Biologics and AERD Care

Clinical Perspective
John V. Bosso, MD
Clinical Associate Professor, Rhinology Division
Medical Director, Penn AERD Center

About AERD

Aspirin Exacerbated Respiratory Disease (AERD), formally called Samter’s Triad, is a chronic inflammatory disorder of the sinuses and lungs. People with AERD develop nasal polyps and in almost all cases have persistent asthma along with a variety of additional sinus and respiratory symptoms. AERD patients also have an allergic-like reaction to aspirin and other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Nearly 10% of asthmatics and 40% of asthmatics with nasal polyps, or chronic sinusitis have AERD, affecting nearly 1.5 million people – though in many cases they go undiagnosed or misdiagnosed as a result of a lack of awareness. It is traditionally difficult to treat and often requires oral corticosteroids and sinus surgery to manage the symptoms. Multiple asthma medications may also be required to gain control.

The History of Desensitization

It was forty years ago when Dr. Donald Stevenson of the Division of Allergy, Asthma & Immunology at Scripps Clinic and my mentor, desensitized two AERD patients to aspirin and noticed that the rate of re-growth of their polyps had slowed down drastically with continued aspirin therapy. Since then, approximately 16 retrospective studies and four double blind, placebo-controlled studies support the use of Aspirin Therapy after Aspirin Desensitization (ATAD) as an efficacious, steroid-sparing treatment for AERD¹. The adoption of this treatment as a post-operative management staple for AERD trickled down slowly to be available in most academic medical centers and ultimately to some independent practitioners as well.

After founding the first AERD Center on the east coast in NY almost 20 years ago and then moving to Penn Otorhinolaryngology – Head and Neck Surgery to form the first multidisciplinary center for AERD in the world four years ago, I was able to combine and coordinate the merits of ATAD with the meticulous surgical outcomes from the rhinologists who pioneered endoscopic sinus surgery. Indeed, over 91% of the patients who were followed for 30 months on ATAD did not require revision surgery² and with the more recent implementation of the Draf 3 surgical technique, I expect that result to approach 95-100%. Wide and complete sinus surgery allows for significantly improved deposition of topical steroids into areas of the sinuses like the frontal recess and skull base where polyps begin to re-form. Further, removal of all bony partitions allows not only for better medication deposition, it eliminates potential surface area that would serve as a nidus for inflammation and polyp regrowth.

Addressing Aspirin Intolerance

Of course, similar to other centers, our rate of aspirin therapy intolerance approaches 10%. Gastrointestinal intolerance is the most common reason for discontinuation³. There is also a small subset of AERD patients that produce so much PGD2 and LTE4 that they have a rash which is commonly characterized as the chronic urticaria of AERD^4,5. These patients do not usually tolerate the AD procedure or ATAD without the addition of zileuton or a T2 biologic agent.

Our group recently sought to clarify the proper dosing of aspirin among subgroups in order to predict and possibly subvert over-treating certain populations. We have also sought to predict which subset of AERD patients better respond to aspirin therapy. Recently, we demonstrated that the dose of aspirin required to prevent polyp regrowth seems to decline after the age of 60⁶. Understanding who responds best and which doses are most appropriate will lead to better informed choices for patients considering ATAD. It should also lead to higher rates of success and less dropouts. Finally, we looked at the safety of ATAD in AERD patients; as every other study reviewing aspirin safety has been performed in the cardiovascular disease subgroup. Less than 2% of our ATAD cohort of 109 patients had serious adverse events, with serious GI bleeding occurring in less than 1%.⁷

The Halo Effects of ATAD

In addition to preventing polyp regrowth and therefore further revision surgeries, improving sense of smell, reducing nasal congestion, improving asthma control and reducing the need for overall corticosteroid use (oral and inhaled), ATAD also provides the unique ability for patients to use aspirin or NSAIDS for other indications, cardiovascular prophylaxis and the reduction in the need for opioid analgesics.3 Further, ATAD has been shown to improve the tolerance to alcohol in AERD patients⁸. None of these properties have been attributed to any of the T2 biologics.

The Role of Biologics

T2 biologics have been effective agents for the treatment of eosinophilic asthma that is refractory to standard therapy or is steroid dependent. Recently, one agent, Dupilumab was approved for use in CRSwNP uncontrolled with topical steroids. Extrapolated data from the Sinus 24 and Sinus 52 studies show that the approximately 30% of patients in the cohorts had history defined AERD and responded equally well to this therapy which has been shown to reduce the size of polyps and improve the sense of smell⁹. Omalizumab and mepolizumab also have data that may soon result in their approval for use in CRSwNP.

I am often asked by colleagues which therapy I would choose for patients in 2020. While I have over 30 years of experience and there are many more studies supporting aspirin therapy, T2 biologics are a welcome addition to the AERD treatment armamentarium. I do not see it as a binary choice. I have some patients who are treated with both ATAD and a T2 biologic. Patient specific considerations, previous therapeutic interventions, co-morbidities, shared decision making and cost are all very important in deciding. New emerging data on sub-endotypes of AERD may aid the process as well as future cytokine profiling.

Maximizing the Value of Care

Ultimately, we will be judged on the “Value” of the care we render which translates into “best outcomes for the lowest cost”. According to Medispan 2019, The cost of the T2 biologics is in the range of $35,000-45,000 per annum. Further, there is the expectation that treatment will be life-long as there is no permanent disease modifying effect of any of these agents and AERD has not been shown to spontaneously remit. Considering that the average age of onset of AERD is around 30¹⁰, the costs to the system (which are not often what the patient experiences) for one patient can be in the multimillion-dollar range over one’s lifetime.

While I use T2 biologics in my allergy practice, I am certain that before I do so there has been complete due diligence for use of all the less costly established therapies – which must have been used properly. Endoscopic sinus surgery (ESS) can be performed multiple times before the cost approaches that of just one year of therapy with a T2 biologic. Complete ESS, properly performed, offers almost immediate relief and a reduction of the polyp score to zero. The post-operative state and resultant open cavities allow for topical steroid therapy, ATAD and other established therapies to be more effective in order to quell the majority of cases at a fraction of the cost of a T2 biologic. Further, surgery reduces the severity of reactions which occur during aspirin desensitization, thus making it a much safer procedure¹¹. The cost of an aspirin desensitization procedure is approximately $1700-3000¹². Aspirin itself costs about 5 cents a tablet. We also do not have long term safety data for most of the T2 biologics to offer to our patients. While they appear to have a good margin of safety overall, the long –term effects on the immune system may not be known for several years hence.

Expanding the Continuum of Care

The exuberance over the new T2 biologic agents is clear. We have waited many years to have these available for our refractory patients. They are a welcome addition for anyone treating severe upper or lower airways inflammation. However, existing therapies such as complete ESS and ATAD when utilized in a multidisciplinary coordinated care environment provide excellent results for the majority of patients and are not yet utilized to their full potential. I believe, therefore, that this combination of treatments is still appropriate to discuss with most patients early on. There will remain a minority of patients who are either intolerant to aspirin, have an aspirin contraindication, have a surgical contraindication, refuse surgery or aspirin desensitization or do not have an excellent response to a combination of these coordinated therapies. Fortunately, for these patients there is now another treatment option available.

COI: Dr. Bosso has served on the scientific advisory boards for: Glaxo SmithKline, Sanofi, Regeneron, Novartis, Optinose and Astra-Zeneca

References

1. White AA, Stevenson DD. Aspirin Exacerbated Respiratory Disease. N Engl J Med 2018; 379(11): 1060-1070.
2. Adappa ND, Ranasinghe VJ, Trope M, Brooks SG, Glicksman JT, Parasher AK, Palmer JN, Bosso JV. Outcomes after complete endoscopic sinus surgery and aspirin desensitization in aspirin-exacerbated respiratory disease. Int Forum Allergy Rhinol 2018; 8(1) : 49-53.
3. Berges-Gimeno MP, Simon RA and Stevenson DD. Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2003; 111(1): 180-186.
4. Cahill KN, Bensko JC, Boyce JA and Laidlaw TM. Prostaglandin D2: a dominant mediator of aspirin-exacerbated respiratory disease. 2015; 135(1): 245-252.
5. Laidlaw TM, Gakpo DH, Bensko JC and Buchheit K. Leukotriene-Associate Rash in Aspirin-Exacerbated Respiratory Disease. J Allergy Clin Immunol Pract 2020; Jul 29; S2213-2198(20)30704-2.
6. Sweis A, Locke T, Kohanski, MA, Palmer JN, Bosso JV and Adappa ND. Age as a Factor in the Treatment of Aspirin- Exacerbated Respiratory Disease: Relationship to required Aspirin Maintenance Dose Post-Desensitization. 2020; Int Forum Allergy Rhinol
7. Sweis AM, Locke TB, Ig-Izevbekhai KI, Lin TC, Kumar A, Corr AM, Kohanski MA, Palmer JN, Bosso JV and Adappa ND. Major complications of aspirin desensitization and maintenance therapy in aspirin-exacerbated respiratory disease. Int Forum Allergy Rhinol. 2020; published online ahead of print Jul 16 2020.
8. Glicksman JT, Parasher AK, Doghramji L, Brauer D, Waldram J, Walters K, Bulva J, Palmer JN, Adappa ND, White AA and Bosso JV. Alcohol-induced respiratory symptoms improve after aspirin desensitization in aspirin-exacerbated respiratory disease. Int Forum Allergy Rhinol 2018; 8(10): 1093-1097.
9. Bachert C, et al. Efficacy and safety of Dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP ASINUS-52) results from two multicenter, randomized, double-blind, placebo-controlled, parallel group phase 3 trials.
10. Bachert c et al. Reduced need for surgery ion severe nasal polyposis with mepolizumab: Randomized trial. J Allergy Clin Immunol 2017; 140(4): 1024-1031.e14
11. Jerschow E, Edin ML, Chi Y, et al. Sinus Surgery Is Associated with a Decrease in Aspirin-Induced Reaction Severity in Patients with Aspirin Exacerbated Respiratory Disease. J Allergy Clin Immunol Pract. 2019;7(5):1580-1588.
12. Shaker M, Lobb A, Jenkins P, et al. An economic analysis of aspirin desensitization in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2008;121(1):81-87.