Chronic idiopathic urticaria; background & clinical presentation Presented by Watt Mitthansiri, MD. August 2, 2013

1. Chronic Idiopathic
Urticaria
Episode 1:
Background and clinical
presentation
Wat Mitthamsiri, M.D.
Allergy and Clinical Immunology Unit
Department of Medicine
King Chulalongkorn Memorial Hospital

2. Outline
• Urticaria: General information
• Chronic idiopathic urticaria
– Epidemiology
– Pathophysiology
– CIU and other conditions
– Clinical presentation
• Investigation & management : To be
continued in next episode.

3. Urticaria
Definition

4. Urticaria
• Recurrent wheals
– Usually pruritic
– Pink-to-red edematous plaques
– Often have pale centers.
• The wheals are transient, mostly
last for <24 hours.
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

5. Urticaria
• The appearance of pruritic,
erythematous, cutaneous elevations
that blanch with pressure, indicating
the presence of dilated blood vessels
and edema
T. Poonawalla, et al. Am J Clin Dermatol 2009; 10(1); 9-21

6. Urticaria
• The sudden appearance of wheals
and/or angioedema
• Wheal consists of 3 typical features:
– A central swelling of variable size
– Almost invariably surrounded by a reflex
erythema
– Associated itching or burning sensation
– A fleeting nature
– Skin returning to its normal appearance,
usually within 1–24 h
EAACI/GA2LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria, Allergy 2009: 64: 1417–1426

7. Urticaria
Classification

8. Urticaria: Classification
• By duration
– Acute:
• Wheals occurring for <6 weeks,
– Chronic:
• Any pattern of recurrent urticaria occurring at
least twice a week for at least 6 weeks
• The development of cutaneous wheals that
occur on a regular basis (usually daily) for >6
weeks with individual lesions lasting from 4
to 36 hours.
T. Poonawalla, et al. Am J Clin Dermatol 2009; 10(1); 9-21
Grattan C, et al. J Am Acad Dermatol 2002; 46: 645–657.

9. EAACI/GA2LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria, Allergy 2009: 64: 1417–1426

10. Urticaria: Classification
• By etiology
– Drug reactions
– Foods or food additives
– Inhalation, ingestion of, or contact with
antigens
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

11. Urticaria: Classification
• By etiology
– Transfusion reactions
– Infections:
• Bacterial
• Fungal
• Viral
• Helminthic
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

12. Urticaria: Classification
• By etiology (continued)
– Insects (papular urticaria)
– Collagen vascular diseases
• Cutaneous vasculitis
• Serum sickness
– Malignancy:
• Angioedema with acquired
C1and C–1 inactivator (C–1
INH) depletion
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

13. Urticaria: Classification
• By etiology (continued)
– Physical urticarias
• Cold urticaria
• Cholinergic urticaria
• Dermographism
• Pressure urticaria (angioedema)
• Vibratory angioedema
• Solar urticarial
• Aquagenic urticaria
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

14. Urticaria: Classification
• By etiology (continued)
– Urticaria pigmentosa: systemic
mastocytosis
– Hereditary diseases
• Hereditary angioedema
• Familial cold urticaria
• C3b inactivator deficiency
• Amyloidosis with deafness and urticaria
(Muckle-Wells syndrome)
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

15. Urticaria: Classification
• By etiology (continued)
– Chronic autoimmune urticaria and
angioedema
• (40-45% of chronic urticaria)
– Chronic idiopathic urticaria and
angioedema
• (55-60% of chronic urticaria)
– Idiopathic angioedema
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

16. Urticaria: Classification
EAACI/GA2LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria, Allergy 2009: 64: 1417–1426

17. Chronic Idiopathic Urticaria
(CIU)
Epidemiology

18. Epidemiology
• Various incidence reports from 20-90%
in all chronic urticaria
• This condition is thought to affect at
least 0.1% of the population
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.
Greaves MW. N Engl J Med 1995; 332: 1767–1772.

19. Epidemiology
• 79% from 554 urticarial patients
between 1956-1967 in a hospital in
Cambridge
• 76% (1,657 out of 2,350 cases) in 32
years in a review in 1988
Champion RH. Br J Dermatol 1988; 119: 427–436.
Champion RH, et al. Br J Dermatol 1969; 81: 588–597.

20. Epidemiology: Thailand
• A retrospective report from
Department of Dermatology, Siriraj
Hospital, during 2000–2004.
• From total of 450 patients with chronic
urticaria, 337 patients (75%) were
diagnosed as CIU
– 66 were male (20%)
– 271 were female (80%)
– Mean age = 34 years (range: 15–80 years)
K. Kulthanan et al. J Derm 2007; 34: 294–301

21. K. Kulthanan et al. J Derm 2007; 34: 294–301

22. K. Kulthanan et al. J Derm 2007; 34: 294–301

23. Chronic Idiopathic Urticaria
(CIU)
Pathophysiology

24. Pathophysiology
• Gross
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

25. Pathophysiology
• Gross
– Infiltrative hives
– With palpably elevated borders that vary
in size or shape
– But generally are rounded
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

26. Pathophysiology
• Microscopic
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

27. Pathophysiology
• Microscopic
– Non-necrotizing perivascular mononuclear
cell infiltrate (mainly T helper lymphocytes)
– Occasional prominent eosinophil
accumulation
– Only skin biopsy in patients with delayed
pressure urticaria that is virtually
indistinguishable chronic urticaria
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.
Mekori Y, et al. J Allergy Clin Immunol 1983; 72(6):681–684.

28. Pathophysiology
• Microscopic
– Elias et al, reported:
• 50% T lymphocytes
• No B cells
• 20% monocytes
• 10% mast cells
• T cell subtype varied greatly and revealed no
predominant pattern
Elias J, et al. J Allergy Clin Immunol 1986; 78: 914–918.

29. Pathophysiology
Elias J, et al. J Allergy Clin Immunol 1986; 78: 914–918.

30. Pathophysiology
• Microscopic (continued)
– 10-fold increase of mast cells
– 4-fold increase of mononuclear cells
– Circulating basopenia related perhaps to
migration into skin
Grattan C, et al. Clin Exp Allergy 1997; 27(12):1417–1424.
Ying S, et al. J Allergy Immunol 2002; 109(4):694–700.

31. Pathophysiology
• Increased skin mast cell
• Increased histamine in blister fluid
compared with fluid from normal
control subjects
• Increased total skin histamine content
• But this is not consistent findings in all
study
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.
Nettis E, et al. Allergy 2001; 56(9):915.

32. Pathophysiology
• In one report, the authors failed to
indicate an increased number of mast
cells
• They hypothesized that there might
be:
– Increase in number of basophils
– Increase in histamine content in each cell
• But it has not been proved
Smith C, et al. J Allergy Clin Immunol 1995; 96(3):360–364.

33. Pathophysiology
• Eosinophil major basic protein
deposition in skin found in half of
patients
• But only a fraction of the patients had
obvious eosinophil infiltration
Peters M, et al. J Invest Dermatol 1983; 81(1):39–43.

34. Pathophysiology
• Early lesions: Neutrophil found along
with infiltration of eosinophils
• More intense inflammatory infiltrate in
patient with positive IgE receptor Ab
• Combination of neutrophils,
eosinophils, CD4+ lymphocytes, and
monocytes resembled a cutaneous
late-phase reaction
Sabroe R, et al. J Allergy Clin Immunol 1999; 103:484–493.

35. Chronic Idiopathic Urticaria
(CIU)
Associated conditions

36. CIU and Allergy
• No increased incidence of:
– Eczema
– Allergic rhinitis
– Asthma
– Compared with person without chronic
urticaria
• The IgE levels of patients are within
normal limits
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

37. CIU and Allergy
• A report of chronic urticaria cases
from Thailand found that:
– Prevalence of atopy was not increased
– Symptomatic dermographism found in
3.8% of patient
• An increased incidence of
dermographism from 8–22% found in
patients with chronic urticaria
Gorevic PD, et al. Int J Dermatol 1980; 19: 417–435.
K. Kulthanan et al. J Derm 2007; 34: 294–301

38. CIU and Infection
• Various infections have been reported
to be the associating factors of CU:
– Parasitic infection
– Hepatitis
– H. pyroli
• Concurrent infections can exacerbate
the condition
• In most cases, treatments of infections
does not improve urticarial symptoms
K. Kulthanan et al. J Derm 2007; 34: 294–301

39. CIU and Autoimmunity
• Autoimmune hypothyroidism
(Hashimoto’s thyroiditis)
– Association found with the presence of
peroxidase or thyroglobulin Ab.
– Incidence: 12–14%
– 24% incidence of antithyroglobulin Ab or
antimicrosomal Ab or both, found in
patients with chronic urticaria
Kikuchi Y, et al. J Allergy Clin Immunol 2003; 112(1):218.
Leznoff A, et al. Arch Dermatol 1983; 119(8):636–640.
Leznoff A, et al. J Allergy Clin Immunol 1989; 84(1):66–71.

40. CIU and Autoimmunity
• Autoimmune hypothyroidism
(Hashimoto’s thyroiditis)
But…
– Thyroid status did not relate to the
occurrence of urticaria
– Hives persist even with euthyroid
achievement
– Autoantibodies persist also
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

41. CIU and Autoimmunity
• CIU and autoimmune hypothyroidism
in Thai
From 100 patients + 100 volunteers studied
– 21 cases with CIU: positive for thyroid Ab
(vs 9 cases in volunteers)
– 9 cases: negative for thyroid Ab when
repeating the tests after 3 months
– 12 patients still had persistent elevation of
Ab after 3 months
Kullavanijaya P, et al. J Med Assoc Thai 2002 Aug; Vol. 85 (8), pp. 901-6.

42. CIU and Autoimmunity
• CIU and autoimmune hypothyroidism
in Thai
TFT was performed in 12 patients with
persistent elevation of Ab.
– 9 cases had autoimmune thyroiditis with
euthyroidism
– 1 case had subclinical hyperthyroidism
– 1 case had autoimmune hyperthyroidism
– 1 case had subclinical hypothyroidism
Kullavanijaya P, et al. J Med Assoc Thai 2002 Aug; Vol. 85 (8), pp. 901-6.

43. CIU and Autoimmunity
• 10% incidence of circulating IgG or
IgM anti-IgE Ab found in subjects with
chronic urticaria and occasionally cold
urticaria
• Hypothesis: Ab stimulate cutaneous
mast cells degranulation and lead to
– Acute hives
– Late-phase reaction
– Cellular infiltration
Gruber B, et al. J Invest Dermatol 1988; 90(2):213–217.

44. CIU and Autoimmunity
• Anti-IgE receptor Ab found in 30–40%
of patients
• An additional 10% of patients with
anti-IgE Ab
• These studies demonstrated
autoreactivity to autologous serum
(injections of serum into the patient
induced a hives)
Hide M, et al. N Engl J Med 1993; 328(22):1599–1604.
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

45. CIU and Autoimmunity
Becky M. et al. Current Allergy and Asthma Reports 2005, 5:270–276

46. CIU and Autoimmunity
• Reactivity with the α-subunit of IgE
receptor was confirmed in about 40% of
patients
• Demonstrated by using activated rat
basophil leukemia cells transfected with
– α-subunit of the IgE receptor
– Human basophils
– Cutaneous mast cells
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

47. CIU and Autoimmunity
• IgG anti-α Ab might give a role for
complement to augment histamine
release
• Role of C5a is demonstrated:
– Activation of the classical complement
pathway
+Cross-linking of the IgE receptor by autoAb
=Chemotactic for neutrophils, eosinophils,
and monocytes -> infiltration occured
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

48. CIU and Autoimmunity
• Pathogenic autoAb: IgG1 and/or IgG3
• IgG4 is rarely contributory
• IgG2 anti-α does not lead to basophil
histamine release
• IgG2 caused false-positive
immunoblots
Soundararajan S, et al. J Allergy Clin Immunol 2005; 115(4):815–821.

49. CIU and Autoimmunity
• Presence of IgG antibody to the low-
affinity IgE receptor on eosinophils
(CD23)
– Degranulation of eosinophils
– Activation of basophils and maybe mast
cells by eosinophil cationic proteins
Puccetti A, et al. I Clin Exp Allergy 2005; 35(12):1599–1607.

50. CIU and Autoimmunity
• Hyporesponsiveness of basophils of
chronic urticaria patients upon
stimulation with anti-IgE was
demonstrated long time ago
• But hyperresponsiveness of basophil to
autologous serum was found:
– In either patients with or without
autoantibody (idiopathic)
Luquin E, et al. Clin Exp Allergy 2005; 35(4): 456–460.
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

51. CIU and Autoimmunity
• Basophils from chronic urticaria
patients are either hypo-or
hyperresponsive to stimuli
• Suggesting abnormality in signal
transduction?
– ‘Ras’-related pathways of MAP kinase
activation
– Abnormality to increased levels of ‘SHIP’
Vonakis B, et al. J Allergy Clin Immunol 2007; 119(2):441–448.
Confino-Cohen R, et al. J Allergy Clin Immunol 2002; 109(2):349–356.

52. Incomplete jigsaw
• From mentioned data:
– Perivascular infiltrate in chronic urticaria
should be a late-phase reaction
– Or at least a variant of it
• But there is still some discrepancies (as
some examples in next 2 slide)
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

53. Incomplete jigsaw
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.

54. Incomplete jigsaw
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.
Issues Late phase reaction CIU
Basophil -More prominent in nose lung
and skin
-Less prominent
Eosinophil -Very prominent in asthma and
nasal polyp
-Induce or cause late phase
reaction
-Vary from none to
very prominent in the
lesion
Monocyte -Minimally elevated -Markedly elevated
(up to 20%)
Lymphocyte -Less prominent
-Th2 predominance in atopy
-More prominent
-No Th2

55. Incomplete jigsaw
• Why the reaction is limited only to
mast cell in the skin?
• Complement-mediated activation via
C5a has been proposed to explain why
only skin mast cells are triggered in
CIU rather than mucosal mast cells
which lack responsiveness to the C5a
receptor
Allen P Kaplan, Middleton’s Allergy: Principles and Practice 7th edition, 2009: 1063-1081.
Becky M. et al. Current Allergy and Asthma Reports 2005, 5:270–276

56. Incomplete jigsaw
• OK, then why autoAb may act only in
some distinct regions of the skin?
• What about most CIU subjects who
lack autoantibodies or histamine-
releasing activity (HRA)?
• Obviously we need more explanation
Becky M. et al. Current Allergy and Asthma Reports 2005, 5:270–276

57. Without autoimmunity
• In antibody-negative subjects
• There is evidence of other histamine-
releasing factors acting on both mast
cells and basophils
– Cytokines
– Complement components
• Suggesting great heterogeneity in
serum HRA
Becky M. et al. Current Allergy and Asthma Reports 2005, 5:270–276

58. Chronic Idiopathic Urticaria
(CIU)
Clinical course

59. Clinical course
• 47% of 78 patients with CIU had
remission within 1 year
• 32% of 86 patients with CIU, the
symptoms were resolved after a 3-year
• No difference in the natural course of:
– Urticaria alone
– Angioedema alone
– Urticaria with angioedema
Quaranta JH, et al. Ann Allergy 1989; 62: 421–424.
Kozel MM, et al. J Am Acad Dermatol 2001; 45: 387–391.

60. Clinical course
• The retrospective report from Siriraj: The
only Thai report available in PubMed
and MedLine database
K. Kulthanan et al. J Derm 2007; 34: 294–301

61. Clinical course
• From 337 patients with CIU in that
report
– 66 were male (20%)
– 271 were female (80%)
– Mean age = 34 years (range: 15–80 years)
– Anti-thyroglobulin Ab positive: 16%
– Anti-microsomal Ab positive: 12%
K. Kulthanan et al. J Derm 2007; 34: 294–301

62. Clinical course
• In 61 patients
– ASST had been done to detect the autoAb
to a high affinity IgE receptor (FCε RIα) on
the mast cell surface
– 15 patients (24.5%) had positive ASST
results
• So…they were diagnosis of autoimmune
urticaria
K. Kulthanan et al. J Derm 2007; 34: 294–301

63. Clinical course
• CIU patients:
– 34.5% were free of symptoms after 1 year
– Median disease duration: 390 days
• Autoimmune urticaria patients:
– 56.5% were free of symptoms after 1.2 years
– Median disease duration: 450 days
K. Kulthanan et al. J Derm 2007; 34: 294–301

64. K. Kulthanan et al. J Derm 2007; 34: 294–301
CIU CAU

65. Pruritus
• A study in 100 patients with CIU
– Mean(+/-SD) clinical course = 30.2(+/- 53)
months (range 2–384)
Frequency of attack
– 68 patients had daily pruritus
– 23 patients had >/= 1 pruritus/wk
G.Yosipovitch, et al. British Journal of Dermatology 2002; 147: 32–36.

66. Pruritus
• A study in 100 patients with CIU
Attacking time of the day
– 25 patients had pruritus in the morning
– 18 patients had pruritus at noon
– 37 patients had pruritus in the evening
– 46 patients had pruritus in the night
G.Yosipovitch, et al. British Journal of Dermatology 2002; 147: 32–36.

67. Pruritus
• A study in 100 patients with CIU
Related symptoms
– Heat sensation (n=45)
– Sweating (n=15)
– Pain (n=9)
G.Yosipovitch, et al. British Journal of Dermatology 2002; 147: 32–36.

68. Pruritus
• A study in 100 patients with CIU
Location of pruritus
– Arms (n=86)
– Back (n=78)
– Legs (n=75)
– Scalp (n=13)
– 13 patients had symmetrical pruritus
G.Yosipovitch, et al. British Journal of Dermatology 2002; 147: 32–36.

69. Pruritus
• Effects of daily activities on pruritus
G.Yosipovitch, et al. British Journal of Dermatology 2002; 147: 32–36.

70. Pruritus
• Effects of pruritus on quality of life
– Sleep
• 64 patients were woken by their itch
• 62 paitents had difficulty falling asleep.
– Mood
• 52 patients: more agitated
• 43 patients: difficulty in concentrating
• 14 patients: being depressed.
G.Yosipovitch, et al. British Journal of Dermatology 2002; 147: 32–36.

71. Pruritus
• Effects of pruritus on quality of life
– Diet
• 34 patients: change in eating habits
• 9 patients: special diet to relieve their itch
– Sexual life
• 33 patients: Reduction in sexual desire
• 27 had reduced sexual function
G.Yosipovitch, et al. British Journal of Dermatology 2002; 147: 32–36.

72. Take Home Message
• Urticaria is a common skin condition
• Urticaria is classified by duration of of
symptom as acute (<6 wk) and chronic
(>6 wk)
• There are a lot of possible etiology that
causes urticaria

73. Take Home Message
• In chronic urticaria, mostly, etiology
can’t be identified, so it’s labeled as
chronic idiopathic urticaria (CIU)
• Pathophysiology of CIU is not
completely understood
• CIU can seriously affect the patient’s
quality of life.

74. Chronic Idiopathic Urticaria
Episode 2:
Investigation and Management
-To be continued-