Chronic spontaneous urticaria (part 1)

Lalita Tearprasert; M.D.8 July 2016

Chronic Spontaneous Urticaria(CSU)

Part

1

Outline

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

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Overview of Urticaria

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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.

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

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

Wheals and angioedema are not always urticaria

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.

Histopathology


Diagnosis & Classification

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First step in diagnosis is a thorough history


Approach


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Approach12

Classification

Sarbjit S. Saini. Middleton's 8th edition.Moolani Y, et al. F1000Research 2016, 5(F1000 Faculty Rev):177.


Based on duration and the presence of triggering factors

Old term : CIU

Old term : Physical Urticaria

80%

20%

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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 factors14


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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.

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Chronic Spontaneous urticaria (CSU)

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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.

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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

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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

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Coexpression with allergic disease21

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.

• 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 presentation22

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• 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.

Severity24


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%


• 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.

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Most patients suffer from chronic spontaneous urticaria for > 1 year

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

CIU CAU27

• 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.

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Remission of CU in children

1 yr. = 18.5%3 yr. = 54%5 yr. = 67.7%

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Remission of CAU VS non-CAU in children


CAU1 yr. = 18.9%3 yr. = 63.1%5 yr. = 72.1%

non-CAU1 yr. = 18.2%3 yr. = 62.5%5 yr. = 64.9%

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Pathogenesis

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• 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

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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

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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.

• 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.

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1.)

2.)

3.)

4.)

http://drrajivdesaimd.com.

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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.

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.

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• 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.

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Ferrer Clin Transl Allergy (2015) 5:30.Sarbjit S. Saini. Middleton's 8th edition.


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

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• 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.

Potential explanation of the immunology underlying CSU40

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.

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• 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 autoimmunityMark Boguniewicz, M.D. Allergy Asthma Proc 29:433–438, 2008.


Thyroid autoimmunity43

• 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.

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" ASST test "

• In 1986, Grattan reported that the serum from 12 patients suffering from active CSU were able to induce a positive autologous skin reaction (7/12 patients)


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• 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.

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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%)

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Mast cell

Activation of cutaneous mast cells by antireceptor antibodyfollowed by activation of complement with generation of C5a

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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


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Human leucocyte antigen (HLA)

• HLA class II typing is consistent with the concept that CIU is a heterogeneous disease, and supports an autoimmune 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.

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• 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.

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Confino-Cohen R, et al. J Allergy Clin Immunol 2012;129:1307-13.

A strong association was found between CU and major autoimmune diseases

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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


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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


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

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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.

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Coagulation cascade


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• 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.

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Asero et al. J Allergy Clin Immunol 2007;119:705-10.

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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)

• 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.

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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


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Cell activation in CSU 62

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


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Investigation & Management(To be continued in Part 2)

Health & Medicine

Chronic spontaneous urticaria (part 1)