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 MedicineKing 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

Gathering information

History taking

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, painTorsten 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

exerciseTorsten Z, A Summary of the New International EAACI/GA2LEN/EDF/WAO Guidelines in Urticaria, WAO Journal 2012; 5:S1–S5 .

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

Torsten Z, A Summary of the New International EAACI/GA2LEN/EDF/WAO Guidelines in Urticaria, WAO Journal 2012; 5:S1–S5 .

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 causeOren 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):46-56Brehmer-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.

CU-Q2oL

Recommended investigation

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



•Norwalk virus•Feco-oral and contact transmission•Most common cause of viral gastroenteritis in humans•Affect people of all ages

Infection



•Fifth disease (Slapped cheek syndrome)•Anemia in AIDS•Reactive arthritis•Hydrop fetalis•Aplastic crisis

Infection



•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

Infection



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 M Abd El-Azim, et al., J Investig Allergol Clin Immunol 2011; Vol. 21(7): 546-550

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 diseaseKanokvalai 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)M Abd El-Azim, et al., J Investig Allergol Clin Immunol 2011; Vol. 21(7): 546-550

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 minutesM Abd El-Azim, et al., J Investig Allergol Clin Immunol 2011; Vol. 21(7): 546-550

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

D-dimer: There are reports about• 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

D-dimer: There are reports about• 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


Managementin

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

General Principle

• All we can do now is just symptomatic Rx

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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


recommendations


• Low cost• Good safety profile

• Good evidence of efficacy

recommendations


recommendations


• Low/medium low cost• Good safety profile

• Insufficient evidence of efficacy

recommendations


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

recommendations


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•Good safety profile•Very low level of evidence for efficacy

recommendations


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

recommendations


•High cost•Good safety profile•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

EAACI/GA2LEN/EDF/WAO guideline: management of urticaria, Allergy 2009: 64: 1427–1443.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 7Dose (mg) 40 40 40 35 30 25 20

• Start with prednisone 40 mg/d

Adjusting steroid


Day 1 2 3 4 5 6 7Dose (mg) 40 40 40 35 30 25 20


Day 8 9 10 11 12 13 14Dose (mg) 15 20 10 20 5 20 -

Adjusting steroid


Day 1 2 3 4 5 6 7Dose (mg) 40 40 40 35 30 25 20


Day 8 9 10 11 12 13 14Dose (mg) 15 20 10 20 5 20 -

Day 15 16 17 18 19 20 21Dose (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



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Managementin

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

-Thank you-

Chronic idiopathic urticaria part 2: investigation and management

Health & Medicine

Transcript of Chronic idiopathic urticaria part 2: investigation and management