Chronic spontaneous urticaria (part2)

Lalita Tearprasert; M.D.
26 Aug 2016
Chronic Spontaneous Urticaria
(CSU)
Part

Outline
Part 1
• Overview of Urticaria
• Diagnosis & Classification of Urticaria
• Chronic Spontaneous urticaria (CSU)
- Epidemiology
- Pathophysiology
- Clinical presentation
Part 2
• Investigation & Management

• Should focus on a directed history and physical
examination
• Aim for investigations
- Make a solid diagnosis
- Explore causes
Hide M et al. Allergology International. 2012;61:517-527.
Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline: update 2013.
Fine LM. Consensus and Controversies in the European and American Guidelines. Curr Allergy Asthma Rep (2015) 15: 30.
4

Routine diagnostic measures
• EAACI/GA2LEN/EDF/WAO urticaria guideline 2013
• Thai Clinical Practice Guideline (Urticaria/Angioedema) 2014
1.) CBC
2.) ESR or CRP
3.) Elimination of the possibility of underlying causes such
as medications (eg. NSAIDs) or foods
Clinical Practice Guideline 2557. (Urticaria/Angioedema).
Different recommended for investigations
5

• AAAAI/ACAAI Joint Task Force (Practice parameter 2014)
1.) CBC
2.) ESR or CRP
3.) Elimination of the possibility of underlying causes such
as medications (eg. NSAIDs) or foods
4.) LFT
5.) TSH
Choi SH and Baek HS. Korean J Pediatr 2015;58(5):159-164.
6

Complete blood count
• Elevated eosinophil count
>> Parasitic infections, drug induced reactions
• Elevated neutrophil count
>> Urticarial vasculitis
.
R. J. Powell et al. Urticaria and Angioedema BSACI guideline. Clinical & Experimental Allergy, 2015 (45) 547–565.
Acute phase response (ESR, CRP)
• Vasculitis
• Chronic infections
7

Elimination : Medications, Foods
• Type I allergy is a rare cause of CSU in patients who present
with daily or almost daily symptoms, but may be considered
with intermittent symptoms
- clears within 24–48 hr. if the relevant allergens are eliminated
• Pseudo-allergic (non-allergic hypersensitivity reactions)
to NSAIDs, food or food additives may be more relevant for
CSU with daily symptoms
- minimum of 3 weeks before beneficial effects are observed
8

C. E. H. Grattan. Aetiopathogenesis of Urticaria.
Aggrevating factors
9

10

Extended diagnostic measures
11

Infections
• Bacterial, viral, parasitic, or fungal infections
• JTF and the EAACI : routine assessment for
infections is not recommended
• Frequency and relevance of infectious diseases varies
between different patient groups and different
geographical regions
• More research is needed to make definitive recommendations
regarding the role of infection in urticaria
12

• 919 adults seen at the Allergy Center, Bari
• An area where marinated fish is very frequently eaten
Ventura MT. Int Arch Allergy Immunol 2013;160:297–300.
13

• H.pylori
• Streptococci
• Staphylococci
• Versania
• Giardia lamblia
• Mycoplasma pneumonia
• Hepatitis virus
• Novovirus
• Parvovirus 19
• Anisakis simplex
• Entamoeba spp.
• Blastocystis ssp.
Pathogen that found
associated with CSU
14

Allergic testing
• Based on clinical history >> avoid false-positive results
• Skin prick testing (SPT)
- Negative could be to exclude and helps to reassure
the patient that allergy is not the cause and may
contribute to improved adherence with long-term
anti-histamines
15

Malignancy
• Routine screening for malignancies is not suggested
• Not sufficient evidence available for a causal correlation
of urticaria with neoplastic diseases
16

Functional autoantibodies
In Vitro
In Vivo
• Basophil histamine release assays (BHRA)
• Direct immunoassays : Western blotting, ELISA, Flow cytometry
• Autologous serum skin test (ASST)
• Autologous plasma skin test (APST)
Asero R, et al. J Allergy Clin Immunol 2006;117:1113-7.
About 50% of patients with CU are positive on ASST
only ½ of them are able to induce histamine release from cultured bas
17

• Gold standard investigation for functional autoantibodies
C.E.H. Grattan et al. British Journal of Dermatology 2007 157, pp1116–1123.
• A histamine release > 16.5% is a positive test result in both
children and adults
• 1-2 mL of serum
• Histamine release is measured from
stimulated and unstimulated cells
Basophil histamine release assays
(BHRA)
18

• Time consuming procedure
• Difficult to standardized (requires fresh
basophils from heathy donor)
• Remain confined to research centers
• May miss nonfunctional autoantibodies
Limitation of BHRA
Grattan, Sabroe, and Greaves. J Am Acad Dermatol 2002;46:645-57.
Alpay A. et al. Dermatology Research and Practice Volume 2013.
R. J. Powell et al. Clinical & Experimental Allergy 2015, 45, 547–565.
Role in the clinical management of CU
remains unclear
19

Direct immunossays
• Investigation for non-functional and functional
autoantibodies
• Still need to be validated
- Western blotting
- ELISA
- Flow cytometry
20

Criado PR, et al. An Bras Dermatol. 2015;90(1):74-89.
Konstantinou et al. Allergy 2009: 64: 1256–1268.
5 ml. of venous blood
- ASST : sterile glass tubes
- APST : sterile glass tubes containing
0.125mol/L sodium citrate
• Kept at room temperature for 30 minutes
• Centrifugation at 2500 rpm
• 0.05-0.1 ml. undiluted serum or plasma intradermal
with 27 G needle
ASST, APST
• Wait for 30 minutes
21

Criado PR, et al. An Bras Dermatol. 2015;90(1):74-89.
Konstantinou et al. Allergy 2009: 64: 1256–1268.
Positive test :
Mean diameter of autologous serum/ plasma - saline = 1.5 mm.or greater
22

• Practical screening tool (Low cost and simplicity), best in vivo
• Evaluates the presence of serum histamine-releasing factors
of any type, not just histamine-releasing autoantibodies
• Positive test result does not distinguish between the presence of
FcεRI autoantibodies, anti-IgE antibodies, or histamine-releasing
factors
• Prevalence of a positive ASST result ranges from 50 - 60%
in patients with CSU
• Sensitivity of approximately 70% and a specificity of 80%
ASST
Kanokvalai K. et al. Asian Pacific Journal OF Allergy And Immunology (2006) 24: 201-206.
Bagenstose, Levin, and Bernstein. J Allergy Clin Immunol 2004;113:134-40.
23

• Asero et al. described that APST was more sensitive than ASST in patien
authors
• Heparin, EDTA, and sodium citrate were used as anticoagulants
while preparing plasma for the APST. It has been reported that
heparin inhibits mast cell and basophil degranulation, thus leading
to false negative results
• All relevant studies so far have reported that both the APST
and ASST can be used
ASST vs APST
24

Konstantinou et al. EAACI/GA2LEN task force consensus report. Allergy 2009: 64: 1256–1268.
• Adult CU patients in published studies ranges from 4.1% to 76.5%
using different criteria for positivity
25

• Low PPV ranging from 13.8 - 85%
• High NPV ranging from 59 -100%
Konstantinou et al. EAACI/GA2LEN task force consensus report. Allergy 2009: 64: 1256–1268.
• Positive ASST reactivity in 30–50% of adult patients with allergic or
nonallergic respiratory symptoms and 40–45% of healthy individuals
26

Other Autoantibodies
• ANA should be measured only if a connective tissue disorder
is clinically suspected
• Routine testing for SLE, rheumatoid arthritis, autoimmune thyroid
disease, and the IgE receptor autoantibody as well as treatment
of these diseases with a focus on or expectation to resolve the
chronic urticaria is not recommended
• Thyroid antibodies
- Antithyroglobulin antibodies
- Thyroid peroxidase antibodies
• Rheumatoid factor
• ANA
27

Thyroid function & Antibodies
• Suggests a diagnosis of autoimmune urticaria
• Such patients are often euthyroid but require monitoring over time
• 20% of patients with chronic urticaria have antithyroid antibodies
(compared to 6% in the general population)
28

Other tests
• Blood basophil count
• D-dimer
• Skin biopsy
29

D-dimer
• Increase D-dimer level in CSU
- 10-35% in Previous study
- 48.3% in Thai study
• Positive correlation between plasma
D-dimer levels and the severity of
disease activity
- 47.5% in Thai study
Triwongwaranat D, et al. Asia Pac Allergy 2013;3:100-105.
Asero R.J Allergy Clin Immunol October 2013. Volume 132, Issue 4, Pages 983–986.
30

Skin biopsy
• Unusual pattern of presentation or in cases of suspected vasculitis
- systemic symptoms (fever and arthralgia or arthritis)
- lesions lasting for more than 24 hr.
- associated with tenderness, petechiae, purpura or skin staining
as the lesions fade
Indications
31

Gold of treatment
33

Guidelines
1.) Japanese Dermatological Association (JDA) guidelines
Guidelines for the diagnosis and treatment of urticaria 2011
2.) EAACI/GA2LEN/EDF/WAO urticaria guideline 2013
3.) Thai Clinical Practice Guideline (Urticaria/Angioedema) 2014
4.) Practice parameter 2014. The diagnosis and management
of acute and chronic urticaria.
5.) BSACI guideline for the management of chronic urticaria
and angioedema 2015
34

35

Sarbjit S. Saini. Middleton's 8th edition.
H1 antihistamine
36

Age approved & Pregnancy catagory
37

www.drugs.com. Access date 15 Aug 2016.
38

• Rupatadine n=63
• Desloratadine n=69
• Placebo n=67
Potter et al. Pediatr Allergy Immunol 2016: 27: 55–61.
39

Potter et al. Pediatr Allergy Immunol 2016: 27: 55–61.
40

• Rescue therapy
• Short course of oral corticosteroids (maximum of up to
10 days)
• Evidence for treatment with systemic steroids for CSU is scant,
especially that for long term prognosis is poor
• Depending on the country, it must be noted that steroids are also
not licensed for chronic urticaria (e.g.,in Germany prednisolone is
only licenced for acute urticaria)
Corticosteroids
41

42

43

• BSACI 2015: Updosing with a single antihistamine is preferable
to mixing different antihistamines (Grade B)
- A lack of response to high-dose antihistamine therapy should
raise the possibility of an underlying diagnosis such as vasculitis
44

Maurer et al. JEADV 2015, 29 (Suppl. 3), 16–32.
45
Benefit of High-dose (4 times standard dose)
monotherapy

• Fexofenadine
• Desloratadine
• Levocetirizine
• Rupatadine
H1 antihistamine that have evidence
for increase dosage to 4-fold
46

• All patients should be offered the choice of at least 2 nonsedating H1
antihistamines because responses and tolerance vary between
individuals (Strength of recommendation A)
47

48

LTRA
• Addition to an H1 antihistamine for poorly controlled urticaria
(Little evidence as monotherapy)
• Offered 2-4 week, no evidence in > 4 weeks
• Montelukast is usually chosen
• Benefit in NSAID-exacerbated urticaria, ASST-positive CSU
and some physical urticaria
C.E.H. Grattan et al. British Journal of Dermatology 2007 :157, pp1116–1123.
Bernstein et al. J Allergy Clin Immunol 2014;133:1270-7. Practice parameter 2014.
R. J. Powell et al. BSACI guideline. Clinical & Experimental Allergy 2015, 45, 547–565.
49

50

51

Immunosuppressive drugs
• Studies on immunosuppressants in chronic urticaria lack
strength due to their small size
• Clear-cut response initial 1–4 weeks
• eg. cyclosporine, tacrolimus, mycophenolate mofetil,
methotrexate, azathioprine and mizoribine
Greenberger World Allergy Organization Journal 2014, 7:31.
Fine LM, et al. Curr Allergy Asthma Rep (2015) 15: 30.
52

Ciclosporin
• Ciclosporin has been the best studied immunsuppressive
drug for CSU to date
• Moderate, direct effect on mast cell mediator release
• Effective in about 2/3 of patients with severe autoimmune
urticaria unresponsive to antihistamines
• Cannot be recommended as standard treatment due to a
high incidence of adverse effects
• Regular assessment of renal and hepatic function
53

54

Trojan and Khan. Curr Opin Allergy Clin Immunol. 2012 Aug;12(4):412-20.
55

Neverman and Weinberger. J Allergy Clin Immunol Pract 2014;2:434-8.
56

57

Omalizumab
• Recombinant humanized immunoglobulin G1 (IgG1)
monoclonal antibody
• Binding IgE --> inhibits binding of IgE to the high-affinity
IgE receptor (FcεRI) on mast cell & basophil surface
• Down-regulating the FcεRI receptor
• Decrease the release of circulating interleukin-6 and
TNF-α
• Decrease the recruitment of T cells, eosinophils, and
macrophages in the inflammatory response
58

Picture from UpToDate.
Maurer M, et al. N Engl J Med 2013, 368:924–35.
Bound free IgE
59
• Rapid onset due to
1) binding to free IgE antibodies,
within a few hours of administration,
that reduces the binding of IgE to
the high affinity receptor FcεRI
on basophils and mast cells
2) downregulation of the
expression of FcεRI
- basophils (within 2 weeks)
- mast cells (within 8 weeks)

• FDA approved in CSU : Patients ≥12 years of age
• Dose in CSU : 150-300 mg. every 4 weeks
(Not dependent on serum IgE or body weight)
• Route : Subcutaneous injections
• Site : Deltoid, Thigh
• Pregnancy catagory B
• Side effects : Anaphylaxis, Anaphylactoid
(First 3 times must observe 2 hours then next time observe 30 minutes)
60

• Aim : Assess the efficacy and safety of different doses of omalizumab
for the treatment of CSU in a meta-analysis of clinical trial results
• Inclusion criteria : Only double-blind, randomized, placebo-controlled
studies with omalizumab-treated versus placebo-treated patients with
CSU were included
• 7 RCTs, 1312 patients with CSU
Zhao et al. J allergy Clin Immunol 2016;137:1742-50.
61

• Results :
- Patients treated with omalizumab (75-600 mg every 4 weeks) had
significantly reduced weekly itch and weekly wheal scores compared
with the placebo group.
- Omalizumab's effects were dose dependent, with the strongest
reduction in weekly itch and weekly wheal scores observed with 300 mg.
(relative risk, 4.55; P < 0.00001)
- Rates of adverse events were similar in the omalizumab and placebo.
Zhao et al. J allergy Clin Immunol 2016;137:1742-50.
62

• Onset of effect (reductions of
pruritus and urticarial lesions)
occur within a 1 week of a single
subcutaneous injection of 150 or
300 mg
Maurer M, et al. N Engl J Med 2013, 368:924–35.
63

Other treatment
• Plasmapheresis
- Reduction of functional autoantibodies
- Temporary benefit, High costs
- For autoantibody-positive CSU patients who are unresponsive
to all other forms of treatment
• Phototherapy
- UV-A, PUVA, and UV-B (nb-UVB) treatment for 1–3 months
can be added to antihistamine treatment
• Intravenous immunoglobulins (IVIG)
Only trials of low
quality or case
series have been
published
64

Other drugs
• Tricyclic antidepressants : Doxepin
• Colchicine
• Dapsone
• Sulfasalazine
• Treatment (Thyroxine) is not indicated in euthyroid individuals
with CU and thyroid autoimmunity
• Methotrexate
• Interferon
• Tranexamic acid
• Sodium cromoglicate
65

Follow-up evaluation
• Before changing to an alternative therapy,
it is recommended to wait for 1–4 weeks to
allow full effectiveness
• Re-evaluate the necessity for continued or
alternative drug treatment every 3–6 months
66

67

68

Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2014.
Comparison between EAACI & JTF
69

Bernstein et al. J Allergy Clin Immunol 2014;133:1270-7. Practice parameter 2014.
70
First generation
H1 antihistamine

* Short course of corticosteroids may be used for severe exacerbations
(e.g. 1 mg/kg prednisolone twice a day, up to 40 mg total per day, for 3
days)
71

Treatment of special populations
72

73

Children
• More sensitive to higher doses of sedating H1-antihistamines
than adults
• First-line recommended: Second generation H1-antihistamines,
weight-adjusted up-dosing if symptoms persist after 2 weeks
• Only medications with proven efficacy and safety in the pediatric
population should be used
74

Belloni Fortina and Fontana. Current Treatment Options in Allergy (2014) 1:287–298.
Depend on - Age (Licenced age also differs from country to country)
- Availability (Syrup/ Tablet)
75

Pregnant woman
• Systemic treatment should generally be avoided, especially
in the first trimester
• To date, no reports of birth defects in women having used modern
second-generation antihistamines during pregnancy
• Suggestion prefer loratadine and cetirizine
• Cyclosporine, although not teratogenic, is embryo-toxic in
animal models and is associated with preterm delivery and low birth
weight in human infants (Class C)
76

Lactation woman
• All H1-antihistamines are excreted in breast milk in low
concentrations
• Use of second-generation H1-antihistamines is advised
• BSACI 2015
- Pregnancy : Lowest dose of CPM, cetirizine or loratadine
- Lactation : Lowest dose of cetirizine or loratadine (avoid CPM)
77

Factors associated with longer duration or
more difficult to treat chronic urticaria
Greenberger World Allergy Organization Journal 2014, 7:31.
78

Chronic spontaneous urticaria (part2)

Chronic spontaneous urticaria (part2)

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