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(J Allergy Clin Immunol 2012;129:1307-13)




Sadudee (Boonmee) Klakayan, MD
Introduction
• Chronic urticaria (CU) : recurrent urticarial lesion
  for more than 6 week with symptoms present at
  least 3 times weekly
• When the cause is not detected after intensive
  clinical and laboratory investigation, it is defined
  as idiopathic
• autoimmune mechanisms have been proposed as
  responsible for the development of some of the
  cases of chronic idiopathic urticaria (CIU)
                            (J Allergy Clin Immunol 2012;129:1307-13)
Physical urticaria                                Chronic urticaria

- Cold urticaria
- Cholinergic urticaria
- Dermographism
- Pressure urticaria
- Solar urticaria                  Autoimmune chronic            Chronic idiopathic
-Aquagenic urticaria                     urticaria                   urticaria
                                           45%                         55%
Urticarial vasculitis


                          IgG antiFcεRIα          IgG antiIgE
                             subunit
                                                    5-10%
                             35-40%
• Thyroid disease is the most frequently
  investigated disease in association with CIU
• Arthur Leznoff et al.
  - 17 of 140 cases (12.1%) of chronic urticaria, demonstrated thyroid
  autoimmunity with thyroid microsomal antibodies (TMAs)
  ≥ 1: 1600
  - 8 of 17 pt. had goiter or thyroid dysfunction
  - age and sex and thyroid features were similar to pt.with
  autoimmune thyroiditis
  - CUA may have an autoimmune basis
                                      (Arch Dermatol 1983;119:636-640)
Are autoantibodies present in patient with
subacute and chronic urticaria ?

• Survey of autoantibodies in patients with
  idiopathic subacute and chronic urticaria
• 25 pt. vs 75 control (serum tested for
  autoantibodies)
• age 15 to 73 years (mean 48 yr)



                            J Investig Allergol Clin Immunol. 2001;11(1):16-20
• 1 pt. inflammatory bowel disease
  1 pt. multiple myeloma
  otherwise no other diagnoses of disease
  specifically involving immunity other than
  atopy
• No study patients had diagnosis of
  autoimmune thyroid disease



                            J Investig Allergol Clin Immunol. 2001;11(1):16-20
• Antibodies to thyroid peroxidase (TPO)
  common in urticaria 20% vs controls 0%
  (p < 0.01)

• Rheumatoid factor(RF) increased in urticaria
  16% vs controls 0% (p < 0.05)

• Neither H. pylori antibody nor other
  autoantibodies were present in significant
  numbers of urticaria patients compared to
  controls.

                           J Investig Allergol Clin Immunol. 2001;11(1):16-20
• Conclusion : pt. with urticaria more likely to
  have a thyroid autoantibody to TPO or to have
  RF
• This survey demonstrates that some markers
  of autoimmunity (TPO and RF)may be
  increased in urticaria patients, but other
  markers of autoimmunity were not found


                            J Investig Allergol Clin Immunol. 2001;11(1):16-20
(J Allergy Clin Immunol 2012;129:1307-13)
Objective
• Aimed to characterize the association
  between CU, autoimmune diseases, and
  autoimmune/inflammatory serologic markers
  in a large unselected population




                       (J Allergy Clin Immunol 2012;129:1307-13)
Methods
• Maccabi Healthcare Services (MHS) in Israel

• Using an automated search on the MHS central
  database

• Collected data on all pt. diagnosis of CU by either
  allergist and clinical immunology or dermatologist
  between January 1, 1993, and March 1, 2010 using
  the ICD-9-CM

                             (J Allergy Clin Immunol 2012;129:1307-13)
• Excluded : physical urticaria, cholinergic urticaria,
  dermographism, and urticaria without
  specification of ‘‘chronic’’ have distinct ICD-9-CM
• control subjects  pt. who visited
  - dermatologists
  - family physicians
  - allergist
  not given diagnosis of CU or any other specific
  disease but were given diagnoses with the ICD-9-
  CM “ Patient under observation ”
• Control subjects matched with cases by age and
  sex
                             (J Allergy Clin Immunol 2012;129:1307-13)
• For each patient, collected information on
  diagnostic history of
  - hypothyroidism, hyperthyroidism,
  - systemic lupus erythematosus (SLE)
  - rheumatoid arthritis (RA)
  - celiac disease
  - type 1 diabetes mellitus
  - Sjögren syndrome
• The first registration date for each diagnosis
  was collected
                           (J Allergy Clin Immunol 2012;129:1307-13)
• Laboratory tests :
  - antithyroid peroxidase antibodies
  - antithyroglobulin antibodies
  - antinuclear antibodies
  - rheumatoid factor
  - anti–dsDNA antibodies
  - anticardiolipin antibodies
  - anti–transglutaminase IgA antibodies
  - anti–parietal cell antibodies
  - mean platelet volume (MPV)

• Studies for antibodies to FcεRI or IgE were not available in
  Israel for routine clinical work

• Each patient, calculated the number of laboratory tests
  performed and the proportion of abnormal test results
                                  (J Allergy Clin Immunol 2012;129:1307-13)
RESULTS
Study group                                Control group


                   Diagnoses of                                 Control
                   CU =12,778 pt                              =10,714 pt.




         Women =                      men = 4,306     women =               men = 1,526
      8,472 (66.3%)                    (33.6%)      9,188 (85.7%)            (14.3%)


           Average age 45.3 +/- 18.5 years            Average age 44.2 +/- 14.2 years


(J Allergy Clin Immunol 2012;129:1307-13)
Thyroid disease and CU
(J Allergy Clin Immunol 2012;129:1307-13)
With in 10 yr




(J Allergy Clin Immunol 2012;129:1307-13)
Journal club: Chronic urticaria and autoimmunity
Other autoimmune disease and CU
(J Allergy Clin Immunol 2012;129:1307-13)
With in 10 yr




(J Allergy Clin Immunol 2012;129:1307-13)
Journal club: Chronic urticaria and autoimmunity
• few autoimmune diseases were diagnosed during the first 6 months
after the diagnosis of CU
• most continuously revealed over more than 10 years

• suggest that accompanying autoimmune diseases were independently
diagnosed and not as part of the CU workup
• OR of pt with CU with additional autoimmune
  disease = 17.343 compared with control
  (95% CI, 14.222-21.148; P < .0005)

• 1,872 pt with CU with autoimmune diseases
  - 12.5% (n =1591)  1 autoimmune disease
  - 2.1% (n = 263)  2 autoimmune diseases
  (hypothyroidism and another, mostly RA)
  - 0.1% (n= 16)  3 autoimmune diseases
  - 1 pt. 4 autoimmune diseases
  - 1 pt. 5 autoimmune diseases
                           (J Allergy Clin Immunol 2012;129:1307-13)
Serologic and Labortory markers and CU
Abnormal high




306 CU pt.with hypothyroidism have Antithyroid Ab( ATG,ATPO)

                                 (J Allergy Clin Immunol 2012;129:1307-13)
• Pt. CU group 11,514 pt. with euthyroid
   Lab       CU patient   Control   OR               P value
             With
             euthyroid

   ATPO Ab   312          6         24.24            < 0.0001


   ATG       74           1         17.37            <0.0001




                                    (J Allergy Clin Immunol 2012;129:1307-13)
Discussion
• This study is the first large control study
  demonstrating a correlation between CU and
  the main autoimmune diseases and serologic
  markers

• women affected twice as often as men
• Thyroid disease were most common autoimmune
  disease accopanying pt with CU
  from this study Pt with CU Dx
  - hypothyroidism = 10%
  - hypertrhyroidism = 2.6%
  signinicant than control and normal population
  group

• Antithyroid peroxidase and antithyroglobulin more
  significant prevalent in Pt. with CU than control
  group and physician were also diagnosed thyroid
  disease
• Aversano et al hypothesized that inflamatory
  status induced by thyroid- stimulating hormone
  led to flares of urticaria and production of
  antithyroid antibodies
• The author suggest that the association between
  CU and thyroid disease might due to share
  susceptability to autoimmune or chronic
  inflammatory process ( finding of other
  autoimmune disease were more common in CU
  pt.)
• Rheumatoid arthrits second most common
  autoimmune disease in pt. with CU
   - 1.9% of female pt. with CU (significant more
     prevalent than control group and normal
     population)
   - Rheumatoid factor +ve often in female and male
     pt. with CU than control

• Type I DM, Sjögren syndrome, celiac disease and SLE
significant more prevalent in female pt. with CU than
control
• Strengths of this study
  - large population of pt. with CU
  - compared with large match control group
  - retrospective study : correlation of CU and
  autoimmunity and proinflammatory marker
• Limitation of study
  - retrospective study : to evaluate
  autoimmune diasease and serologic marker
  that have effect or relation to CU required
  detail information and closed follow up
Conclusion
• Clinical implications:
  - CU is probably one of the autoimmune
  diseases
  - Understanding the disease process might
  help the development of individualized
  therapies and increase awareness of
  comorbidities, as well as help in the prediction
  of disease prognosis
Journal club: Chronic urticaria and autoimmunity
• Over the past 2 decades, studies have suggested an
  autoimmune mechanism underlying the pathophysiology of
  CIU in up to 50% of the patients

• Clinicians have also observed an association between CIU and
  thyroid antibodies in approximately 15 to 25% of CIU patients

• purpose of study
  - to determine correlation of biomarkers for autoimmunity
  (ANA or ATA, either individually or in combination with the CU
  Index) and disease severity in CIU
• CU index : commercial basophil histamine release assays to
  screen for a functional autoantibody to FcεRI
                                   Ann Allergy Asthma Immunol 108 (2012) 337–341
Methods
• Retrospective analysis patients with an ICD-9 diagnosis
  of chronic idiopathic urticaria from October 1, 2007
  through September 30, 2009
  in allergy clinic at tertiary care in Wisconsin

• 195 pt. (age ≥ 18) were included

• Exclusion : if they had primarily physical or cholinergic
  urticaria, acute urticaria, food or drug-related urticaria,
  vasculitis, mastocytosis, or exclusively angioedema
  without evidence of urticaria.

                                  Ann Allergy Asthma Immunol 108 (2012) 337–341
• Classified into 2 groups: they
  - Controlled if they required only H1/H2
  antihistamines with or without a leukotriene
  receptor antagonist (LTRA) for control of their
  hives
  - Refractory if they continued to have physical
  evidence of urticaria on this regimen


                           Ann Allergy Asthma Immunol 108 (2012) 337–341
• Laboratory data
  - ANA
  - anti-thyroperoxidase antibody (ATPO)
  - anti-thyroglobulin antibody (ATG)
  - CU Index (basophil histamine release assay)
• positive result were
  - CU Index (>10)
  - ANA (titer > 1:160)

                               Ann Allergy Asthma Immunol 108 (2012) 337–341
Results
• Demographic data




• All four biomarkers (CU Index, ANA, ATG, ATPO) were measured in 25% of
CIU patients
• at least 1 biomarker was measured in 84% of patients
• No autoimmune biomarker was measured in 32 (16%) CIU patients


                                        Ann Allergy Asthma Immunol 108 (2012) 337–341
Results
• Percentage of patients with positive autoimmune
  biomarkers




                            Ann Allergy Asthma Immunol 108 (2012) 337–341
Results
• Autoimmune biomarkers and disease severity

                                      80%



                                            46%
                          50%
                                30%




                           Ann Allergy Asthma Immunol 108 (2012) 337–341
Results
• Test characteristics of combinations of autoimmune
  biomarkers
                                   4.5
                         2.3




                                    3.1




                               Ann Allergy Asthma Immunol 108 (2012) 337–341
Results   Sensitivity, specity,PPV,NPV for identify a
          refractory outcome in CIU




                                       • CU Index has
                                       superior SPEC and
                                       PPV for identifying a
                                       refractory outcome
                                       in CIU

                                       • combinations of
                                       ANA and anti-thyroid
                                       antibodies
                                       slightly better SENS
                                       and NPV



                      Ann Allergy Asthma Immunol 108 (2012) 337–341
• Cost of order the autoimmune biomarkers
  - ANA= $84.20
  - ATG = $128.00
  - ATPO= $118.00
  - CU Index = $436.00
  - combination of the ANA, ATG, and ATPO = $330.20

• Need for establishing screening tools to identify pt.
  who are likely to remain refractory to conventional
  therapy and allow for an optimal and appropriate
  management in a timely and cost-effective manner
                                Ann Allergy Asthma Immunol 108 (2012) 337–341
Journal club: Chronic urticaria and autoimmunity
Mediator of hives and swelling
Mast cell (cutaneous)      Histamine
                           Prostaglandin D
                           Leukotrienes C and D
                           Platelet activating factor or 1-O-alkyl-2-
                           acetyl-sn-glyceryl-3-phosphorylcholine


Complement system          Anaphylatoxins C3a, C4a,C5a:
                           histamine

Hageman factor dependent   bradykinin
pathway
Mononuclear cells          Histamine-releasing factors,
                           chemokine

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Journal club: Chronic urticaria and autoimmunity

  • 1. (J Allergy Clin Immunol 2012;129:1307-13) Sadudee (Boonmee) Klakayan, MD
  • 2. Introduction • Chronic urticaria (CU) : recurrent urticarial lesion for more than 6 week with symptoms present at least 3 times weekly • When the cause is not detected after intensive clinical and laboratory investigation, it is defined as idiopathic • autoimmune mechanisms have been proposed as responsible for the development of some of the cases of chronic idiopathic urticaria (CIU) (J Allergy Clin Immunol 2012;129:1307-13)
  • 3. Physical urticaria Chronic urticaria - Cold urticaria - Cholinergic urticaria - Dermographism - Pressure urticaria - Solar urticaria Autoimmune chronic Chronic idiopathic -Aquagenic urticaria urticaria urticaria 45% 55% Urticarial vasculitis IgG antiFcεRIα IgG antiIgE subunit 5-10% 35-40%
  • 4. • Thyroid disease is the most frequently investigated disease in association with CIU • Arthur Leznoff et al. - 17 of 140 cases (12.1%) of chronic urticaria, demonstrated thyroid autoimmunity with thyroid microsomal antibodies (TMAs) ≥ 1: 1600 - 8 of 17 pt. had goiter or thyroid dysfunction - age and sex and thyroid features were similar to pt.with autoimmune thyroiditis - CUA may have an autoimmune basis (Arch Dermatol 1983;119:636-640)
  • 5. Are autoantibodies present in patient with subacute and chronic urticaria ? • Survey of autoantibodies in patients with idiopathic subacute and chronic urticaria • 25 pt. vs 75 control (serum tested for autoantibodies) • age 15 to 73 years (mean 48 yr) J Investig Allergol Clin Immunol. 2001;11(1):16-20
  • 6. • 1 pt. inflammatory bowel disease 1 pt. multiple myeloma otherwise no other diagnoses of disease specifically involving immunity other than atopy • No study patients had diagnosis of autoimmune thyroid disease J Investig Allergol Clin Immunol. 2001;11(1):16-20
  • 7. • Antibodies to thyroid peroxidase (TPO) common in urticaria 20% vs controls 0% (p < 0.01) • Rheumatoid factor(RF) increased in urticaria 16% vs controls 0% (p < 0.05) • Neither H. pylori antibody nor other autoantibodies were present in significant numbers of urticaria patients compared to controls. J Investig Allergol Clin Immunol. 2001;11(1):16-20
  • 8. • Conclusion : pt. with urticaria more likely to have a thyroid autoantibody to TPO or to have RF • This survey demonstrates that some markers of autoimmunity (TPO and RF)may be increased in urticaria patients, but other markers of autoimmunity were not found J Investig Allergol Clin Immunol. 2001;11(1):16-20
  • 9. (J Allergy Clin Immunol 2012;129:1307-13)
  • 10. Objective • Aimed to characterize the association between CU, autoimmune diseases, and autoimmune/inflammatory serologic markers in a large unselected population (J Allergy Clin Immunol 2012;129:1307-13)
  • 11. Methods • Maccabi Healthcare Services (MHS) in Israel • Using an automated search on the MHS central database • Collected data on all pt. diagnosis of CU by either allergist and clinical immunology or dermatologist between January 1, 1993, and March 1, 2010 using the ICD-9-CM (J Allergy Clin Immunol 2012;129:1307-13)
  • 12. • Excluded : physical urticaria, cholinergic urticaria, dermographism, and urticaria without specification of ‘‘chronic’’ have distinct ICD-9-CM • control subjects  pt. who visited - dermatologists - family physicians - allergist not given diagnosis of CU or any other specific disease but were given diagnoses with the ICD-9- CM “ Patient under observation ” • Control subjects matched with cases by age and sex (J Allergy Clin Immunol 2012;129:1307-13)
  • 13. • For each patient, collected information on diagnostic history of - hypothyroidism, hyperthyroidism, - systemic lupus erythematosus (SLE) - rheumatoid arthritis (RA) - celiac disease - type 1 diabetes mellitus - Sjögren syndrome • The first registration date for each diagnosis was collected (J Allergy Clin Immunol 2012;129:1307-13)
  • 14. • Laboratory tests : - antithyroid peroxidase antibodies - antithyroglobulin antibodies - antinuclear antibodies - rheumatoid factor - anti–dsDNA antibodies - anticardiolipin antibodies - anti–transglutaminase IgA antibodies - anti–parietal cell antibodies - mean platelet volume (MPV) • Studies for antibodies to FcεRI or IgE were not available in Israel for routine clinical work • Each patient, calculated the number of laboratory tests performed and the proportion of abnormal test results (J Allergy Clin Immunol 2012;129:1307-13)
  • 16. Study group Control group Diagnoses of Control CU =12,778 pt =10,714 pt. Women = men = 4,306 women = men = 1,526 8,472 (66.3%) (33.6%) 9,188 (85.7%) (14.3%) Average age 45.3 +/- 18.5 years Average age 44.2 +/- 14.2 years (J Allergy Clin Immunol 2012;129:1307-13)
  • 18. (J Allergy Clin Immunol 2012;129:1307-13)
  • 19. With in 10 yr (J Allergy Clin Immunol 2012;129:1307-13)
  • 22. (J Allergy Clin Immunol 2012;129:1307-13)
  • 23. With in 10 yr (J Allergy Clin Immunol 2012;129:1307-13)
  • 25. • few autoimmune diseases were diagnosed during the first 6 months after the diagnosis of CU • most continuously revealed over more than 10 years • suggest that accompanying autoimmune diseases were independently diagnosed and not as part of the CU workup
  • 26. • OR of pt with CU with additional autoimmune disease = 17.343 compared with control (95% CI, 14.222-21.148; P < .0005) • 1,872 pt with CU with autoimmune diseases - 12.5% (n =1591)  1 autoimmune disease - 2.1% (n = 263)  2 autoimmune diseases (hypothyroidism and another, mostly RA) - 0.1% (n= 16)  3 autoimmune diseases - 1 pt. 4 autoimmune diseases - 1 pt. 5 autoimmune diseases (J Allergy Clin Immunol 2012;129:1307-13)
  • 27. Serologic and Labortory markers and CU
  • 28. Abnormal high 306 CU pt.with hypothyroidism have Antithyroid Ab( ATG,ATPO) (J Allergy Clin Immunol 2012;129:1307-13)
  • 29. • Pt. CU group 11,514 pt. with euthyroid Lab CU patient Control OR P value With euthyroid ATPO Ab 312 6 24.24 < 0.0001 ATG 74 1 17.37 <0.0001 (J Allergy Clin Immunol 2012;129:1307-13)
  • 30. Discussion • This study is the first large control study demonstrating a correlation between CU and the main autoimmune diseases and serologic markers • women affected twice as often as men
  • 31. • Thyroid disease were most common autoimmune disease accopanying pt with CU from this study Pt with CU Dx - hypothyroidism = 10% - hypertrhyroidism = 2.6% signinicant than control and normal population group • Antithyroid peroxidase and antithyroglobulin more significant prevalent in Pt. with CU than control group and physician were also diagnosed thyroid disease
  • 32. • Aversano et al hypothesized that inflamatory status induced by thyroid- stimulating hormone led to flares of urticaria and production of antithyroid antibodies • The author suggest that the association between CU and thyroid disease might due to share susceptability to autoimmune or chronic inflammatory process ( finding of other autoimmune disease were more common in CU pt.)
  • 33. • Rheumatoid arthrits second most common autoimmune disease in pt. with CU - 1.9% of female pt. with CU (significant more prevalent than control group and normal population) - Rheumatoid factor +ve often in female and male pt. with CU than control • Type I DM, Sjögren syndrome, celiac disease and SLE significant more prevalent in female pt. with CU than control
  • 34. • Strengths of this study - large population of pt. with CU - compared with large match control group - retrospective study : correlation of CU and autoimmunity and proinflammatory marker • Limitation of study - retrospective study : to evaluate autoimmune diasease and serologic marker that have effect or relation to CU required detail information and closed follow up
  • 35. Conclusion • Clinical implications: - CU is probably one of the autoimmune diseases - Understanding the disease process might help the development of individualized therapies and increase awareness of comorbidities, as well as help in the prediction of disease prognosis
  • 37. • Over the past 2 decades, studies have suggested an autoimmune mechanism underlying the pathophysiology of CIU in up to 50% of the patients • Clinicians have also observed an association between CIU and thyroid antibodies in approximately 15 to 25% of CIU patients • purpose of study - to determine correlation of biomarkers for autoimmunity (ANA or ATA, either individually or in combination with the CU Index) and disease severity in CIU • CU index : commercial basophil histamine release assays to screen for a functional autoantibody to FcεRI Ann Allergy Asthma Immunol 108 (2012) 337–341
  • 38. Methods • Retrospective analysis patients with an ICD-9 diagnosis of chronic idiopathic urticaria from October 1, 2007 through September 30, 2009 in allergy clinic at tertiary care in Wisconsin • 195 pt. (age ≥ 18) were included • Exclusion : if they had primarily physical or cholinergic urticaria, acute urticaria, food or drug-related urticaria, vasculitis, mastocytosis, or exclusively angioedema without evidence of urticaria. Ann Allergy Asthma Immunol 108 (2012) 337–341
  • 39. • Classified into 2 groups: they - Controlled if they required only H1/H2 antihistamines with or without a leukotriene receptor antagonist (LTRA) for control of their hives - Refractory if they continued to have physical evidence of urticaria on this regimen Ann Allergy Asthma Immunol 108 (2012) 337–341
  • 40. • Laboratory data - ANA - anti-thyroperoxidase antibody (ATPO) - anti-thyroglobulin antibody (ATG) - CU Index (basophil histamine release assay) • positive result were - CU Index (>10) - ANA (titer > 1:160) Ann Allergy Asthma Immunol 108 (2012) 337–341
  • 41. Results • Demographic data • All four biomarkers (CU Index, ANA, ATG, ATPO) were measured in 25% of CIU patients • at least 1 biomarker was measured in 84% of patients • No autoimmune biomarker was measured in 32 (16%) CIU patients Ann Allergy Asthma Immunol 108 (2012) 337–341
  • 42. Results • Percentage of patients with positive autoimmune biomarkers Ann Allergy Asthma Immunol 108 (2012) 337–341
  • 43. Results • Autoimmune biomarkers and disease severity 80% 46% 50% 30% Ann Allergy Asthma Immunol 108 (2012) 337–341
  • 44. Results • Test characteristics of combinations of autoimmune biomarkers 4.5 2.3 3.1 Ann Allergy Asthma Immunol 108 (2012) 337–341
  • 45. Results Sensitivity, specity,PPV,NPV for identify a refractory outcome in CIU • CU Index has superior SPEC and PPV for identifying a refractory outcome in CIU • combinations of ANA and anti-thyroid antibodies slightly better SENS and NPV Ann Allergy Asthma Immunol 108 (2012) 337–341
  • 46. • Cost of order the autoimmune biomarkers - ANA= $84.20 - ATG = $128.00 - ATPO= $118.00 - CU Index = $436.00 - combination of the ANA, ATG, and ATPO = $330.20 • Need for establishing screening tools to identify pt. who are likely to remain refractory to conventional therapy and allow for an optimal and appropriate management in a timely and cost-effective manner Ann Allergy Asthma Immunol 108 (2012) 337–341
  • 48. Mediator of hives and swelling Mast cell (cutaneous) Histamine Prostaglandin D Leukotrienes C and D Platelet activating factor or 1-O-alkyl-2- acetyl-sn-glyceryl-3-phosphorylcholine Complement system Anaphylatoxins C3a, C4a,C5a: histamine Hageman factor dependent bradykinin pathway Mononuclear cells Histamine-releasing factors, chemokine

Notas del editor

  1. Tested autoantibodies included those to thyroglobulin, sDNA, SSA/SSB, ENA, cardiolipin, beta2-glycoprotein I, myeloperoxidase, proteinase-3, smooth muscle, ANA, human lysosomal-associated membrane protein, and bactericidal permeability increasing protein
  2. antibodies toFcεRI or IgE were not collected because they are not available in Israel forroutine clinical work.
  3. The control subjects were patientswho visited dermatologists, family physicians, or allergy specialists duringthis period and were not given a diagnosis of CU or any other specificdisease but were given diagnoses with the ICD-9-CM ‘‘patient underobservation’’ diagnosis. Control subjects were frequency matched with casesby age and sex.
  4. ทั้ง clinical hypo hyper and euthyroid
  5. In the past 4 to 5 years, multiple commercial basophil histamine release assays have been developed and made available to screen for a functional autoantibody to FcR1 One such assay is the Chronic Urticaria (CU) Index (IBT-Viracor Labs, Lenexa, Kansas)
  6. ATA =antithyroid antibody
  7. When multiple biomarkerswere examined, a given combination was considered positiveif any of the tests were positive