Post on 07-May-2015
description
Sadudee (Boonmee) Klakayan, MD
(J Allergy Clin Immunol 2012;129:1307-13)
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)
Chronic urticaria
Autoimmune chronic urticaria
45%
IgG antiFcεRIα subunit35-40%
IgG antiIgE5-10%
Chronic idiopathic urticaria
55%
Physical urticaria- Cold urticaria- Cholinergic urticaria- Dermographism- Pressure urticaria- Solar urticaria-Aquagenic urticaria
Urticarial vasculitis
• 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)
• 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
Are autoantibodies present in patient with subacute and chronic urticaria ?
• 1 pt. inflammatory bowel disease 1 pt. multiple myelomaotherwise 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
Diagnoses of CU =12,778 pt
Women =8,472 (66.3%)
men = 4,306 (33.6%)
Control =10,714 pt.
women = 9,188 (85.7%)
men = 1,526 (14.3%)
Control group
(J Allergy Clin Immunol 2012;129:1307-13)
Average age 45.3 +/- 18.5 years Average age 44.2 +/- 14.2 years
Study group
Thyroid disease and CU
(J Allergy Clin Immunol 2012;129:1307-13)
With in 10 yr
(J Allergy Clin Immunol 2012;129:1307-13)
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)
• 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
(J Allergy Clin Immunol 2012;129:1307-13)
306 CU pt.with hypothyroidism have Antithyroid Ab( ATG,ATPO)
Abnormal high
• Pt. CU group 11,514 pt. with euthyroid
Lab CU patientWith euthyroid
Control OR P value
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
• 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 FcεRIAnn 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, 2009in 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
ResultsSensitivity, specity,PPV,NPV for identify a refractory outcome in CIU
• CU Index has superior SPEC and PPV for identifying a refractory outcomein CIU
• combinations of ANA and anti-thyroid antibodiesslightly 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
Mediator of hives and swellingMast cell (cutaneous) Histamine
Prostaglandin DLeukotrienes C and DPlatelet activating factor or 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine
Complement system Anaphylatoxins C3a, C4a,C5a: histamine
Hageman factor dependent pathway
bradykinin
Mononuclear cells Histamine-releasing factors, chemokine