Chronic spontaneous urticaria (part2)

Lalita Tearprasert; M.D.26 Aug 2016

Chronic Spontaneous Urticaria(CSU)

Part

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

Investigations

3

• 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 CRP3.) Elimination of the possibility of underlying causes such as medications (eg. NSAIDs) or foods

Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline: update 2013.Clinical Practice Guideline 2557. (Urticaria/Angioedema).

Different recommended for investigations

• AAAAI/ACAAI Joint Task Force (Practice parameter 2014)

1.) CBC 2.) ESR or CRP3.) Elimination of the possibility of underlying causes such as medications (eg. NSAIDs) or foods4.) LFT5.) TSH

Choi SH and Baek HS. Korean J Pediatr 2015;58(5):159-164. Fine LM. Consensus and Controversies in the European and American Guidelines. Curr Allergy Asthma Rep (2015) 15: 30.

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

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

Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline: update 2013.

C. E. H. Grattan. Aetiopathogenesis of Urticaria.

Aggrevating factors

Extended diagnostic measures


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

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.

• 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.

• H.pylori• Streptococci• Staphylococci• Versania• Giardia lamblia• Mycoplasma pneumonia

• Hepatitis virus• Novovirus• Parvovirus 19• Anisakis simplex• Entamoeba spp.• Blastocystis ssp.

Fine LM. Consensus and Controversies in the European and American Guidelines. Curr Allergy Asthma Rep (2015) 15: 30.

Pathogen that found associated with CSU

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

R. J. Powell et al. Urticaria and Angioedema BSACI guideline. Clinical & Experimental Allergy, 2015 (45) 547–565.

Malignancy

• Routine screening for malignancies is not suggested

• Not sufficient evidence available for a causal correlation of urticaria with neoplastic diseases


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. Fine LM. Consensus and Controversies in the European and American Guidelines. Curr Allergy Asthma Rep (2015) 15: 30.

About 50% of patients with CU are positive on ASSTbut sera from only ½ of them are able to induce histamine release from cultured basophils in vitro

• 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)

• 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

Direct immunossays

• Investigation for non-functional and functional autoantibodies

• Still need to be validated - Western blotting - ELISA - Flow cytometry


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

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

• 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. Alpay A. et al. Dermatology Research and Practice Volume 2013.

Bagenstose, Levin, and Bernstein. J Allergy Clin Immunol 2004;113:134-40.

• Asero et al. described that APST was more sensitive than ASST in patients with CAU. However, has not yet been approved by other 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

Alpay A. et al. Dermatology Research and Practice Volume 2013.

ASST vs APST

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

• 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

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

Choi SH and Baek HS. Korean J Pediatr 2015;58(5):159-164.Fine LM. Consensus and Controversies in the European and American Guidelines. Curr Allergy Asthma Rep (2015) 15: 30.

• Thyroid antibodies - Antithyroglobulin antibodies - Thyroid peroxidase antibodies• Rheumatoid factor• ANA

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)

R. J. Powell et al. Clinical & Experimental Allergy 2015, 45, 547–565.Clinical Practice Guideline 2557. (Urticaria/Angioedema).

Other tests

• Blood basophil count• D-dimer• Skin biopsy


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.

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

R. J. Powell et al. Urticaria and Angioedema BSACI guideline. Clinical & Experimental Allergy, 2015 (45) 547–565.

Indications

Treatment

Gold of treatment


Guidelines1.) Japanese Dermatological Association (JDA) guidelines Guidelines for the diagnosis and treatment of urticaria 20112.) EAACI/GA2LEN/EDF/WAO urticaria guideline 20133.) Thai Clinical Practice Guideline (Urticaria/Angioedema) 20144.) Practice parameter 2014. The diagnosis and management of acute and chronic urticaria.5.) BSACI guideline for the management of chronic urticaria and angioedema 2015

Clinical Practice Guideline 2557. (Urticaria/Angioedema).

Sarbjit S. Saini. Middleton's 8th edition.

H1 antihistamine


Age approved & Pregnancy catagory

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

http://www.drugs.com/

• Rupatadine n=63• Desloratadine

n=69• Placebo n=67

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

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

• 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)

Hide M et al. Allergology International. 2012;61:517-527.Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline: update 2013.

Corticosteroids


• 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


Maurer et al. JEADV 2015, 29 (Suppl. 3), 16–32.

Benefit of High-dose (4 times standard dose) monotherapy

• Fexofenadine• Desloratadine• Levocetirizine• Rupatadine

H1 antihistamine that have evidence for increase dosage to 4-fold


• 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)



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.

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.

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 functionC.E.H. Grattan et al. British Journal of Dermatology 2007 157, pp1116–1123.


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

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

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

Choi SH and Baek HS. Korean J Pediatr 2015;58(5):159-164.

Picture from UpToDate.Maurer M, et al. N Engl J Med 2013, 368:924–35.

Bound free IgE

• 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)


• 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.

• 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.

• 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.

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

Other drugs

• Tricyclic antidepressants : Doxepin

• Colchicine• Dapsone • Sulfasalazine

• Treatment (Thyroxine) is not indicated in euthyroid individuals

with CU and thyroid autoimmunity

R. J. Powell et al. Clinical & Experimental Allergy 2015, 45, 547–565.Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline: update 2013.

• Methotrexate• Interferon• Tranexamic acid • Sodium cromoglicate

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


Hide M et al. Allergology International. 2012;61:517-527.

Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline 2014.

Comparison between EAACI & JTF

Bernstein et al. J Allergy Clin Immunol 2014;133:1270-7. Practice parameter 2014.

First generationH1

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)


Treatment of special populations

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


Belloni Fortina and Fontana. Current Treatment Options in Allergy (2014) 1:287–298.Zuberbier et al. EAACI/GA2LEN/EDF/WAO urticaria guideline: update 2013.

Depend on - Age (Licenced age also differs from country to country) - Availability (Syrup/ Tablet)

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)


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)


Factors associated with longer duration or more difficult to treat chronic

urticaria

Greenberger World Allergy Organization Journal 2014, 7:31.

Chronic spontaneous urticaria (part2)

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