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Chronic spontaneous urticaria

Chronic spontaneous urticaria

Presented by Pornsiri Sae-lim, MD.

September25, 2020

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Chronic spontaneous urticaria

  1. 1. Chronic Spontaneous Urticaria (CSU) PORNSIRI SAE-LIM , MD PEDIATRIC ALLERGY AND IMMUNOLOGY DEPARTMENT KING CHULALONGKORN MEMORIAL HOSPITAL
  2. 2. Overview • Diagnosis & Classification of Urticaria • Epidemiology & Pravalance • Natural history & Prognosis • Pathogenesis • Investigation • Management
  3. 3. Urticaria • 20 % persons will experience an episode of urticaria in their lifetime • 1% of the general population : Chronic urticaria • Characterized by the development of wheals (hives), angioedema or both Urticaria and Angioedema. Middleton’s Allergy: Principles and Practice, 9th ed.
  4. 4. wheal 3 typical features: • Central swelling of variable size, almost invariably surrounded by reflex erythema • Itching or sometimes burning sensation • fleeting nature, with the skin returning to normal appearance, usually within 30 minutes to 24 hours T. Zuberbier1,The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria 2018
  5. 5. Angioedema in urticaria patients is characterized : • Sudden, pronounced erythematous or skin coloured swelling of the lower dermis and subcutis or mucous membranes, • Sometimes pain, rather than itch. • Resolution slower than that of wheals (can take up to 72 hours) T. Zuberbier1,The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria 2018
  6. 6. Classification Based on duration and the presence of triggering factors Urticaria Acute Symptom for < 6 weeks Chronic Symptom for < 6 weeks Spontaneous CSU ( No obvious external specific trigger ) Inducible CIndU ( known trigger ) Old term : CIU Old term : Physical Urticaria
  7. 7. Some guidelines and experts identify a subset of patients on the basis of serologic evidence of a presumed autoimmune etiology - Chronic autoimmune urticaria (CAU) : 30% to 40% - Chronic spontaneous urticaria (CSU) : remaining 60% to 70% Sarbjit S. Saini. Middleton’s 9th edition
  8. 8. Epidemiology & Prevalance • 1% of the general population in the United States • The prevalence is thought to be similar in other countries • More common in adults • Female:male 2:1 • Average age : the third to fifth decades of life • The coexpression of allergic disease diagnosis in patients with CU appears to be slightly higher than in the general population
  9. 9. Natural history & Prognosis • Self-limited disorder in most patients • Average duration of disease is 2 to 5 years • Rates of spontaneous remission at 1 year : approximately 30% to 50% • Persist beyond 5 years : one-fifth of patients • Parameters reported to be associated with longer CSU disease • Angioedema • Features of severe disease • Autologous serum skin test (ASST)
  10. 10. Sarbjit S. Saini, Immunol Allergy Clin N Am 34 (2014) 33–52
  11. 11. Pathogenesis
  12. 12. Skin histologic feature •Skin mast cells that have degranulated in the dermis •Perivascular leukocyte infiltrate composed of lymphocytes, eosinophils, neutrophils,and also basophils that have migrated to the skin lesion •Both mast cells and basophils release histamine and other inflammatory mediators(prostaglandins, leukotrienes C4, D4, E4; cytokines) •Histamine appears to be a central mediator: the prominent of pruritus and the beneficial response to Antihistamines •both Th2 and Th1 cytokines are noted in CU lesions Sarbjit S. Sai. J ALLERGY CLIN IMMUNOL PRACT
  13. 13. Recently, epithelial-derived cytokines that favor the TH2 profile ◦ IL-33 ◦ IL-25 ◦ thymic stromal lymphopoietin the dermis of lesional skin along with the vasoactive agents vascular endothelial growth factor and calcitonin gene-related peptide, but these factors were not observed in uninvolved skin
  14. 14. Sarbjit S. Sai. J ALLERGY CLIN IMMUNOL PRACT
  15. 15. Autoimmmune theory • 30% to 40% autoimmune disease of CIU : immunoglobulin G (IgG) autoantibodies to either IgE or the subunit of the high- affinity IgE receptor • Thyroid autoantibodies & thyroid dysfunction occur at higher frequency in patients with CSU ◦ Thyroid disease occurs in approximately 12% of subjects with CSU, which is twice the rate of the general population Sarbjit S. Sai. J ALLERGY CLIN IMMUNOL PRACT
  16. 16. Sarbjit S. Sai. J ALLERGY CLIN IMMUNOL PRACT
  17. 17. • serum factor behaved similarly to a cross-linking anti-IgE was observed in CU patients • based on an in vivo skin-test response called the ASST • 7 of 12 (58%) CU patients developed wheal and flare reactions within 30 minutes at the site of intradermal injection of their own serum Sarbjit S. Sai. J ALLERGY CLIN IMMUNOL PRACT
  18. 18. • CU serum contained IgG antibodies against the Fc region of IgE • Led to a dose- dependent histamine release from the blood basophils of healthy subjects Histamine-releasing activity (HRA) Sarbjit S. Sai. J ALLERGY CLIN IMMUNOL PRACT
  19. 19. The lack of concordance among ASST, HRA, and other antibody platforms such as ELISA or Western blotting remains a problem in identifying the proper test to define the entity of CAU Urticaria and Angioedema. Middleton’s Allergy: Principles and Practice, 9th ed.
  20. 20. Skin Mast cells Skin mast cells number are increased or not remains controversial Mast cell degranulation is a central event of the lesions in urticaria Histamine levels are elevated in biopsied skin ◦ Increase compound 48/80-induced histamine responses via skin chambers ◦ Increae levels of Mas-related gene X2, a novel G protein coupled receptor ◦ CD34 -derived mast cells spontaneously release histamine total serum tryptase are within the normal range but higher than the average measure
  21. 21. Blood basophils CSU basophils are different not only in number but also in function • basophil hyporesponsiveness or hyporeleasability • Blood basopenia Basophil presence in both lesional sites and nonlesional skin tissues : the PGD2 pathway via the CRTh2 receptor is implicated Degree of basopenia is correlated with disease severity and may reflect blood basophil recruitment to the skin lesions
  22. 22. basophil hyporesponsiveness •Reduced ability to release histamine after IgE receptor activation •Blood basophil IgE receptor respond of CIU : two phenotypes • CIU responders (CIU-Rs) : histamine degranulation profile similar normal subjects • CIU nonresponders (CIU-NRs) • CD63 induction on CSU basophils : • confirmed the existence of these two functional phenotypes
  23. 23. Sarbjit S. Saini. Middleton’s 9th edition
  24. 24. Sarbjit S. SainiJ ALLERGY CLIN IMMUNOL PRACT JULY/AUGUST 2018
  25. 25. The diagnosis work up
  26. 26. Complete blood count Acute phase response (ESR, CRP) • Elevated eosinophil count >> Parasitic infections, drug induced reactions • Elevated neutrophil count >> Urticarial vasculitis • Vasculitis • Chronic infections R. J. Powell et al. Urticaria and Angioedema BSACI guideline. Clinical & Experimental Allergy, 2015 (45) 547–565
  27. 27. 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
  28. 28. Functional autoantibodies In Vitro • Basophil histamine release assays (BHRA) • Direct immunoassays : Western blotting, ELISA, Flow cytometry In Vivo • 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
  29. 29. Basophil histamine release assays (BHRA) • 1-2 mL of serum • Histamine release is measured from stimulated and unstimulated cells A histamine release > 16.5% is a positive test result in both children and adults C.E.H. Grattan et al. British Journal of Dermatology 2007 157, pp1116–1123 Role in the clinical management of CU remains unclear
  30. 30. ASST, APST 5 ml. of venous blood - ASST : sterile glass tubes - APST : sterile glass tube 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 ASST, APST Criado PR, et al. An Bras Dermatol. 2015;90(1):74-89. Konstantinou et al. Allergy 2009: 64: 1256–1268
  31. 31. Positive test : Mean diameter of autologous serum/ plasma - saline = 1.5 mm.or greater
  32. 32. ASST 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% 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
  33. 33. APST • APST was more sensitive than ASST in patients 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 Alpay A. et al. Dermatology Research and Practice Volume 2013.
  34. 34. Other Autoantibodies • Thyroid antibodies - Antithyroglobulin antibodies - Thyroid peroxidase antibodies • Rheumatoid factor • ANA
  35. 35. Skin biopsy Indications 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 . J. Powell et al. Urticaria and Angioedema BSACI guideline. Clinical & Experimental Allergy, 2015 (45) 547–565
  36. 36. MANAGEMENT OF URTICARIA
  37. 37. H1 Antihistamine that have evidence for increase dosage to 4-fold • Fexofenadine • Desloratadine • Levocetirizine • rupatadine • ilastine
  38. 38. Corticosteroid • not recommended for long-term • short course : control acute symptoms until other modalities take effect • 30 mg/d for 3 days and then taper by 5 mg/d for a total course of 8 dayss • Angioedema can be treated with 40 mg for 2 days and then discontinued without any taper Sarbjit S. SainiJ ALLERGY CLIN IMMUNOL PRACT JULY/AUGUST 2018
  39. 39. Severity : UAS7 • The sum UAS score of 7 consecutive days • Used in routine clinical practice to determine disease activity & response to treatment Sum of score: 0-6 for each day is summarized over one week (maximum 42) T. Zuberbier1,The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria 2018
  40. 40. Clinical Practice Guideline 2557.(Urticaria/Angioedema).
  41. 41. 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
  42. 42. Omalizumab 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)
  43. 43. Follow up & evaluation Before changing to an alternative therapy, • 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
  44. 44. Pregnant and lactating women •Systemic treatment should generally be avoided, especially in the first trimester • No reports of birth defects in women having used modern 2nd-generation antihistamines during pregnancy • Ciclosporin is associated with preterm delivery and low birth weight Zuberbier1,The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria 2018

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