Chronic idiopathic urticaria part 2: investigation and management

Chronic Idiopathic
Urticaria
Episode 2:
Gathering information,
investigation and management
Wat Mitthamsiri, M.D.
Allergy and Clinical Immunology Unit
Department of Medicine
King Chulalongkorn Memorial Hospital

Outline
• Gathering information
– History
– Remarkable notes about PE
– Assessment
• Recommended investigations
• Management in general population
• Management in special population
(children and pregnant woman

History taking
• Time of onset of disease
• Frequency and duration of wheals
• Diurnal variation
• Occurrence in relation to weekends,
holidays, and foreign travel
• Shape, size, and distribution of wheals
• Associated angioedema
• Associated subjective symptoms of
lesion, e.g. itch, pain
Torsten Z, A Summary of the New International EAACI/GA2LEN/EDF/WAO Guidelines in Urticaria, WAO Journal 2012; 5:S1–S5.

History taking
• Family+personal Hx of urticaria & atopy
• Previous or current allergies, infections,
internal diseases, or other possible causes
• Psychosomatic/psychiatric diseases
• Surgical implantations and events during
surgery
• Gastric/intestinal problems (stool,
flatulence)
• Induction by physical agents or exercise

History taking
• Use of drugs
– NSAIDs
– Injections
– Immunizations
– Hormones
– Laxatives
– Suppositories
– Ear and eye drops
– Alternative remedies

History taking
• Observed correlation to food
• Relationship to the menstrual cycle
• Smoking habits
• Type of work
• Hobbies
• Stress
• Quality of life related to urticaria and
emotional impact
• Previous Rx and response to Rx

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

Muckle–Wells syndrome
• A rare autosomal dominant disease
• Comprises of
– Sensorineural deafness
– Recurrent hives
– Amyloidosis
• Other possible symptoms: episodic
fever, chills, and painful joints.
• Caused by a defect in the CIAS1 gene
which creates the protein cryopyrin
Mukle T, et al., Q J Med. 1962 Apr;31:235-48.
Lieberman A. et al., J Am Acad Dermatol. 1998 Aug;39(2 Pt 1):290-1.

Schnitzler Syndrome
• Characteristics
– Chronic urticaria
– Intermittent fever
– Osteosclerotic bone lesions
– Monoclonal gammopathy
• Sometimes also: joint
pain/inflammation, weight loss,
malaise, fatigue, swollen lymph
nodess and hepato/splenomegaly
• Unknown cause
Oren S, et al., IMAJ 2002;4:466±467
Koning H, et al., Seminars in arthritis and rheumatism 37, 2007, (3): 137–48.

Gleich's Syndrome
• A rare disease with
– Angioedema
– Increased IgM Ab
– Eosinophilia
• First described in 1984
• Unknown cause
Gleich G, et al., N Engl J Med. 1984 Jun 21;310(25):1621-6.

Wells Syndrome
• A rare disease with pruritic or tender
cellulitis-like eruption
• Typical histologic features:
– Edema
– Flame figures
– Marked eosinophils infiltration in the
dermis
• Unknown cause
Wells G, et al., Trans St Johns Hosp Dermatol Soc. 1971;57(1):46-56
Brehmer-Andersson E, et al. Acta Derm Venereol. 1986;66(3):213-9.

History taking
Michihiro H. et al., Japanese Guidelines for Diagnosis and Treatment of Urticaria in Comparison with Other Countries, Allergology International. 2012;61:517-527

Physical examination
Remarkable note:
• Test for dermographism where
indicated by history
• Antihistamine should be discontinued
for at least 2–3 days

Assessment
• Disease activity assessment
– Urticaria activity score
• Effects on patient’s quality of life
– Health Related Quality of Life (HRQL)
• General HRQL
• Disease-specific HRQL: Chronic Urticaria
Quality of Life Questionnaire (CU-Q2oL)
EAACI/GA2LEN/EDF/WAO guideline: management of urticaria, Allergy 2009: 64: 1427–1443.

Assessment

Assessment: Japanese

HRQL
Centers for Disease Control and Prevention. Measuring Healthy Days. Atlanta, Georgia: CDC, November 2000.
• http://www.cdc.gov/hrqol/hrqol14_measure.htm

HRQL
Murphy B, et al. Australian WHOQoL instruments: User’s manual and interpretation guide. World Health Organization (1993).
WHOQoL Study Protocol. WHO (MNH7PSF/93.9).

CU-Q2oL
Baiardini I, et al. Allergy. 2005 Aug;60(8):1073-8.

Recommended Tests

Infection
• H. pylori
• Streptococci
• Staphylococci
• Yersinia
• Giardia lamblia
• Mycoplasma pneumonia

Infection
• Hepatitis virus
• Norovirus
• Parvovirus B19
• Anisakis simplex
• Entamoeba spp
• Blastocystis spp
• Dental or ENT infections

Infection
• Hepatitis virus
• Norovirus
• Parvovirus B19
• Entamoeba spp
•Norwalk virus
•Feco-oral and contact
transmission
•Most common cause of
viral gastroenteritis in
humans
•Affect people of all ages

Infection
• Hepatitis virus
• Norovirus
• Parvovirus B19
• Entamoeba spp
•Fifth disease (Slapped
cheek syndrome)
•Anemia in AIDS
•Reactive arthritis
•Hydrop fetalis
•Aplastic crisis

Infection
• Hepatitis virus
• Norovirus
• Parvovirus B19
• Entamoeba spp
•Nematodes parasite
•Host: fish and marine
mammals
•possible cause of recurrent
acute spontaneous urticaria
Foti C, et al. Acta Derm Venereol 2002;82:121–123

Malignancy?
• No longer suggested
• No evidence available for a correlation
of urticaria with neoplastic diseases

Thyroid diseases
• 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.

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

Thyroid diseases
• A case-controlled study (140 vs 181)
found that CIU was associated with
• Hashimoto’s thyroiditis > Graves’
disease
• Female > male
Filliz C. et al., Eur J Dermatol 2006; 16 (4): 402-5

Thyroid diseases
• A study trying to figure out the
pathophysiologic relationship of anti-
thyroid and anti-FceRIa Ab reported
negative finding:
– Incubation of patient sera with FceRIa:
decreased ability to detect anti-FceRIa Ab
– But not thyroglobulin or thyroid
peroxidase
– Incubation with thyroid antigens did not
activation of mast cells
Jonathan DM., et al. Journal of Investigative Dermatology (2010) 130, 1860–1865.

Thyroid diseases
• So…epitopic cross-reactivity does not
explain the increased prevalence of
Hashimoto’s thyroiditis in CIU patients
• The frequent concurrence of
Hashimoto’s thyroiditis and CIU likely
reflects a genetic tendency toward
autoimmune diseases
Jonathan DM., et al. Journal of Investigative Dermatology (2010) 130, 1860–1865.

Thyroid diseases
• A recent case-controlled study of 115
patient found that
– Patients with CIU and autoimmune
thyroid disease had greater risk of
angioedema (16.2 times)
• Odds ratio
– Hypothyroidism: 4.6 (CI = 1.00-21.54)
– Hyperthyroidism: 3.3 (CI = 0.38-28.36).
Ruy FBGM., et al., Sao Paulo Med J. 2012; 130(5):294-8

Other autoantibodies
• Autologous Serum Skin Test (ASST)
• in vitro histamine release from
basophils: Histamine releasing assay

ASST
• In-vivo test detecting functional
autoantibody
• Sensitivity about 70%
• Specificity about 80%
• Positive in about 40% of CIU patients
(30-50% in previous literature)
M Abd El-Azim, et al., J Investig Allergol Clin Immunol 2011; Vol. 21(7): 546-550
Sabroe R., et al. J Am Acad Dermatol. 1999;40:443-50.

ASST
• A small report found that positive
ASST patients tend to have
– Less inflammatory process than the ASST
negative patient
• Less TNF-alpha
• Less chemokines
• Less expression of adhesion molecules
• ASST negative patients might be more
refractory to Rx
Stefania P., et al., Int Arch Allergy Immunol 2002;128:59–66

ASST
• But newer study reported that patients
with ASST positive tend to have:
– More frequent urticaria attacks
– Higher urticaria activity score
– Lower absolute eosinophil count
– Lower serum IgE titer
– Significantly higher antithyroid Ab titer
– Significantly higher B-cell percentage

ASST
• Another report found that patients with
positive ASST…
– No significantly different clinical variables:
• Disease severity, duration, attack frequency
• Presence of angioedema
• Family history of urticaria
• Family/personal history of atopy
• Family/personal history of autoimmune (eg.
thyroid disease, DM, vitiligo, and rheumatoid)
– Significantly associated with distribution of
wheals on the face and extremities
Hayder R. ISRN Dermatology Volume 2013, Article ID 291524, 4

ASST in Thai
• Only 1 study of 85 patient during 2002-
2003
– 24.7% of patients had a positive ASST
• There was no significant difference
between patients with positive ASST
and negative ASST in these variables:
– Severity (wheal no., wheal size, itching
scores and body area involvement)
– Duration of the disease
Kanokvalai K. et al., Asian Pac J Allergy Immunol. 2006 Dec;24(4):201-6.

ASST: Teniques
• ID injection of 50 μL at volar forearm of:
– Autologous serum
– histamine
– Sterile physiological saline
• Avoid areas known to have had
spontaneous wheals in previous 48 hours
– Mast cells may be refractory to further
activation (local tachyphylaxis)

ASST: Teniques
• Measure the wheal after 30 minutes
(15 minutes for histamine)
– At its 2 longest perpendicular diameters
– Calculate the average value
• A positive ASST result was defined as:
– Serum-induced wheal diameter was
larger than saline-induced wheal
diameter ≥1.5 mm, at 30 minutes

Histamine releasing assay
• Gold standard of detecting functional
autoantibodies
• Time-consuming procedure
• Difficult to standardize
• Requires fresh basophils from healthy
donors
Grattan CE, et al. J Am Acad Dermatol. 2002;46:645-57,

Other tests
• Blood basophil count
• Skin biopsy
• Skin biopsy
– Histologic pattern does not correlate with
the severity of urticaria
– And can’t be used as a guide to Rx

Other tests
D-dimer: There are reports about
• Positive autologus plasma skin testing
(APST) is higher than that of positive
autologus serum skin testing (ASST)
(80% vs. 50%)
• This difference suggested that
coagulation cascade is possibly
involved in the pathogenesis of CIU
Asero R, et al., J Allergy Clin Immunol 2006;117:1113-7.

Other tests
• Increased level of D-dimer in chronic
urticaria patient
– 10-35% in previous study
– 48.3% in a Thai study
• Positive correlation between plasma
D-dimer level and disease severity
Daranporn T. Asia Pac Allergy 2013;3:100-105.

Other tests
• No statistically significant difference in
plasma D-dimer level between:
– APST positive and negative groups
– ASST positive and negative groups.
• This may be an alternative way to
evaluate disease severity in patients
with CIU
Daranporn T. Asia Pac Allergy 2013;3:100-105.

Other tests
• There are potential tests that may be
useful in the future
• But they still need to be validated
– Western blotting
– ELISA
– Flow cytometry using chimeric cell lines
expressing the human FcεRIα
Grattan CE, et al., J Am Acad Dermatol 2002; 46: 645-57; quiz 57-60

In Japanese guideline

Management
in
General Population

General Principle
• Specific Rx

General Principle
• Specific Rx = Remove cause

General Principle
• Specific Rx = Remove cause
•Cause???

General Principle
• All we can do now is just
symptomatic Rx

Goal of Rx
• 1st stage: Symptom free

Goal of Rx
• 1st stage: Symptom free
• Final stage: Drug free

recommendations

recommendations
•Low cost
•Very good safety profile
•Very good evidence of efficacy

recommendations
2nd Generation = 1st Line
•Cetirizine
•Desloratadine
•Fexofenadine
•Levocetirizine
•Acrivastine
•Ebastine
•Mizolastine

recommendations
•Low cost
•Good safety profile
•Good evidence of efficacy

recommendations
•Low/medium low cost
•Insufficient evidence of efficacy

recommendations
Patients with cellular infiltration
•May be refractory to antihistamines
•May respond completely to a brief burst of
corticosteroid

recommendations
•Medium to high cost
•Moderate safety profile
•Moderate level of evidence for efficacy
•Recommended only for patients with severe
disease refractory to antihistamine
•Far better risk/benefit ratio compared with
steroids.

recommendations
•Moderate, direct effect on mast cell mediator release
•Only agent to inhibit basophil histamine release
Zuberbier T, et al. Acta Derm Venereol 1996;76:295–297.

recommendations
•Low cost
•Very low level of evidence for efficacy

recommendations
•Low cost
•Medium level of side effects
•Low level of evidence for efficacy

recommendations
•High cost
•Low level of evidence for efficacy
•Dramatically effective in selected patient
Spector SL, et al., Ann Allergy Asthma Immunol 2007;99:190–193

recommendations
• There is a strong recommendation
against the long-term use of
corticosteroids outside specialist
clinics
• If there is no special indication, we
recommend against the routine use of
old sedating first generation
antihistamines

recommendations
• We recommend against the use of
astemizole and terfenadine
– Pro-drugs requiring hepatic metabolism
to become fully active
– Cardiotoxic if this metabolism was
blocked by concomitant administration of
ketoconazole or erythromycin

recommendations
• Suggest the same first line treatment
and up-dosing for children (weight
adjusted)
• Suggest the same first line treatment in
pregnant or lactating women
– (but safety data in a large meta-analysis is
limited to loratadine)

Autoantibody reduction
• Plasmapheresis
– Benefit in severely affected patients
– High costs
– AutoAb-positive patients who are
unresponsive to all other treatment.

Autoantibody reduction
• Immunomodulatory Rx:
– Intravenous immunoglobulins (IVIG)
– Methotrexate
– Azathioprine
– Mycophenolate mofetil
– Cyclophosphamide
– Anti-IgE (Omalizumab)
– Tacrolimus

Hannuksela M, et al., Acta Derm Venereol 1985;65:449–450.
Borzova E, et al., J Am Acad Dermatol 2008;59:752–757.
Other Rx
• Phototherapy
– UV-A and UV-B Rx for 1–3 months can be
added to antihistamine treatment
• These agents were just case reports
and only be used in large centers as
last options

Other Rx: Combinations
• Nonsedating H1-antihistamines with:
– Stanazolol
– Montelukast
– Zafirlukast
– Mycophenolate mofetil
– Narrowband UV-B

Other Rx: Monotherapy
• There are reports but poor evidence of…
– Ketotifen
– Montelukast
– Warfarin
– Hydroxychloroquine
– Oxatomide
– Doxepin
– Nifedipine
– Autologs whole blood Injection

Other Rx
• Monotherapy: Only case-control
report, no RCT about…
– Dapsone
– Sulfasalazine
– Methotrexate
– Interferon
– Plasmapheresis
– IVIG

F/U evaluation
• Re-evaluate the necessity for
continued or alternative drug
treatment every 3–6 months.

recommendations
These agents might be added in
some patients
•Hydroxyzine or diphenhydramine
•Doxepin
•Prednisone

Adjusting medication
• Sometimes, sedating antihistamine
might be needed
– Hydroxyzine or diphenhydramine
200mg/day divided into 3 or 4 doses
• Or sometimes, Doxepin
– It can interact with H1 receptors
– And also possesses some H2 receptor
activity
• But beware of sedation

Adjusting medication
• Drugs must be taken as prescribed and
not just as needed
– Daily administration minimizes or prevents
outbreaks
– Use of antihistamines after the onset of
lesions occurs is too late
– Ratio of histamine vs antihistamine at the
cutaneous endothelial cell H1 receptor
determines the response
– If histamine level exceeds antihistamine
level, Rx will be ineffective

Adjusting steroid
Day 1 2 3 4 5 6 7
Dose (mg) 40 40 40 35 30 25 20
• Start with prednisone 40 mg/d

Adjusting steroid
Day 1 2 3 4 5 6 7
Dose (mg) 40 40 40 35 30 25 20
Day 8 9 10 11 12 13 14
Dose (mg) 15 20 10 20 5 20 -

Adjusting steroid
Day 1 2 3 4 5 6 7
Dose (mg) 40 40 40 35 30 25 20
Day 8 9 10 11 12 13 14
Dose (mg) 15 20 10 20 5 20 -
Day 15 16 17 18 19 20 21
Dose (mg) 20 - 20 - 20 - 20

Adjusting steroid
• Then taper steroid dosage by 2.5–5.0
mg every 2-3 weeks
• Nearly 3 months would be needed to
discontinue the steroid
• Sometimes, steroid cannot be tapered
below a certain dosage
– That dosage may be maintained for 1-2
month
– Then try tapering again

Adjusting steroid
• Common problem
– Good control of on the steroid ‘on’ day
– Prominent exacerbation on the ‘off’ day
• Solution
– Separate prednisone into b.i.d. dosage
– After good control, try tapering the
evening dosage first
– Or daily dosage might be used

Adjusting steroid
• Some patient unable to metabolize
prednisone to prednisolone
– Low dosage of methylprednisolone is
often effective
• Antihistamines :continued and should
not be tapered until steroid is no
longer required

Rx associated condition
• Rx of associated infection
• Rx of inflammatory processes
– Gastritis
– Reflux esophagitis
– Inflammation of the bile duct or gall
bladder

• Rx of food and drug intolerance
– Diet containing only low levels
pseudoallergens : instituted and
maintained for at least 3–6 month
– In pseudoallergy, a diet must be
maintained for a minimum of 3 weeks
before beneficial effects are observed.

• Rx psychological factors
• Symptomatic relief should be offered
while searching for causes

Unrecommended Rx
• Tranexamic acid
• Sodium cromoglicate (SCG)
• Sedating H1-antihistamine+cimetidine
• Sedating H1-antihistamine+terbutaline
• Leukotriene antagonist monotherapy
– Montelukast
– Zafirlukast
• Montelukast+desloratadine
• Monotherapy with H2 receptor
antagonist

Management
in
Special Population

Children
• Same first line treatment and up-dosing
(weight adjusted) is recommended as in
adults
• But…
• Nonsedating H1-antihistamines is not
licensed for use in children <6 months
of age

Pregnant woman
General concept:
• Systemic Rx should generally be
avoided in pregnant women, especially
in the 1st trimester
• But pregnant women have the right to
best possible Rx

Pregnant woman
Evidence?
• No systematic study on safety of Rx in
pregnant women with urticaria
• No study on negative effects of
increased levels of histamine occurring
in pregnant woman with urticaria, too.
• No reports of birth defects in women
having used 2nd generation
antihistamines during pregnancy

Pregnant woman
In real world
• 2nd generation antihistamines can be
bought over-the-counter and widely
used in self-Rx
• So… many women might have used
these drugs at the beginning of
pregnancy before the pregnancy was
confirmed

Pregnant woman
For highest safety possible, the current
suggestion is that:
• Use of 2nd generation antihistamines
should be limited to loratadine
• With the possible extrapolation to
desloratadine

Take Home Message
• History is the most important
diagnostic tool
• Investigations is for cause searching
• ASST is the best in-vivo test for
autoreactivity but basophil histamine
release assay is the gold standard

Take Home Message
• Non-sedating H1-receptor antagonist
antihistamine is the 1st line and
mainstay of treatment
• Treatment in children use the same
principle as normal adult
• In pregnant woman, available data
limited only to loratadine
• Other potential agents need more
study

Chronic idiopathic urticaria part 2: investigation and management

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Chronic idiopathic urticaria part 2: investigation and management