Chronic idiopathic urticaria; background & clinical presentation

Chronic Idiopathic Urticaria

Episode 1:Background and clinical presentation

Wat Mitthamsiri, M.D.Allergy and Clinical Immunology Unit

Department of MedicineKing Chulalongkorn Memorial Hospital

Outline

• Urticaria: General information• Chronic idiopathic urticaria– Epidemiology– Pathophysiology– CIU and other conditions– Clinical presentation

• Investigation & management : To be continued in next episode.

Urticaria

Definition

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.

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

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

Urticaria

Classification

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.

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


• By etiology– Drug reactions– Foods or food additives– Inhalation, ingestion of, or contact

with antigens



• By etiology– Transfusion reactions– Infections: • Bacterial• Fungal• Viral• Helminthic



• 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



• By etiology (continued)– Physical urticarias• Cold urticaria• Cholinergic urticaria• Dermographism• Pressure urticaria (angioedema)• Vibratory angioedema• Solar urticarial• Aquagenic urticaria



• 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)



• 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



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


(CIU)

Epidemiology

Epidemiology

• Various incidence reports from 20-90% in all chronic urticaria

• This condition is thought to affect at least 0.1% of the population


Greaves MW. N Engl J Med 1995; 332: 1767–1772.

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.

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

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


(CIU)

Pathophysiology

Pathophysiology• Gross


Pathophysiology• Gross– Infiltrative hives–With palpably elevated borders that

vary in size or shape– But generally are rounded


Pathophysiology

• Microscopic


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.

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.

Pathophysiology

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

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.

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


Nettis E, et al. Allergy 2001; 56(9):915.

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 provedSmith C, et al. J Allergy Clin Immunol 1995; 96(3):360–364.

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.

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.


(CIU)

Associated conditions

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


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.


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

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.


• 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



• CIU and autoimmune hypothyroidism in ThaiFrom 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.


• CIU and autoimmune hypothyroidism in ThaiTFT 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.


• 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.


• 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.



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


• 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


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



• 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.


• 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.

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.



• 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.

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)


Incomplete jigsaw


Incomplete jigsaw


Issues Late phase reaction CIUBasophil -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

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



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


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



(CIU)

Clinical course

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.

Clinical course

• The retrospective report from Siriraj: The only Thai report available in PubMed and MedLine database


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%


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


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



CIU CAU

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.

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


Pruritus


Related symptoms– Heat sensation (n=45)– Sweating (n=15)– Pain (n=9)


Pruritus


Location of pruritus– Arms (n=86)– Back (n=78)– Legs (n=75)– Scalp (n=13)– 13 patients had symmetrical pruritus


Pruritus• Effects of daily activities on

pruritus


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.


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


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

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.


Episode 2:

Investigation and Management

-To be continued-

Chronic idiopathic urticaria; background & clinical presentation

Health & Medicine

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