Auto-inflammatory Syndromes - Twitter summary from #CSACI19 meeting

Dr. Ellis @DrAnneEllis: Dr. Marcus Shaker "Auto-inflammatory Syndromes".

Recurrent fever - common things are more common! Recurrent viral illness (think day care) recurrent bacterial infection (think immunodeficiency), pseudo fever explain most.

Cryopyrinopathies are rare but described association with celiac disease.

Cryopyrin Associated Periodic Syndromes (CAPS) include Familial Cold Autoinflammatory syndrome (FCAS), Muckle-Wells Syndrome and Neonatal onset multisystem inflammatory disease (NOMID).

Canakinumab (human monoclonal antibody targeted at interleukin-1 beta) led to a 98% response rate for CAPS in the pivotal @NEJM publication.

Autoinflammatory syndromes are issues with the innate immune syndrome rather than adaptive.

TRAPS presents with recurrent fevers, serositis, abdominal pain, rash, myalgias and amyloidosis. Treatment is steroids and anti-Il1.

Shaker: Sometimes discussing auto-inflammatory conditions can feel like Alphabet Soup.

Chronic Sinusitis - Twitter summary from #CSACI19 meeting

Dr. Ellis @DrAnneEllis: About to give my interactive workshop on Dilemmas in Chronic Rhinosinusitis.

Polyp recurrence after endoscopic sinus surgery is almost 90%.

Dr. Desroisers - Not everything that can be added to a sinus rinse should go into the nose! Many dangers to 'home remedies'.

Inflammation is central to the multifactorial etiology of chronic rhinosinusitis. Eosinophils are a biomarker of the underlying disease if Type 2 inflammation is causing issues.

CRS epithelium heals poorly following injury. Microbiome is disrupted post sinus surgery as well. Those who do not do well post ESS are more likely to have Staph aureus.

Mary McHenry MD @maryjmchenry: Many reasons to treat other than the patient has stuffy nose: CRS impairs sleep, QoL, sense of smell, risk for antibiotics, risk for Type 2 disease, side effects of antibiotics - the list goes on!

Dupilumab led to polyp resolution as impressive as surgery in the Phase 3 trials - Desrosiers "it's like surgery to the immune system".

Stepwise approach to management of CRS -medication, well performed surgery, post EES budesonide irrigation.

Mary McHenry MD @maryjmchenry: Biologic therapy for CRSwNP: "surgery of the immune system" as per Dr Desrosiers (ENT). A great way to describe biologic therapy for Type 2 inflammation.

Food allergy, OIT and Epicutaneous immunotherapy (EPIT) - Twitter summary from #CSACI19 meeting

Dr. Ellis @DrAnneEllis: Epicutaneous immunotherapy - a "patch" is applied with standardized, controlled allergen content with an aim to increase tolerance to a food - peanut and milk best studied thus far. PEPITES was a pivotal Phase 3 study of EPIT, showed benefit of the peanut patch over placebo patch, but it didn't meet the FDA requirement for the confidence interval to claim true statistical significance. Adverse events to patch were common - (most, local irritation at the patch site) but almost completely matched numerically in the placebo arm.



Food allergy - Only 3 ways to treat allergies (click to enlarge the image).

Dr. Mariam Hanna, MD @PedsAllergyDoc: Dr Chan reviews EPIT- PEPITES reviewed, 5 Canadian co-authors - 356 peanut allergic children (age 4-11yo), intervention 250mcg protein - primary outcome 35% vs 13% didn’t meet FDA lower bound confidence interval (clinical relevance of this?).

Final comments from Dr. Chan re immunotherapy: 1) The ship has sailed, 2) Use of OIT outside research is a reality and 3) No one size fits all. Most importantly: Oral food challenges and OIT go hand in hand.

Stuart Carr @allergydoc4kidz: EPIT: Relatively small increase in peanut threshold but perhaps sufficient to protect against cross contamination and some evidence of improved QOL.

Dr. Ellis @DrAnneEllis: Many other trials underway with the EPIT technology developed by @DBVTechnologies We look forward to seeing the results!

AR101 and PALISADE trial evaluated the Peanut OIT product from @aimmune - 600mg of peanut protein allows 60% of patients to meet the primary outcome of tolerating a large dose of peanut on oral food challenge at the conclusion of trial.

Adverse events, including anaphylaxis, were unfortunately not uncommon - 14.2% had systemic allergic reactions in the active group. But this is not actually surprising based on other studies of OIT.

Lancet study by Dr. Derek Chu from @MacHealthSci highlights the issues with anaphylaxis from peanut OIT. Avoidance of peanut leads to less anaphylaxis, but avoidance doesn't improve the underlying condition the way OIT does...risks/benefits/SHARED DECISION MAKING key:).

Summary - OIT is very controversial. Pros and Cons to EPIT, OIT and avoidance. Once again, we need to talk or our patients and ensure Shared Decision Making is in place.

Quality of life improves throughout the entire journal of oral immunotherapy.

Wait times for oral food challenges in Canada are long. Even busy centers who do lots of them still face 1 to 2 year wait lists.

Dr. A for Allergy MD @Health_Ontario_: Chan: Systemic reactions and severe reactions strikingly low in young pre school children compared to the older children in #OIT.

Chronic Urticaria - Twitter summary from #CSACI19 meeting

Dr. Mariam Hanna, MD @PedsAllergyDoc:

Dr Begin - Reviewing Omalizumab’s mechanism of action: 1) Formation of Allergen-specific blocking complexes. 2) Decrease in free allergen-specific IgE. 3) Disarming/dissociation of IgE from its receptor.

Proposed mechanism for Chronic Spontaneous Urticaria (CSU):
1) Autoimmune urticaria - anti IgE and to receptor
2) Autoallergic urticaria - IgE against self

Dr. Ellis @DrAnneEllis: Ligelizumab is a new "Hyper-Xolair" - much higher affinity for IgE antibody - showing promise for the management of chronic spontaneous urticaria (CSU).



Chronic Urticaria Treatment Options (click to enlarge the image).

Starting off the morning with Dr. Franks Siebenhaar from Charite, Germany- the role of PAF in itch of urticaria.

Chronic Urticaria is chronic - 20% of patients have hives for more than 20 years. Chronic urticaria is associated with a low QOL.

CSU in children - if symptoms are severe, it predicts it will be long lasting.

Goal of management for CSU: "Treat the disease until it is gone".

Treatment algorithm for CSU in international guidelines - 2nd generation antihistamines first and foremost - then double the dose, then quadruple the dose, then omalizumab.

Response to antihistamines indeed is dose dependent. 4 fold updosing has clearly been shown to more effective than licensed doses.

Siebenhaar: Mast cells are immunologic bombs.

Platelet Activating Factor (PAF) Increases vascular permeability - can cause a wheal and flare reaction similar to histamine. PAF induces itch just like other neuropeptides. Importantly, however, PAF does not release histamine from skin mast cells. Yet we still see a wheal and flare reaction. So it's independent. PAF levels have been shown to be elevated in chronic spontaneous urticaria (CSU).

Rupatadine is designed to inhibit both histamine and PAF. Has proven in vivo anti histamine as well as anti PAF activities. Siebenhaar: Rupatadine is also clearly efficacious in the treatment of cold induced urticaria. Histamine causes itch. PAF causes itch and burning sensation. Recent study in Japan show clear benefit of itch reduction with rupatadine regardless of the reason for their itchy skin. Siebenhaar: PAF should be considered a target for treatment of urticaria.

No clinically relevant drug interactions have been observed for any second generation antihistamines.

Antihistamines - Twitter summary from #CSACI19 meeting

Dr. Mariam Hanna, MD @PedsAllergyDoc:

Bilastine for refractory CSU. Trial: Q2 wks, double dose unless complete response. Many improved with daily antihistamine and with doubling to 40mg. No significant improvement in use of Bilastine 40mg vs 80mg. May benefit from biologic? Minimal somnolence.

Cross over study looking at onset of action for Bilastine to evaluate the effects of fasting - 1/3 less absorption with food, by day 4 no change in onset of action or wheel/flare response... therefore if taking regularly, taking on an empty stomach not essential.

Dr. Wasserman on seasonal allergic rhinitis with Rupatadine - 10 vs 20mg didn’t improve control for mild sx, dosing with 20mg for those that are more severely impacted may benefit with higher dose, comparable reactions, 7% somnolence regardless of dose.

What about perennial allergic rhinitis and Rupatadine, improved TNSS but if ongoing symptoms, updose to ‘double’ and patients improve in about 2 weeks. **somnolence more frequent at higher doses.

Dr. Vanderleek - to approve a peds antihistamine - need a pharmacokinetic study and safety study to enter into a younger age group... Bilastine for 2-11 years?

Indication in Japan for use of Rupatadine with pruritis associated with eczema (again 20mg for those with ongoing sx at 10mg).

Impairment of 50mg of Benadryl is WORSE than 0.1% blood alcohol level.

Educate families to the dangers to first generation antihistamines!! Poisonings and overdoses frequently reported. Efficacy poor. Dr Sussman asks: who still drives a car from the 1940s?

Biologics beyond asthma and atopic dermatitis - Twitter summary from #CSACI19 meeting

Dr. Ellis @DrAnneEllis: Next up Dr. Michael Wechsler from National Jewish Health center in Denver "Future role of biologics beyond asthma and atopic dermatitis".

Complex interactions between the Type 2 cytokines IL-4, 5, 13 - key and central drives of Type 2 inflammation with broad effects.

Other type 2 driven diseases - eosinophilic esophagitis (EoE), EGPA, chronic eosinophilic pneumonia, chronic rhinosinusitis (CRS) with or without nasal polyps, allergic rhinitis, AERD.

All have many features in common - epithelial barrier dysfunction, tissue remodeling, microbiome alterations.



Asthma Treatment Options (click to enlarge the image).

Eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome) - essentially an eosinophilic vasculitis that presents with asthma, eosinophilia, rash, neuropathy.

Mepolizumab (anti IL-5) was shown in a pilot study conducted by Dr Wechsler - relapse rate reduced by 50% while reducing steroid dosing by 50% as well.

MIRRA EGPA Mepolizumab study - 78% of patients treated with anti IL-5 achieved one of 3 outcomes - remission, more than 50% reduction in steroid dose, or relapse free compared to 32% of placebo treated patients.

Benralizumab (anti-IL5R) also has been shown to be highly efficacious in the treatment of EGPA as well, not surprisingly.

Chronic Rhinosinusitis (CRS) - more than 500,000 sinus surgeries performed per year in the US for patients who fail medical management. Unfortunately benefits often not long lasting.

Dupilumab (anti-IL4R) already approved in the USA for CRS with nasal polyps. Symptoms improve early. Polyps regress significantly after 10 injections. Dupilumab reduced the proportion of patients who used systemics steroid for any reason or sino-nasal surgery.

Both mepolizumab and omalizumab have published positive results of the treatment of CRS with nasal polyps.

Unfortunately results of anti-Il5 for EoE have been disappointing. Need to move on to anti-IL5R or anti-IL4/13 for benefits to be seen.

Allergic bronchopulmonary aspergillosis (ABPA) anti-IgE and anti-IL5 have been used/reported to good effect - no RCT's, however.

Dr. Wechsler finds FeNO a very useful biomarker. Often persistently elevated in patients who fail anti-IgE or anti-IL5 based therapies.

Previously, we believed FeNO was a biomarker of eosinophilic inflammation. Clearly, it can't be just that if it remains elevated after you deplete all eosinophils with anti-IL5 therapy. Recent work suggests it's IL-13 mediated.

Dr. Wechsler uses FeNO to select dupilumab earlier. If FeNO is not that elevated, will turn to eosinophil count to choose an anti-IL5 therapy, if eos are not high, he looks at IgE levels. If all 3 biomarkers are low he goes on to more in depth evaluations to rule out mimickers.

I would argue that if any patient is at the point where you are considering a biologic, the work up to rule out non-asthma is mandatory.

Important to remember that all the biologics reduce exacerbations by ~50%. They don't eliminate them. Over time the exacerbations tend to be driven by Type 1 inflammatory processes (e.g. viral infections).

GERD, vocal cord dysfunction (VCD) are important complicators of severe asthma (not complications).

Bronchial thermoplasty (BT) can be helpful for those patients who are not TH2 high (low IgE, low Eos, low FeNO).

Azithromycin also useful add on for Th2 low asthma - 500 mg three times per week shown to reduce exacerbations in patients who continue to exacerbate despite adherence to ICS/LABA.

Patients who fail to respond to mepolizumab were able to get their sputum eosinophils finally reduced when switched to reslizumab in a study by Dr. P Nair.

Being allergic vs. non-allergic doesn't predict response to Spiriva.

Dermatitis/eczema - Twitter summary from #CSACI19 meeting

Dr. Ellis @DrAnneEllis: Starting off with Dr Lisa Swanson from Denver speaking on Dermatitis.

AD often presents at an early age and follows a classic distribution. When there is no itch, and odd distribution, rethink the diagnosis.

Patients with eczema have an increased risk of ADHD, depression, anxiety, sleep deprivation. Even when they do sleep, sleep is less restful in kids with Atopic Dermatitis - leads to impaired growth. Swanson: Always do ointments in little kids - better adherence to skin.

Olive oil worsens atopic dermatitis and should be avoided.

Calcineuren inhibitors highly effective in children - pimecrolimus safety study over 2400 patients show safety of long term use and no lymphoma or other malignancy signals.

Dupilumab is indicated for patients with moderate to severe atopic dermatitis in patients aged 12 and up. Dupilumab is dosed based on weight in the adolescent age group. Swanson: Itch improved faster with dupilumab than skin clearance.

Eye symptoms the most common side effect of dupilumab - conjunctivitis, blepharitis and eye pruritus. Common enough you need to warn people.

For now there is a warning to avoid live vaccines while on Dupixent.



Atopic dermatitis maintenance (click to enlarge the image).

Contact dermatitis is more common in people with a background history of atopic dermatitis. Allergic contact dermatitis (ACD) tends to be more severe than irritant dermatitis.

Nickel is the most common contact allergen. Rash on the lower abdomen or earlobe. Dimethylglyoxime test can determine if something contains nickel. ID reaction - common complication of nickel allergy.

Wet wipe dermatitis now 2nd in line for common causes of allergic contact dermatitis.

Toilet seat dermatitis - due due to cleaner or a chemical in the toilet seat itself. Treat with soft seat liner.

Every ingredient in kids slime is an irritant - borax, glue and soap. Slime dermatitis now very common in kids.

Guttate psoriasis is the most common type of psoriasis in children. Guttate = tear drops. Swanson: Psoriasis loves the belly button. To the point where you see a rash affecting the belly button its psoriasis until proven otherwise. Palmoplantar psoriasis - very well demarcated.

Seborrheic dermatitis - associated with going to bed with wet hair or incomplete shampooing.

Swanson: Perioral dermatitis can look like eczema or acne - common with steroid nebulizers or is otherwise idiopathic. Responds to elidel/tacrolimus. One month or oral antibiotics works 100% of the time.

Asymmetrical facial rash in a child is a fungal infection until proven otherwise. Tinea corporis can be managed with topical antifungals but scalp involvement needs systemic therapy.

Pustules on the hands and feet of a baby - think scabies.

Mycosis fungoides - persistent eczematous or tinea- like rash. Needs a biopsy to diagnose.

Mary McHenry MD @maryjmchenry: Update on biologic agents: side effects important to know about including infusion reactions, Type 1 IgE reactions, cytokine reactions, and Type IV delayed reactions.

Many considerations for starting a biologic in atopic patient: Impact on infections, risk in environments with high parasite infestation, lack of data in children and pregnant women, BUT so far safety data is encouraging. Exciting times in allergy!

Dr. Ellis @DrAnneEllis: Hypersensitivity reactions to biologics are, in general, actually rare.

Anaphylaxis, tryptase and MCAS - Twitter summary from #CSACI19 meeting



Anaphylaxis - Different Causes. Click here to enlarge the image.

Dr. Ellis @DrAnneEllis: Dr Moshe Ben Shoshan-care gaps in anaphylaxis.

The prevalence of anaphylaxis in the general population is at least 1.6%.

British guidelines recommend tryptase measurements in all cases of acute allergic reactions to confirm or refute the diagnosis of anaphylaxis.

Mary McHenry MD @maryjmchenry: Biomarkers for anaphylaxis include tryptase, histamine and 24hr urinary histamine - most useful is tryptase that can detect severe reactions if drawn within 60-90 min of reaction. No good evidence from high quality studies that steroids play a role in the treatment of anaphylaxis. Epinephrine is first line. Always!

Dr. Mariam Hanna, MD @PedsAllergyDoc: In UK: measure tryptase with children presenting with anaphylaxis or unknown picture acutely and repeat tryptase to get baseline level when well. Recent Canadian data suggests 87% of the time there will be an increase in tryptase from patients baseline. Canadian data: tryptase rarely drawn, less than 50% assessed by allergist, kids assessed more frequently than adults, 20% risk of recurrent reactions esp. in asthmatics or food allergy (except peanut - due to higher awareness), epinephrine underused!!

Dr. Ben-Shoshan: Factors why epinephrine is not used:
1) availability of epinephrine
2) poor symptom recognition
3) fear of using epinephrine (pain, side effects, etc.)

Dr. Ellis @DrAnneEllis: Suspected drug induced anaphylaxis had very low rates of referral to Allergists for confirmation / to refute the diagnosis.

The majority of anaphylaxis in mastocytosis is due to hymenoptera stings (wasps, hornets, yellow jackets etc).

Asthma is an important cofactor in anaphylaxis - 43 or 48 deaths due to anaphylaxis in the Pumphrey-study had evidence of pre-existing asthma and also weren't well controlled.

Wheat dependent exercise induced anaphylaxis is probably secondary to a "steal" phenomenon of blood supply where exercise leads to increased intestinal permeability and increased allergen absorption.

Asthma, insects, mastocytosis, age, male sex important predictors of increased risk of severe anaphylaxis.

Dr Mariana Castells - Idiopathic anaphylaxis - from mast cells to mastocytosis. Idiopathic anaphylaxis is at the center of mast cell disorders.

Every tissue has a different mast cell phenotype.

The alpha chain of fibrinogen is a preferred target of beta tryptase.

Many drugs can activate mast cell degradation through IgE independent mechanisms.

Mast cells that are spindle shaped and stain CD25 positive are not normal mast cells - prelude to mastocytosis. Andrew O'Keefe, MD @draokeefe: Dr Castells: Mast cell disorders can be very challenging to diagnose, even bone marrow biopsy can appear normal, unless you look for mast cells that stain CD25+. One measurement of serum tryptase is not enough. Significant increases from baseline may be seen though appear in the “normal” range, below 12. Dr Castells: every patient who has had anaphylaxis has PTSD. We in medicine underestimate the impact of anaphylaxis on patients.

Dr. Mariam Hanna, MD @PedsAllergyDoc: Dr. Castells shares an important clinical pearl: Tryptase is your friend. If in doubt, do a tryptase!

Dr. Ellis @DrAnneEllis: However, one third of the population does not have 2 copies of the tryptase gene and thus we lose that as a biomarker.

Strong advocacy to measure tryptase levels in all cases of anaphylaxis acutely.

Fuplications in TPSAB1 gene lead to increased levels of tryptase and symptoms similar to mast cell activation syndrome.

Many pathways/phenotypes of anaphylaxis recognized now. Type 1, cytokine release, complement mediated and mixed.

In MCAS - if a patient doesn't respond to antihistamines, cromolyn and montelukast combination therapy, its probably not actually MCAS.

Dr Castells - every person who have experienced anaphylaxis have a form of PTSD - fear is huge - unmet need in our practice.



Mast cell activation (MCA) and MCA syndrome (MCAS): They are not the same (click to enlarge the image).

Step doses for drug provocation tests to NSAIDs (ingestion challenges)

Hypersensitivity to non‐steroidal anti‐inflammatory drugs (NSAIDs) are of great concern because they are frequently encountered in daily clinical practice. Drug provocation tests (DPT) are particularly needed for NSAIDs.

This retrospective study from the University Hospital of Montpellier (France) evaluated eliciting dose thresholds during NSAIDs DPT. 311 positive DPT were analyzed.

The following steps for future DPT were suggested:

1. for the rapid absorption group (Acetylsalicylic acid, ibuprofen, ketoprofen, tiaprofenic acid), every 30 min: 20%‐30%‐50% of daily therapeutic dose

2. for the moderate absorption group, every 30 min: for diclofenac 5%‐15%‐30%‐50% and for celecoxib, 20%‐80%

3. for the slow absorption group, piroxicam, 25%‐75% separated by a 3h interval.

A surveillance period of 3h after the last dose is mandatory for patients.

DPT protocols for NSAID are empirical, driven by the knowledge on patterns of DHR, cross‐reactivity between NSAID and pharmacological effects of these all drugs.

References:

Data‐driven step doses for drug provocation tests to non‐steroidal anti‐inflammatory drugs (NSAIDs), 2019.
https://onlinelibrary.wiley.com/doi/abs/10.1111/all.14075

Dupilumab is very effective in difficult‐to‐treat adult atopic dermatitis patients

Dupilumab was approved for the treatment of moderate to severe atopic dermatitis (AD) in 2018. This study evaluated the effect of 16 weeks treatment with dupilumab on clinical response and serum biomarkers in adult patients with moderate‐severe AD.

Effectiveness of dupilumab was expressed as number of patients achieving EASI‐50 (Eczema Area and Severity Index) or EASI‐75, as well as patient reported outcomes measures (Patient‐Oriented Eczema Measure, Dermatology Life Quality Index, Numeric Rating Scale pruritus).

138 patients were treated with dupilumab in daily practice were included. This cohort consisted of patients with very difficult‐to‐treat AD -- 60% of them patients did not improve on 2 or more immunosuppressive drugs.

After 4 months, at week 16, the mean percent change in EASI score was 73%.

The most reported side effect was conjunctivitis, occurring in 34% patients. This is way higher than the reported incidence of 11-13% in the drug brochure.

During dupilumab treatment, disease severity related serum biomarkers (TARC, PARC, periostin, and IL‐22), eotaxin‐1, and eotaxin‐3 significantly decreased.

References:

Dupilumab is very effective in a large cohort of difficult‐to‐treat adult atopic dermatitis patients: First clinical and biomarker results from the BioDay registry. Lieneke FM AriĆ«ns et al.
https://onlinelibrary.wiley.com/doi/abs/10.1111/all.14080