anti-IgE
auto-antibody
(5-10%)
IgG directed to alpha
subunit
(40%)
47
Mast cell

48. Activation of cutaneous mast cells by antireceptor antibody
followed by activation of complement with generation of C5a
48
A. P. Kaplan & M. Greaves.Clinical & Experimental Allergy, 2009 (39) 777–787.

49. Involvement of C5a could also explain
the otherwise puzzling lack of clinical evidence
of pulmonary or systemic involvement in
autoimmune urticaria, because lung mast cells
but not dermal mast cells are deficient in C5a receptors
A. P. Kaplan & M. Greaves.Clinical & Experimental Allergy, 2009 (39) 777–787.
49

50. Human leucocyte antigen (HLA)
• HLA class II typing is consistent with the concept that CIU is a heterogen
pathogenesis in a subset of patients
• CIU patients revealed a significantly increased frequency
of HLA class II (HLA DRBI*04)
• Association of HLA-B44, HLA-DRB1*01 and HLA-DRB*15 alleles
with CU suggests that there is a genetic component in the
pathogenesis of CU
O'Donnell B. et al. Br J Dermatol 1999; 140:853–8.
Coban M. et al. Int Arch Allergy Immunol 2008;147:135–139.
50

51. • 12,778 patients given a diagnosis of CU by either
allergy or dermatology specialists
(66.3% were women, average age of 45.3 +/- 18.5 years)
• Control group comprised of 10,714 patients
• During 17 years in Israel
Confino-Cohen R, et al. J Allergy Clin Immunol 2012;129:1307-13.
51

52. Confino-Cohen R, et al. J Allergy Clin Immunol 2012;129:1307-13.
A strong association was found between CU
and major autoimmune diseases
52

53. Chronic infections
• Persistent bacterial, viral, parasitic, or fungal infections
have been suspected to trigger urticarial chronic
spontaneous urticaria
- H. pylori, streptococci, staphylococci, yersinia, Giardia lamblia,
mycoplasma pneumonia, hepatitis virus, norovirus,
parvovirus B19, anisakis simplex, entamoeba spp,
blastocystis spp
• Varies between different patient groups and different
geographical regions
Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2009.
53

54. Helicobacter pyroli
• Evidence of H. pylori infection is found in up to 50% of
the general population in most regions of the world and
in at least 30% of patients with chronic idiopathic urticaria
• Treat the H. pylori has no significant effect on the course
of the chronic urticaria
• Induces autoantibody formation due to the immunogenicity
of its cell envelope polysaccharide Lewis x and y blood
group antigens
A. P. Kaplan & M. Greaves.Clinical & Experimental Allergy, 2009 (39) 777–787.
54

55. Huiyuan Gu, et al. Gastroenterology Research and Practice Volume 2015.
55

56. A.G.Abdou, et al. International Journal of Dermatology, vol. 48, no. 5, pp. 464–469, 2009.
• Prevalence of H. pylori infection in chronic urticaria patients
was not significantly different from that in normal control subjects
• But the severity of urticarial symptoms was greater in the
H. pylori-positive than in the H. pylori-negative group
• 10 trials on the effectiveness of H. pylori eradication on CU and
found that the benefit of HP eradication inpatients with CU is
weak and conflicting
A. Shakouri, et al. Current Opinion in Allergy and Clinical Immunology, vol.10, no. 4, pp. 362–369, 2010.
56

57. Coagulation cascade
Asero et al. Curr Treat Options Allergy (2015) 2:287–293.
57

58. • Extrinsic pathway of the coagulation cascade is activated in chronic
urticaria and that this activation appears to lead to thrombin generation
• Intrinsic pathway is not involved in CU
Asero et al. J Allergy Clin Immunol 2007;119:705-10.
58

59. Asero et al. J Allergy Clin Immunol 2007;119:705-10.
59
The expression of tissue factor (TF), the main initiator of blood
coagulation, is induced by pro-inflammatory cytokines such as IL-6
and tumor necrosis factor alpha (TNF-α)

60. • Coagulation cascade proteins
1.) Directly activate mast cells
- Thrombin cleaves protease-activated receptors 1 (PAR-1)
- Tissue Factor plus factor VIIa through PAR-2
2.) Amplify the inflammation inducing vascular
permeability
3.) Induce mast cell degranulation
Ferrer Clin Transl Allergy (2015) 5:30.
60

61. Increased several markers
• Prothrombin fragment F1+2
• Activated factor VII
• D-dimer (fibrinolysis)
- correlate with the severity and could predict the lack
of response to antihistamines
- not specific for mast cell mediated disease
- not specific to CSU since it is also seen in
bullous pemphigoid and hereditary angioedema
Ferrer Clin Transl Allergy (2015) 5:30.
61

62. Ferrer Clin Transl Allergy (2015) 5:30.
Cell activation in CSU
62

63. Prognostic factors
• 4 factors that seem to be associated with a long
duration
1.) Disease severity
2.) Angioedema
3.) Combination of chronic spontaneous urticaria
with physical urticaria
4.) ASST positive
Maurer et al. Allergy 66 (2011) 317–330.
63

64. Investigation & Management
(To be continued in Part 2)