Sarbjit Saini, MD – Associate Professor at JHU. CIU and response to Anti – IgE therapy. Notes from presentation at 51st Swineford Conference at UVa
General Overview about CU:
CU > 6weeks of hives; 80% are idiopathic; 1% prevalence in US; 2F>M
50% better at one year; >20% will have disease >5yr
angioedema predicts more severe disease.
Coexpression of angioedema in CIU:
50% Urticaria; 40% have Urticaria and Angio; 10% just angioedema
Evaluation of CIU:
exclusion of drug/food (rare);
1/3 with NSAID intolerance;
exclude secondary causes (25% have abnormal thyroid test; thyroid ds is 2 times nl frequency);
consider rare disease (chronic hepatitis, cryoglubulinemia, systemic vasculitis, chronic infections – sinus, dental, H pylori etc)
JACI Feb 2012:hypothyroid 10% CU vs 0.6% in NL
hyperthyroid 2% CU vs 1% in NL
20% of thyroid ds before dx with CU
3-4% dx with thyroid disease with 6 months of Cu
Systemic W/U of 6000 cases of CU:
1.6% of cases had other disease with extensive lab w/u
? do we need to do lab w/u in CIU if only rarely find other diseases?
Approach to CU:
Non sedating anti histamine at normal dosing, if not controlled then updose to 4x nl dosing. If not helpful then add H2 blkr, LTRA, and / or change anti histamines. If still not controlled then consider prednisone burst for 3 – 7 days.
If hives then still persist then into refractory CIU and consider skin biopsy to confirm what is going on and then possibly alternative agents
Why Biopsy?
1) confirm histology ( should see edema, vascular dilation, perivascular infiltrate to include lymphocytes, eosinophils and basophils)
2)Characterize infiltrate:
lymphocytre predominant urticaria +/- eosinophils ( ? use sulfasalazine)
neutrophil predominant (? dapsone or colchicine)
if use alternative agents will need to monitor CBC, LFT’s
- Exclude other disorders ( leuokocytoclastic vasculitis, mastocytosis )
CYA for CIU:
lymph predominant disease; CYA will inhib T Cells as well as MC and basophils
monitor BP, Cr
CIU Proposed Pathophysiology:
trigger of some sort to MC (allergen autoab unkn)
histamine release and other med recruits leukocytes
Basophils are depleted in those with more severe CIU – see basopenia
Suppressed Basophil Histamine Release
Auto ab mechanism:
trigger IgE receptor on MC/Baso; 40% of pts have autoab
looking for autoab assay:
autologous ST, sera for auto ab, HRA with pt sera and donor basophils
these assays don’t cross compare
CIU index:
if some possible HRF with see Baso release
or see expression of new markers
25% of nl have positive CIU index – problem
even pt who go into remission still have positive CIU index – problem
no assay is superior; problems with specificity
Skin MC in CIU:
release to 48/40 in increased in active CIU vs in CIU remission which suggests reversible skin MC hyper- responsiveness.
MC numbers are not increased in CIU biopsy sites. Nor is tryptase elevated in CIU patients. However, tryptase is slightly higher in CIU vs atopic patients. The skin MC in CIU patients have increased spontaneous histamine releasability.
CD34+ MC have increased spontaneous histamine release
Basophils in CIU:
decreased in blood and are recruited to lesional and non lesional tissue
Basophil Histamine Release via FcER1 is reduced during disease and rises in remission
Two functional phenotypes of basophils seen on CIU
Responders (R) and Non responders (NR) – based upon histamine release to polyclonal anti IgE: CIU – R and CIU – NR
Longitudinal follow up of these pt – those with active disease stay in the same phenotype but with remission: baso fxn changed from suppressed to non suppressed state as get better
Also will see # of blood basophils increase with remission – ** blood basophils counts are based upon 120cc of blood. This amount was needed to be drawn and basophils counts done to see difference. Typical CBC basophil count probably not enough volume.
Why Xolair in CIU?:
Xolair impairs ability of IgE to bind to receptor; dec # of FcERI, decrease meds and decreased symptoms. We know this from asthma, AR.
Xolair decrease IgE within a few days then decreases basophil surface IgE and FcERI and function. Then see MC change with tissue MC taking months to drop b/c so longed lived take a long time to drop receptors
Reasons why Xolair might be helpful in CIU:
We know that there is MC activation with late phase infiltrate. This is accompanied by altered basophil FcERI HR, basophils being recruited to skin lesion and basopenia.
Therefore, omalizumab could cause shifts in MC and Baso FcERI function. Be able to distinguish the roles of MC and Baso in CIU based upon onset of action and possibly reduce targets for autoantibodies ( IgE and FcERI)
Random DBPC trial: (Goober AAAAI 2008)
20pt; 18-80yo; symptoms >12 wks; can have angioedema; daily H1 blocker; no steroids or other immunosuppresants < 1 month prior to study
Results:
decreased MD urticaria severity score, within first weeks – with rebound as tapered off
pt reported increased symptom free days
basophil # rise with tx within a month and decrease after stopping drug
Kaplan Xolair in auto immune urticaria: JACI 2008
pt with posit Baso histamine releasing activity
Phase 2 study of Xoalir in resistant CIU:
within one week see decreased symptom score; can see a dose effect as well ( to some degree)
Some conclusions:
This brisk effect of xolair is much faster than would be expected if due to MC alteration
Xolair helps in both CIU and autoimmune CIU
? long term disease benefit – what happens when they stop
risk of anaphylaxis. malignancy, carry epi, high rate of local rxn
Novel role of IgE as opposed to IgE that sits on cells and binds allergen(s)
Basopenia and basophil FceRI mediated response improve
basophil shifts like natural remission
