Assessing biologic therapy response is crucial for ongoing evaluation due to the potential influence of various factors on suboptimal response.1 These factors encompass patient-related elements such as medication adherence, inhalation technique, and comorbidity control2–4 along with potential differences in targeted mechanisms.5

To gauge biological treatment effectiveness,4 parameters like respiratory symptoms, lung function, asthma control, exacerbations, and systemic corticosteroids (SCS) usage and dosage are generally considered.

Recent publications have introduced distinct criteria for categorizing biologic-treated patients as “good responder”, “super-responder”, or “non-responder” (Table 1). For instance, Pepper et al. define “responders” as individuals achieving good asthma control (asthma control test, ACT>20 or asthma control questionnaire, ACQ<1.5) and/or <1 severe asthma exacerbation (SAE) and no hospitalization during a year of treatment and/or the tapering of SCS without losing asthma control and/or forced exhaled volume in first second (FEV1) greater or equal to 80% without bronchodilators.1 A “non-responder” is a subject that, under the biological treatment, has started SCS, has >1 SAE or hospitalization due to asthma. The “super-responders” meet even stricter criteria. Recently, a Delphi consensus was reached for a definition of super-responders9 based on major “super-responders” criteria including no exacerbations, improvement in asthma control and cessation of maintenance SCS; the definition requires improvement in two major criteria and one minor criterion. Kavanagh et al.6 proposed a different classification labeling subjects as super-responders, responders, and non-responders based on SAE reduction and SCS usage after 48 weeks of treatment with biologics. A similar classification was used in a Danish cohort6 followed for 52 weeks with anti-IL-5 treatment. Other authors tend to be stricter in the definition of “super-responders”, as Eger et al.8 who besides previous goals add FEV1 >80% and FeNO <50ppb with good comorbidity control with anti-IL-5 treatment for 104 weeks. In the Netherlands, a very different classification was used for a cohort of 215 subjects receiving reslizumab for 30 weeks.13

Pérez de Llano et al.10 developed the (FEOS) score, emphasizing SAE, SCS dose, symptoms, and FEV1. This weighted system quantifies response quality with higher scores indicating better response (ranges from 0=worsening to 100=best possible response). A score >75 in the FEOS system, suggests a super-responder.11

In asthma, remission has been explored as spontaneous occurrence reached in the population with asthma without treatment.16 The concept of achieving asthma remission through treatment has been less investigated.17 Menzies-Gow et al. proposed criteria for clinical remission, including symptoms absence, lung function stabilization, of clinical symptoms and asthma exacerbations, stabilization of lung function, no SCS usage, and agreement between patient and physician on disease remission, all must be maintained through the last >12 months (with or without normalizing underlying pathology) or complete remission (current negative bronchial hyperresponsiveness test).12 Recently, in the German severe asthma registry Milger et al. demonstrated that clinical remission has more possibility of being achieved at 12 months with biologic treatment (37.6% of 210 subjects) against no biologic treatment (17.2% of 233 subjects).18 The results with long-term treatment (>12 months) are scarce and especially in large cohorts.

Our study aims to determine the prevalence of response (responders, super-responders, and non-responders) and clinical remission in a large real-world cohort of patients with the long-term treatment (>6 months) of anti-IgE and anti-IL-5/IL-5Rα biologics. We also seek to compare various response criteria and identify predictors for non-responders and clinical remission to biologics.

This paper analyzed patients with severe uncontrolled asthma treated with omalizumab and anti-IL-5/IL-5R with a mean treatment duration of 55.3±38.8 months. Patient baseline characteristics varied due to the real-life nature of the study. Notably, subjects receiving reslizumab were limited due to its intravenous administration, making it less favorable. In this real-life cohort, there was an excellent long-term response to biologic treatment with 91.1% of responders from which 55.7% were “super-responders”, and only 8.9% as “non-responders”, with similar results among biologic used.

When analyzing the clinical response and applying the criteria from other authors to our cohort, there were differences between the cohorts’ results. The study by Kavanagh et al.6 obtained 86% of “responders”, 39% of “super-responders”, and 13.8% of “non-responders” after 48 weeks of benralizumab treatment. The cohort from Kavanagh's study had more SAE per year and worse FEV1. Our cohort had a longer duration with biologic treatment with a better chance to achieve the established goals. If we apply their criteria to our cohort, we obtained 7.5% (32) of responders, 58% (249) of super-responders and 34.5% (148) of non-responders. This comparison highlights the difference between subjective (ACT) and objective (SCS and SAE) response criteria.

Results from the Soendergaard et al.7 of subjects treated with anti-IL-5 treatments for 52 weeks reached a complete response by 58%. Applying their criteria, we had the same results, 58% (249). The comparison between both cohorts before biologic treatment reveals slight differences.

Compared with the criteria of response by Eger et al.,8 we would find 16.6% (71) being super-responders which is very similar to 14% in their study. The super-responder criteria are more stringent than Upham et al.9 because of the FEV1 improvement, which is harder to achieve and because anti-IL-5/IL-5Rα biologic treatments do not usually have a decrease in FeNO. By their criteria, there are no non-responders in our analyzed cohort with long-term biologic therapy. Nevertheless, we should mention that from the original 545 subjects in the cohort of Rial et al.,19 25 subjects (4.6%) are non-responders at short-term evaluation using Eger et al. criteria.8 On the other hand, 83.4% (358) would be considered “partial responders” by the authors’ criteria.

With the FEOS10 system, 67.6% (290) of subjects are super-responders. In their cohort, with 3 years of treatment with anti-IL-5/anti-IL-5R, they had 72% super-responders, 22% responders and 5% non-responders.

Under Weschler et al.13 criteria, we obtained 69.7% (299) of super-responders, an excellent result because it is only based on the improvement of one goal (no SAE). All our subjects improved to the minimum criteria. In short-term we had four subjects with adverse effects with omalizumab.

The GEMA14 guidelines are much stricter, we had 64.6% of responders and 35.4% of non-responders.

Using the criteria of Álvarez-Gutiérrez et al.,15 our cohort reached 25.9% of responders, 27% of super-responders and 47.1% of non-responders. The higher percentage of non-responders is because we have many subjects with less than 10% or 100ml of improvement in FEV1.

Our criteria for responders are somewhat flexible, allowing subjects to be considered “responder” by achieving a complete clinically satisfactory goal in two of the three main aspects of severe uncontrolled asthma. We applied the definition of “super-responders” suggested by Upham et al.,9 similar to Kavanagh et al.6 and Soendergaard et al.7 criteria for responders. When the different criteria are applied to our cohort, we show that we are all using the same tools to measure the results, and the combination of them is the differentiating point. We want to highlight that Eger et al.8 and Alvarez-Gutiérrez et al.15 were the only two references considering worsening or the absence of improvement as criteria for non-responders.

Factors such as higher total number of SAE (OR:1.21), ICU admissions (OR:2.69) were associated with being non-responders.

The Soendergaard et al.7 authors determined the need for SCS, a younger onset of asthma and concomitant DM2 as predictors of failure at achieving a complete response to biologics. They also obtained that >0.3×109L eosinophils, allergic rhinitis and lower ACQ score were predictors of complete response. In a regression analysis, Eger et al.8 obtained that <10 years with asthma have a greater OR:3.5 of achieving a super-response.

A recent prospective study from Japan20 prospectively analyzed 54 subjects with biologic treatment for 12 months, looking for clinical remission (corresponding to Upham et al.9 super-responder criteria) and functional remission (clinical remission and FEV1 predicted >80%, eosinophils <300×106L, FeNO <35ppb), corresponding to Menzies-Gow et al.12 definition for clinical remission. They observed 68% of clinical remission (vs. 56.6% of super-responders in our cohort) and 70% of functional remission (vs. 27% of clinical remission in our cohort). The differences observed between the Japanese series and our cohort could be explained by a worse baseline FEV1% predicted (77% vs. 70%, respectively) in our cohort. In this Japanese study, the cut-off value for clinical remission for FEV1% is a higher predicted FEV1 >75% with a sensitivity of 94% and a specificity of 64%.20

Clinical remission by Menzies-Gow et al.12 was experienced by 116 (27%). Our results agreed with those of Milger et al.18 No statistically significant differences were found between biologic treatments. In retrospective phase III studies, only 14.5% (85/586) on benralizumab and 7.7% (48/620) on placebo achieved clinical remission at 12 months.21 In an observational retrospective study (ORBE II) of 204 subjects performed in Spain with benralizumab for 12 months, 43% achieved clinical remission under the Menzies-Gow et al. definition. The greater result in ORBE II could be related to less duration of asthma disease (mean 15 years vs. 19 years, in our cohort) and a higher percentage of subjects with SCS before biologic treatment (29% vs. 74%, in our cohort).22 A recently published cohort of 486 subjects with severe uncontrolled asthma with biologic treatment from Italy, obtained a percentage of clinical remission (Menzies-Gow et al.12 criteria) like ours.23

With mepolizumab, they obtained clinical remission was obtained in 29% at 52 weeks and increased to 33% at 104 weeks of treatment in a real-life cohort (REALITI-A study),24 like our result. A multicenter observational study performed in Spain (REDES study) followed 318 subjects with mepolizumab with the reduction in exacerbation rate as the primary endpoint achieving a reduction of 77.5% compared with the exacerbation rate from the 12 months before mepolizumab.25 A post hoc analysis looking for clinical remission under Menzies-Gow et al.12 obtained that 37% achieved no SCS plus no SAE and ACT >20 (consistent with our definition of super-responder by Upham et al.) and 30% of clinical remission adding the improvement in FEV1.26 We did obtain better results with the super-responder criteria of 56%, some clear differences are observed in the mean SAE rate (3.3 vs. 4.5 in REDES) and subjects with BMI >25 in our cohort were 65% compared to 72.8% in REDES.

A high FEV1% (OR: 0.96), high ACT score (OR: 0.93) before the biologic treatment or N-ERD (OR: 0.52) were associated with reaching clinical remission. A history of ICU admissions (OR: 5.42) and heart disease (OR: 5.54) have a higher risk of not achieving clinical remission.

This study's limitations are its retrospective nature and missing data. However, this weakness is part of real-life studies. Nevertheless, comparative real-life studies are recommended.1,6

These results demonstrated that most patients achieved a satisfactory response to biologics by combining multiple goals. Reducing SAE and hospitalizations, lowering SCS and decreasing the frequency of asthma symptoms were all important outcomes. The most challenging goal is improving FEV1, likely due to asthma's severity and remodeling.27

The study suggests that personalizing the evaluation time based on asthma severity before the biologic treatment could yield better results.

In a large, multicenter, Spanish cohort of severe uncontrolled asthma treated with biologics (anti-IgE, anti-IL-5, anti-IL-5Rα) over an extended period, most of the patients were able to achieve a satisfactory response to biologics and only 8.9% were considered as “non-responders”. Clinical remission was obtained in 27% of subjects. Comparing these results with other studies proves challenging due to variations in the criteria used for assessment. Harmonizing definitions of response and clinical remission to biologics is needed to compare results from different studies.

During the preparation of this work, the authors used ChatGPT in order to reduce the original text. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

No funding was received for the research or preparation of this manuscript.

MVM declares to have received consulting fee from Leti Pharma, fees for lectures from GSK and AstraZeneca and support for attending international meetings from AstraZeneca. EA declares to have received honoraria for lectures from GSK, MSD, AstraZeneca, Sanofi, Gebro Pharma and to have participated in data safety monitoring board for GSK, MSD and AstraZeneca. LSR declares to have received honoraria from AstraZeneca, Sanofi, Takeda and has received support for attending international meetings from Hall-Allergy and an institutional grant for research. MJR declares to have received honoraria from AstraZeneca, GSK, Leti Pharma, Chiesi Pharmaceutics. JM declares to have a contract with GSK, AstraZeneca, Viatris (Mylan-Meda Pharmaceuticals), Sanofi-Genzyme, Regeneron Pharmaceuticals, NOUCOR/Uriach group; has received consulting fee from Sanofi-Genzyme and NOUCOR/Uriach group; has received honoraria from AstraZeneca, GSK, Menarini, MSD, Mitsubishi-Tanabe Pharma, Novartis, Procter&Gamble, Viatris (Mylan-Meda Pharmaceuticals), Sanofi-Genzyme, Regeneron Pharmaceuticals, UCB Pharma; support for attending meetings from GSK, AstraZeneca and has participated in data safety monitoring board for GSK, MSD, Novartis, AstraZeneca, Lilly, Sanofi-Genzyme, Regeneron Pharmaceuticals, Procter&Gamble, NOUCOR/Uriach group. JDO declares to have received consulting fees from GSK, Sanofi, AstraZeneca; has received honoraria from AstraZeneca, GSK, Sanofi, TEVA, Novartis, Chiesi Pharmaceutics. JMRM declares to have received a grant for research from SEAIC, payment for lectures from GSK and AstraZeneca. SQ declares to have received consulting fees from GSK and Sanofi; payment for lectures from GSK, AstraZeneca, Sanofi, TEVA, Novartis and Chiesi Pharmaceutics. JALP declares to have participated in data safety monitoring board for AstraZeneca. FJGB declares to have received grants from GSK; consulting fees from AstraZeneca, ALK-Abelló, Bial, Gebro Pharma, GSK, Sanofi, TEVA, Novartis, Chiesi Pharmaceutics, Rovi, Stallergenes-Greer, Menarini; payment for lectures from AstraZeneca, ALK-Abelló, Bial, Gebro Pharma, GSK, Sanofi, TEVA, Novartis, Chiesi Pharmaceutics, Rovi, Stallergenes-Greer, Menarini; support for attending meetings from ALK-Abelló, Menarini, Sanofi; to have participated in data safety monitoring board for AstraZeneca, GSK, ALK-Abelló, Menarini, Novartis, Sanofi, TEVA. CMR declares to have received payment for lectures from AstraZeneca, Chiesi Pharmaceutics, GSK, Sanofi, TEVA, Novartis; support for attending meetings from Chiesi Pharmaceutics; to have participated in data safety monitoring board for MundiPharma, GSK, AstraZeneca and Sanofi. JMO declares to have received consulting fees from ALK-Abelló; payment for lectures from AstraZeneca, MundiPharma, GSK. AV declares to have received payment for lecture from GSK, AstraZeneca, Novartis and Sanofi. BB declares to have received payment for lecture from Bial; support for attending meetings from Allergy Therapeutics, Sanofi, Stallergenes-Greer, GSK, Bial, Leti Pharma. DB declares to have received a Río Hortega Research Grant from Instituto Carlos III. XMG declares to have received payment for lectures from AstraZeneca, GSK, Gebro Pharma, Sanofi, Chiesi Pharmaceutics; consulting fees from AstraZeneca, GSK, Gebro Pharma, Sanofi, Chiesi Pharmaceutics; support for attending meetings from Sanofi, AstraZeneca, Menarini, FAES Pharma, GSK; to have participated in data safety monitoring board for Sanofi, GSK, AstraZeneca. VdP declares to have received payment for lectures from AstraZeneca, GSK and an institutional grant for research from AstraZeneca. PSC, BC, CP, IM, MJC, LPP, IB declare no conflict of interest.