Journal club: Chronic urticaria and autoimmunity

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)


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 ?

http://www.ncbi.nlm.nih.gov/pubmed/11436965









• 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











• 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.











• 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











Objective

• Aimed to characterize the association between CU, autoimmune diseases, and autoimmune/inflammatory serologic markers in a large unselected population


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


• 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


• 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


• 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


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

Study group

Thyroid disease and CU

With in 10 yr


Other autoimmune disease and CU

With in 10 yr


• 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


Serologic and Labortory markers and CU


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


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


• 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)


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


Results• Percentage of patients with positive autoimmune

biomarkers


Results

• Autoimmune biomarkers and disease severity

80%

46%

50%

30%


Results• Test characteristics of combinations of autoimmune

biomarkers

4.5

2.3

3.1


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


• 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


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

Journal club: Chronic urticaria and autoimmunity

Health & Medicine

Transcript of Journal club: Chronic urticaria and autoimmunity