Chronic Urticaria & Angioedema Assessment and Management

Timothy J. Sullivan, M.D.

Pathophysiology of Urticaria and Angioedema Etiologic assessment Conventional therapies More intense therapies

May 5, 2012

Urticaria

Chronic Urticaria Consultation Response Fight of Flight

Urticaria

Intensely pruritic Sharply circumscribed Raised Evanescent

Chronic Urticaria

Daily or nearly daily lesions

8 weeks or more in duration Frequently (15-50%) accompanied by intermittent angioedema Occasionally associated with acute episodes of anaphylaxis

The 7 Year Itch

Reports of the duration of CUA have provided extremely variable estimates

Brief spontaneous remissions are common

In most studies CUA has gone into durable remission by a median of 4 years.
By 7 years ~80% of patients have remitted

Chronic Urticaria & Angioedema Parallel Objectives

Pharmacologic control

Etiologic assessment

Relief from pruritus Sleep Suppression of visible lesions Planning to manage dangerous complications

Systematic evaluation for known causes

Assessment of Chronic Urticaria

History & physical exam

Challenges for physical urticaria Laboratory studies Exclusion trial to assess exogenous causes

Etiologic Assessment

A treatable or correctable cause can be found in ~35% (perhaps more if the new Vitamin D data are cofirmed)
Pathogenic antibodies to the IgE receptor can be found in 30-50% of patients A probable explanation for the chronic urticaria can be found in the majority of patients

Causes of Chronic Urticaria & Angioedema 323 consecutive patients

350 300 250 200 150 100 50 0

323

35%
112

Studied

Found

The Mast Cell Theory of Chronic Urticaria

Kenneth Matthews, M.D.

Mast cell mediators injected into the skin cause urticarial lesions
Antigen-IgE activation of mast cells causes urticaria Histopathologic exam of acute & chronic urticaria shows mast cell degranulation Antihistamines and antileukotrienes suppress urticaria

Chronic Urticaria What enraged the mast cells?

Physical stimuli
Endogenous antigens Exogenous antigens Metabolic factors

Vitamin D deficiency Thyroid disorders

Vasculitis Autoantibodies

Consistent stimulus-response
Dermatographism Cold Cholinergic Local heat Delayed pressure Stroke with tongue blade Ice cube test 2 minutes Exercise 15-39 minutes 44 C 5 minutes Sandbags 15 lbs 15 minutes

Physical Urticarias

Solar
Aquagenic Vibratory

Specific wavelengths
35 C water compress Vortex 4 minutes

Chronic Urticaria What enraged the mast cells?

Physical stimuli
Endogenous antigens Exogenous antigens Metabolic factors

Vitamin D deficiency Thyroid disorders

Vasculitis Autoantibodies

Can thyroid disease cause CUA?

Hypothyroidism
Hyperthyroidism Thyroid autoimmunity

Antibody to thyroid peroxidase

Antibody to thyroglobulin

~30% of women with CUA

IgE to thyroid antigens

Remission with full thyroid hormone replacement

Chronic Urticaria with Thyroid Autoimmunity

Association recognized for several years

Rumbyrt et al JACI 1995;96:901-5.

7 patients with CUA & TA 7 of 7 had complete remission with full thyroid hormone replacement therapy

Variable results in subsequent studies

Thyroid Suppression

Purpose is to minimize intravascular release of thyroid autoantigens

Supply T4 in amounts sufficient to suppress endogenous secretion 1 g/pound of body weight/day Initial response over 2-3 weeks Check TSH, T4

Thyroid Suppression in CUA-TA

70 60 50 40 30 20 10 0 7 3 61 54 41 32
76%

TA T4 Rx T4 Response T4 Alone T4+H1 T4+More

Can Helicobacter pylori cause CUA?

Immune responses uniform

IgE to Hp antigens Remission with therapy

IgE to Helicobacter pylori

Aceti. Gastroenterology 1991;101:131-7

26 patients with Hp associated gastritis

22 (84%) positive Basophil Histamine Release

Acid elution removed response to Hp

Positive passive sensitization of normal basophils

Specific inhibition shown

18 (69%) positive Hp ELISA for IgE

18 of 22 BHR positive patients ELISA positive

Systematic Review of Studies of Hp Rx and Chronic Urticaria

Federman DG. J Amer Acad Dermatol 2003;49:861-4

10 studies: CUA, Hp, adequate Rx

Remission Rates

Hp eradication 31% Hp not eradicated 22% Hp- remission rate 14%

Hp eradication then remission OR 2.9 (95% CI 1.4 6.8) P=0.005

H. pylori Prevalence & Rx in CUA

350 300 250 200 150 100 50 0 Tested Positive Treated

H. pylori Rx in CUA
40 35 30 25 20 15 10 5 0 10 9 Treated Cured Better 39

Chronic Urticaria What enraged the mast cells?

Physical stimuli
Endogenous antigens Exogenous antigens Metabolic factors

Vitamin D deficiency Thyroid disorders

Vasculitis Autoantibodies

Onset of Allergic Drug Reactions

Previously Sensitized or Unsensitized
18 16 14 12 10 8 6 4 2 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Onset

What is the role of skin testing in the evaluation of CUA?

Food can cause CUA

Possible false positive Possible false negative

Specific exclusion is easier and faster than an exclusion diet IVT a potential alternative

Exclusion Trial

Ingested, topical, inhaled antigens

Rice, chicken, & water (cooked fruit or juices)

Synthetic diet if acceptable to patient

One week, then re-challenge Food, seasoning, preservatives, toothpaste, jewelry, OTC products, supplements, antistatic sheets, air fresheners Everything that goes in or on the patient is a suspect

Can CUA be caused by exogenous antigens?

Potato
Rice Peanut

Laxative
Preservative Toothpaste

Seasoning
Chocolate Anti-static sheets

Supplements
Earring Air freshener

Causes of Chronic Urticaria & Angioedema 323 consecutive patients

70 60 50 40 30 20 10 0 6 32 23

61

CUA-TA CUA-FA CUA-Hp CUA-PU

Chronic Urticaria What enraged the mast cells?

Physical stimuli
Endogenous antigens Exogenous antigens Metabolic factors

Vitamin D deficiency Thyroid disorders

Vasculitis Autoantibodies

Can Vitamin D Deficiency Cause or Exacerbate Chronic Urticaria?

Goetz, D. West Virginia Medical Journal.2011;107:14-20

57 patients with chronic urticaria & angioedema with 25-OH Vitamin D levels below 32 ng/mL

11-80 yrs of age, 77% female

With Vitamin D repletion, 40 (70%) had complete resolution of CUA within 4 weeks

Chronic Urticaria What enraged the mast cells?

Physical stimuli
Endogenous antigens Exogenous antigens Metabolic factors

Vitamin D deficiency Thyroid disorders

Vasculitis Autoantibodies

Schnitzler Syndrome

IgM monoclonal paraproteinemia

Relatively nonpruritic urticaria Intermittent fever Arthralgias, bone pain, hyperostosis Lymphadenopathy Anakinra (IL-1 RA) is beneficial

Chronic Urticaria What enraged the mast cells?

Physical stimuli
Endogenous antigens Exogenous antigens Metabolic factors

Vitamin D deficiency Thyroid disorders

Vasculitis Autoantibodies

Autologous Serum Skin Test

Intradermal injection of autologous serum causes a wheal and flare reaction at 30 minutes in some patients with CUA
Investigation of the mechanism revealed autoimmune chronic urticaria Not all with active autoantibodies positive Not all with positive skin test have autoantibodies

Autoantibody to the subunit of the IgEFcRI receptor

CUA 38%, PV 38%, DM 36%, SLE 20%, BP 13%

Basophil histamine release only with CUA sera Blockade of C5a receptor blocked histamine release Decomplementation blocked histamine release
Fiebiger E. J Clin Invest 1998;101:243-51

Autoimmune Causes of Chronic Urticaria & Angioedema

IgG1 or IgG3 autoantibody to the subunit of the IgEFcRI receptor

Complement activation seems to be a necessary part of the activation process Present in 30% - 50% of CUA patients

Less often an IgG antibody to IgE Commercial laboratory assays available

Common Causes of Chronic Urticaria & Angioedema

13 Autoimmune Thyroid H pylori Food Unknown

15

40

7 25

Laboratory Studies to consider for Chronic Urticaria

CBC, metabolic panel

Antibodies to thyroid peroxidase & thyroglobulin, TSH, free T4 Helicobacter pylori stool antigen 25-OH Vitamin D level Chronic urticaria index CH 50 Skin biopsy Other studies dictated by clinical assessment

Hereditary Angioedema

C1-esterase inhibitor deficiency

Inhibits activated C1 Inhibits activated factor XII and kallekrein

Isolated angioedema of skin, mucous membranes, or gastrointestinal tract Variable onset and frequency of episodes Unresponsive to allergy medications

ACE Inhibitors & Angioedema Clinical Features

Variable interval from initiation of therapy to onset of angioedema

Isolated angioedema of skin, mucous membranes, or gastrointestinal tract Often progresses for hours and resolves over days Usually not responsive to allergy medications

ACE Inhibitors & Angioedema

Brown NJ, JAMA 1997; 232-3

Incidence 1.6/1000 patient years

Recurrence with continued therapy

18.7/100 patient years

Recurrence with discontinuation of ACE inhibitor

1.8/100 patient years

AE can recur up to 3 months after discontinuation of ACEi

ACE Inhibitors & Angioedema Management

Acute angioedema

Assume allergy medications will not be effective

Intubation early
Cricothyrotomy if intubation not feasible

Discontinue ACE inhibitor therapy

ACE Inhibitors & Angioedema Management

Angiotensin receptor blocker (ARB) therapy

Two recent meta-analyses (2009, 2012) indicate ARB therapy is associated with a higher risk of angioedema than placebo or other antihypertensive therapy Risk for confirmed angioedema 0-9.2% in patients with prior ACEi associated angioedema

Bradykinin & ACE

XII Prekallekrein

XIIa Kallekrein Bradykinin

Kininogen

ACE

Bradykinin, HAE, & ACE

XII Prekallekrein

XIIa C1-INH Kallekrein C1-INH Bradykinin

Kininogen

ACE

Chronic Urticaria & Angioedema Parallel Objectives

Pharmacologic control

Etiologic assessment

Relief from pruritus Sleep Suppression of visible lesions Planning to manage dangerous complications

Systematic evaluation for known causes

Conventional Rx for CUA

H1 antihistamines

Nonsedating, q.d. or b.i.d.

Leukotriene receptor antagonists

q.d. or b.i.d.

H2 antihistamines Doxepin h.s. Systemic glucocorticoids

Is Epinephrine Necessary?

If there is a history of prior anaphylaxis

If there have been prior acute severe exacerbations If the patient has risk factors for severe anaphylaxis

Therapy of CUA
Refractory Disease

Systemic glucocorticoids
Cyclosporine

Mycophenolate Tacrolimus

Xolair IVIg Hydroxychloroquine, others

Cyclosporine for CUA - 37 patients

30 25 20 15 10 5 0 10 6 27 21 CYA response CYA alone CYA + No response

73%

Cyclosporine for CUA

2 mg/kg once daily with the evening meal

Congestion of the palms and soles GI upset

Ice cream, antacids, split doses

Monitor BP, renal & hepatic function Mycophenolate (CellCept) or Prograf for failures

IVIg for CUA

400 mg/kg q1-3 months

Lesions regress over 1 week Repeat infusion when lesions recur Insurance will pay in GA if the patient has been shown to have mast cell or basophil activating autoantibodies

Steroid Dependent CUA

25 20 15 10 5 0 Total H1+LTRA CYA IVIg No response

An Approach to CUA
ETIOLOGIC STUDIES

NONSPECIFIC THERAPY

Clinical Assessment Laboratory Assessment Therapeutic Trials Exclusion Trial

H1-antihistamines H1+H2 antihistamines H1+H2+LTRA +Cyclosporine IVIg Omalizumab Systemic steroids Burst, q.o.d., q.d.

Identify Cause Provide Pharmacologic Relief