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In the context of the new coronavirus infection (NCI) COVID-19 pandemic, the rheumatological community is facing new challenges in the treatment of immune-inflammatory rheumatic diseases (IIRDs). It has been shown that rheumatological patients have an increased risk of infections and a severe course of NCI and that IIRD therapy also influences the disease outcomes. In particular, the use of the anti-B-cell medication rituximab (RTM) is associated with a higher risk of severe NCI and increased mortality. The COVID-19 pandemic has highlighted the need to find alternative and safe treatment options for these patients. This work is the continuation of a 12-week study on the efficacy and safety of olok-izumab (OKZ) therapy in patients with rheumatoid arthritis (RA) after switching from anti-B-cell therapy during the SARS-CoV-2 pandemic. Objective: to evaluate the efficacy and safety of OKZ (Artlegia®; solution for subcutaneous administration, 160 mg/ml – 0.4 ml) for the treatment of patients with RA in real-life clinical practice after switching from RTM during the COVID-19 pandemic. Material and methods. The study included 19 patients with a confirmed diagnosis of RA who had received RTM at a dose of 500–1000 mg twice every 14 days at least 6 months ago. As disease activity increased, RTM was replaced with OKZ while therapy with synthetic disease-modifying anti-rheumatic drugs (DMARDs) was continued. At weeks 0, 4, 8, 12 and 24 after switching the biologic DMARD, the number of tender (TJN) and swollen (SJN) joints out of 28, pain intensity on a visual analogue scale, ESR, CRP level, disease activity indices CDAI, DAS28-ESR, DAS28-CRP, HAQ index and the safety profile of the therapy were assessed at each visit. Results and discussion. After 4, 8, 12 and 24 weeks of OKZ administration, there was a statistically significant decrease in mean TJN (from 10 to 6.0, 3.0, 5.0 and 4.0, respectively; p < 0.05) and SJN (from 7.0 to 3.0 by week 4 and to 2.0 by weeks 8, 12 and 24; p < 0.05). At the same time, a decrease in CRP and ESR values was also observed: median CRP decreased from 18 to 0.6 mg/l by week 4 and to 0.5 mg/l by weeks 8, 12 and 24 (p < 0.05), ESR from 30 to 5 mm/h in each study period (p < 0.05). CRP levels normalized by week 4, regardless of baseline values. All RA activity indices showed a positive dynamic compared to baseline values from week 4 onwards in each assessment period. After weeks 4, 8, 12 and 24, the median DAS28-ESR decreased from 5.50 to 3.57; 3.30; 3.08 and 3.01 (p < 0.05); DAS28-CRP – from 5.30 to 3.46; 3.23; 3.26 and 3.12 (p < 0.05); CDAI – from 27.0 to 17.0; 12.0; 15.0 and 12.0 (p < 0.05), respectively. All patients showed a decrease in pain by the 4th week of observation. A statistically significant improvement in functional status was observed after the 4th week of therapy and was maintained until week 24. The median HAQ index decreased from 1.62 to 1.50 at weeks 4, 8 and 12 and to 1.12 at week 24 (p < 0.05). Conclusion. The study showed that the non-medical switch from RTM to OKZ during the COVID-19 pandemic was effective and safe.

Objective: to investigate the efficacy and safety of olokizumab (OKZ) in patients with knee osteoarthritis (OA) with synovitis, persistent pain and ineffectiveness of previous conservative therapy. Material and methods. The study included 15 patients with stage II–III knee OA who fulfilled the ACR criteria and had pain ≥50 mm on a visual analogue scale (VAS), synovitis and treatment failure. The age of patients ranged from 54 to 75 years; the duration of the disease was from 1 to 23 years. The duration of the study was 12 weeks, during which the patients received 3 subcutaneous injections of OKZ at a dose of 64 mg. The effectiveness of the treatment was assessed by the dynamics of pain intensity according to VAS, WOMAC and KOOS indices, the values of the DN4 questionnaire and the quality of life according to EQ-5D. In addition, the general assessment of the patient's health (GHA) according to VAS, the assessment of treatment efficacy by doctor and patient and the need for non-steroidal anti-inflammatory drugs (NSAIDs) were considered. All patients underwent laboratory testing. Results and discussion. During treatment, there was a significant decrease in pain intensity according to VAS, a statistically significant improvement in the KOOS and WOMAC indices (p

Glucocorticoids are the basis for the treatment of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), however, their long-term use is associated with a number of well-known side effects. Despite the fact that a significant number of patients with these diseases require long-term treatment, approaches to long-term therapy remain insufficiently developed. The role of traditional anti-inflammatory drugs remains uncertain due to insufficient efficacy and inconclusive evidence base. A possible solution of this problem is the use of biological agents, in particular, affecting the interleukin (IL-6) axis. This series of clinical observations presents the experience of using the IL-6 inhibitor olokizumab in the treatment of GCA and PMR. The data obtained are consistent with the positive international experience of using drugs of this group and demonstrate both efficiency of disease activity control and a pronounced steroid-sparring effect. Olokizumab is a promising drug for the treatment of GCA and PMR.

The aim of the study was to evaluate in real clinical practice the effectiveness of therapy with an interleukin-6 inhibitor (olokizumab) in patients with rheumatoid arthritis (RA) in terms of clinical and laboratory activity of the disease, as well as patient-reported outcomes (PROs). Material and methods. 10 patients with a reliable diagnosis of RA were examined: the average age of the patients was 45.70±17.9 years, the duration of the disease was 9.0 (3.0; 12.0) years. Patients were with moderate or high disease activity: DAS28-ESR – 5.13 (4.34; 5.80) points; CDAI – 30.00 (24.00; 35.00); SDAI – 31.86 (24.36; 38,59). All patients were prescribed treatment with olokizumab (OKZ) at a dose of 64 mg subcutaneously every 4 weeks against the background of therapy with methotrexate, leflunomide, non-steroidal anti-inflammatory drugs and glucocorticoids (GC) (up to 10 mg/day in terms of prednisolone). Three patients had previously received tocilizumab (intravenously once a month at a dose of 8 mg/kg), the administration of which was discontinued for administrative reasons 6–12 months before the appointment of OKZ. The results of treatment were assessed by the dynamics of clinical, laboratory parameters (DAS28-ESR, SDAI, СDAI, CRP, ESR, IgM RF, ACCP) and outcomes assessed by the patients themselves (PROs): HAQ-DI index, general assessment of the health status of patients (OSZB) according to VAS, pain according to VAS; scales FACIT, SF-36. As psychometric methods, the questionnaire “Type of attitude towards the disease (TOBOL)”, the Hospital Anxiety and Depression Scale (HADS), and the Toronto Alexithymic Scale (TAS-26) were used. Observation was carried out before treatment, after 3 and 6 months of therapy. Results. Against the background of OKZ therapy, after 3 and 6 months, compared with the baseline, there was a significant decrease in the clinical indices of RA activity: DAS28-ESR – 5.13 (4.34; 5.80), 3.53 (2.83; 4.26) and 3.48 (2.8; 4.10) points respectively; CDAI – 30.00 (24.00; 35.00), 11.00 (6.0; 16.00) and 10.0 (5.0; 15.0) points respectively; SDAI – 31.86 (24.36; 38.59), 11.05 (6.07; 16.07) and 10.17 (7.02; 15.02) points respectively; CRP – 14.30 (7.00; 24.70), 0.70 (0.40; 0.90) and 0.65 (0.20; 3.0) mg/l respectively. No significant dynamics of ESR, RF IgM and ACCP was noted. After 3 and 6 months of treatment with OKZ, there was a significant decrease in OSZB and pain severity according to the VAS scale, and an improvement in the functional state of patients was observed according to the HAQ-DI questionnaire of fatigue indicators (FACIT-F) (p0.05). In the process of treatment of OKZ, the attitude of patients to the disease changed from the ergopathic, neurasthenic and sensitive components in the TOBOL profile, before it began, then by its end, the dominant ones were harmonious, ergopathic and sensitive profiles. In addition, starting from the 3rd month of treatment in patients with RA, an adaptive response to the disease prevailed. A decrease in the level of anxiety was revealed, compared with the baseline, after 3 and 6 months of observation, depression indicators did not change significantly. Conclusion. In general, the results of this study indicate the effectiveness of ICD in RA, not only in terms of reducing the clinical and laboratory activity of the disease, but also in terms of outcomes reported by the patient himself, characterizing the quality of life and the psycho-emotional state of patients.

The aim of the study was to investigate the dynamics of clinical and laboratory parameters of inflammatory disease activity and cytokines in patients with rheumatoid arthritis (RA) against the background of olokizumab (OKZ) treatment.Materials and methods. Ten patients with a reliable diagnosis of RA were examined: patients’ age was 46.00 (30.00; 60.00) years, duration of disease was 9.0 (3.0; 12,0) years. All patients had moderate to high disease activity: DAS28-ESR (Disease Activity Score 28 with Erythrocyte Sedimentation Rate) – 513 (4.34; 5,80); CDAI (Clinical Disease Activity Index) – 30.00 (24.00; 35.00); SDAI (Simplified Disease Activity Index) – 31.86 (24.36; 38.59). All patients were treated with OKZ at a dose of 64 mg subcutaneously every 4 weeks on the background of therapy with methotrexate, leflunomide, nonsteroidal anti-inflammatory drugs, and glucocorticoids. Observations were performed before treatment and after 3, 6 months of therapy. Serum levels of 15 cytokines: interleukin (IL) 1β, IL-4, IL-6, tumor necrosis factor α (TNF-α), interferon (INF) γ, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, sCD40L, – were examined using multiplex xMAR technology.Results. After 3 and 6 months of OKZ therapy, there was a significant decrease in DAS28-ESR of 3.53 (2.83; 4.26) and 3.48 (2.8; 4.10); CDAI – 11.00 (6.0; 16.00) and 10.0 (5.0; 15.0); SDAI – 10.0 (5.0; 15.0) and 10.17 (7.02; 15.02); C-reactive protein (CRP) concentrations (initial – 14.30 (7.00; 24.70) mg/l, after 3 months – 0.70 (0.40; 0.90) mg/l and after 6 months – 0.65 (0.20; 3.00) mg/l). After 3 months of treatment we found an increase in IL-6 concentration (initial – 1.89 (1.61; 2.33) pg/ml and 89.98 (35.09; 165.84) pg/ml; p

Aim. Switching to another biologic with the same mode of action provides greater opportunity for long-term management of patients with rheumatoid arthritis (RA). In clinical practice, especially in the context of the COVID-19 pandemic, such switching occurred for non-medical reasons as well. However, there is no information about switching from interleukin 6 (IL-6) receptor (R) inhibitor to direct IL-6 inhibitor. Objective – to assess the efficacy and safety of therapy in RA patients, after switching from IL-6R inhibitors (tocilizumab (TOC), sarilumab (SAR)) to olokizumab (OKZ) for reasons not related to the loss of their efficacy or adverse events. Material and methods. In this retrospective cohort study efficacy parameters and routine biochemical data were analyzed using descriptive statistics – mean values with standard deviation for continuous parameters and absolute and relative frequency for binary variables. Adverse events (AE) were reported according to patient’s files. The statistical significance and changes of the analyzed variables by visits were determined using paired t-test. Fisher’s exact test or chi-square test was used to compare the proportion of patients with improvement/no change and of patients with worsening. All tests were 2-sided, and p

Background. Interleukin (IL) 6 plays an important role in the pathogenesis of comorbid rheumatoid arthritis (RA) depression, and IL-6 inhibitors (i) used to treat RA patients may have an antidepressant effect.Objective – to evaluate the effectiveness of Russian iIL-6 olokizumab (OKZ) in reducing symptoms of depression in patients with moderate/high RA activity.Material and methods. To date, 49 RA patients have been included, of which 43 (87.7%) are women, with an average age of 47.8±12.8 years; with a predominant high activity of RA according to DAS28 (CRP) indices (89.8%), SDAI (79.6%) and CDAI (75.5%) and inefficacy of stable 12-week therapy of сDMARDs. In all patients, a psychiatrist, in accordance with ICD-10, diagnosed depression (chronic or recurrent) of varying severity during a semi-structured interview. At week 0, all patients were randomized by the method of sequential numbers in a ratio of 1:1:1 to one of the 3 study groups: group 1 – cDMARDs+OKZ 64 mg subcutaneously once every 4 weeks (n=18); group 2 – cDMARDs+OKZ 64 mg subcutaneously once every 4 weeks + psychopharmacotherapy (PPT) (n=26); group 3 – cDMARDs+PPT (n=5). The duration of the study is 24 weeks. The dynamics of depression severity was assessed on the PHQ-9, MADRS scales; anxiety – HAM-A; experimental psychological projective techniques were also used.Results. After 12 and 24 weeks of therapy, there was a significant decrease in the severity of depression and anxiety in all groups of patients. However, the difference between the final and initial values of all scales was statistically significantly greater (p

The aim of the article is to study pharmacokinetic characteristics of intravenous olokizumab in patients with moderate COVID-19 to relieve a hyperinflammation syndrome.Materials and methods. The pharmacokinetic study was conducted as a part of a phase III clinical study (RESET, NCT05187793) on the efficacy and safety of a new olokizumab regimen (intravenous, at the doses of 128 mg or 256 mg) in COVID-19 patients. Plasma concentrations of olokizumab were determined by the enzyme immunoassay. The population analysis was performed using a previously developed pharmacokinetic model based on a linear two compartment.Results. The pharmacokinetic analysis included the data from 8 moderate COVID-19 patients who had been administrated with olokizumab intravenously at the dose of 128 mg. According to the analysis results in this population, there was an increase in the drug clearance, compared with the data obtained in healthy volunteers and the patients with rheumatoid arthritis: 0.435, 0.178 and 0.147 l/day, respectively. The parameters analysis within the framework of a population pharmacokinetic model showed that the main factors for the increased olokizumab clearance are a high body mass index. In addition, the presence of COVID-19 itself is an independent factor in increasing the drug clearance.Conclusion. After the intravenous olokizumab administration, an increase in the drug clearance is observed in moderate COVID-19 patients against the background of the disease course. The main contribution to the increased clearance is made by the characteristics of the population of COVID-19 patients associated with the risk of a severe disease and inflammation. When administered intravenously at the dose of 128 mg, a therapeutically significant olokizumab level was maintained throughout the acute disease phase for 28 days.

Background. Production of pro-inflammatory cytokines including interleukin 6 (IL-6) is activated in COVID-19. Using olokizumab which inhibits IL-6 production in treatment of COVID-19 is pathogenetically justified.The aim. To study in real clinical practice the efficacy and safety of using the IL-6inhibitor (olokizumab) in treatment of patients with confirmed COVID-19 pneumonia.Materials and methods. The first group included 41 hospitalized patients with confirmed COVID-19 pneumonia having complex therapy including olokizumab. The control group consisted of 66 patients with confirmed COVID-19 pneumonia who did not have therapy with IL-6 inhibitor. We analyzed clinical (volume of lung involvement, respiratory failure degree, body mass index) and laboratory data (levels of T-troponin, lactate, procalcitonin, natriuretic peptide, C-reactive protein, fibrinogen, D-dimer, ferritin, erythrocyte sedimentation rate, glomerular filtration rate).Results. The groups did not differ in gender, age, body mass index of patients, volume of lung tissue injury, and duration of hospitalization (p > 0.05). Respiratory failure of 2–3rd degree was more common in patients of the first group (χ2 = 6.3; p = 0.010). The initial levels of C-reactive protein (50.9 [34.2; 76.2] and 32.2 [9.9; 69.1] mg/L respectively; p = 0.009) and fibrinogen (6.0 [5.3; 6.7] and 5.2 [4.3; 6.2] g/l respectively; p = 0.005) in patients having therapy including olokizumab were significantly higher than in the control group. The levels of erythrocyte sedimentation rate, fibrinogen and ferritin, D-dimer, detected upon admission of patients to the hospital, didn’t have statistically significant differences. At discharge, the erythrocyte sedimentation rate in patients receiving olokizumab was statistically significantly lower (9.0 [5.5; 14.5] and 13.0 [7.0; 27.0] mm/h; p = 0.018).Conclusions. Using olokizumab in the treatment patient with COVID-19 pneumonia has demonstrated a positive effect on clinical and laboratory parameters (erythrocyte sedimentation rate, fibrinogen level) in patients with pronounced inflammatory changes and respiratory impairment.

Rheumatoid arthritis (RA) is a chronic immune-mediated rheumatic diseases (IMRDs) manifested with progressive destruction of joints, systemic inflammation of visceral organs and a wide range of co-morbidities associated with chronic inflammation. Among the cytokines involved in the pathogenesis of RA and certain other IMRDs, the role of interleukin (IL) 6 is of special interest. The introduction of mAbs tocilizumab (TCZ) and later sarilumab (SAR), both blocking the receptor of this cytokine, into clinical practice was an important achievement in the treatment of IIRDs at the beginning of the 21st century. As a novel approach in the treatment of RA, the humanized mAb against IL-6 olokizumab (OKZ) is in development by the Russian company R-PHARM under the license agreement with UCB Pharma. The review examines new data on efficacy and safety of OKZ in RA and the prospects of its use in rheumatology

Treatment algorithms for systemic sclerosis have not been completely developed. Effectivity of medications are usually used in clinical practice has a low level of evidence. Therefore, it is necessary to find a new treatment approaches for this nosological form. In the paper described clinical case of olokizumab treatment in a patient with diffuse systemic sclerosis with interstitial lung disease, polyserositis, severe microcirculatory alterations.

The COVID-19 pandemic has significantly changed the understanding of the safety profile of therapies for immunoinflammatory rheumatic diseases (IRDs). This is primarily due to the negative impact of a number of basic anti-inflammatory drugs (DMARDs) and biological DMARDs on the course and outcomes of a new coronavirus infection. A number of studies have shown that anti-B-cell therapy (rituximab) gave a statistically significant increase in the risk of severe COVID-19 and an increase in mortality. At the same time, the analysis of real clinical practice data dictated the need to establish a number of restrictions on the use of certain classes of biological DMARDs and to search for alternative therapy programs to maintain control over disease activity.Purpose of the study – to evaluate the efficacy and safety of the drug Artlegia® (olokizumab), solution for subcuta neous injection, 160 mg/ml – 0.4 ml, manufactured by R-Pharm JSC, Russia) for the treatment of patients with rheuma toid arthritis in real clinical practice after switching with rituximab during the COVID-19 pandemic.Materials and methods. The study included 14 patients with a confirmed diagnosis of rheumatoid arthritis (RA), who were previously on rituximab therapy at a dose of 1000–500 mg twice with an interval of 2 weeks, who received at least one course of therapy with this drug. As RA worsened, patients were switched to olokizumab against the background of standard DMARDs. At 4, 8, 12 weeks after the switch, the severity of pain was assessed on the VAS scale, the number of painful and swollen joints (TJC28 and TSC28), the level of acute phase markers of inflammation, the DAS28 disease activity index calculated using ESR and CRP, and the CDAI (clinical activity index), functional state index HAQ, as well as assessment of the safety profile of therapy.Results. Data analysis was performed using median values (Me) were used for data analysis. A significant decrease of TJC28 was after the injection of olokizumab (Artlegia®) in 8 and 12 weeks (Me baseline = 10; Me 8 weeks = 4; Me 12 weeks = 4; p

Background. Olokizumab is a new interleukin-6 (IL-6) inhibitor that has demonstrated good efficacy and safety for the treatment of adult patients with moderate to high-grade activity of rheumatoid arthritis in combination with methotrexate with insufficient efficacy of methotrexate monotherapy.Aim of the study was to evaluate the effectiveness of olokizumab in relation to the patient’s reported outcomes (PROs) based on the results obtained in the CREDO 1 phase III study.Material and methods. The study included 428 patients with rheumatoid arthritis who were randomized into 3 groups: group 1 – patients who received 64 mg of olokizumab subcutaneously every 2 weeks (q2w) (n=143); group 2 –patients who received 64 mg of olokizumab every 4 weeks (q4w) (n=142); group 3 – patients who had placebo q2w (n=143). PROs included: Health Assessment Questionnaire-Disability Index (HAQ-DI); Patient Global Assessment of Disease Activity (PtGA-VAS); Subject’s Assessment of Pain (VAS); fatigue according to the FACIT-F scale; quality of life according to the EQ-5D questionnaire; physical and mental components of the SF-36 scale. The effectiveness of olokizumab was evaluated by the dynamics of the average PROs values and the proportion of patients who reported improvement compared to the baseline level of ≥ minimum clinically important differences (MCID) for each PROs by weeks 12 and 24 of follow-up.Results. 396 patients out of 428 included completed the study. When included in the study, patients of different therapeutic groups did not differ in socio-demographic indicators, duration, activity of rheumatoid arthritis, as well as in PROs indicators. Olokizumab therapy, regardless of the dosage regimen of the drug, resulted in a significant improvement in all PROs compared to placebo after 12 weeks, and this improvement sustained until 24 weeks of therapy. The proportion of patients who reached and exceeded MCID at weeks 12 and 24 of follow-up was statistically significantly higher in both olokizumab groups compared to placebo for PtGA, VAS pain, HAQ-DI, FACIT-F. The number of patients who reached or exceeded the MCID on the physical component of the SF-36 scale at week 12 was significantly higher in both olokizumab groups, and at week 24 only in the group 2 compared to the placebo group. The mental component of SF-36 improved in a significantly higher percentage of patients in the group 2 compared to placebo group at weeks 12 and 24, while the group 1 did not significantly differ from placebo group in improving the mental component of SF-36.Conclusions. Olokizumab therapy in patients with moderate to high-grade activity of rheumatoid arthritis is associated with a significant improvement in all PROs. There was no significant difference between the dosage regimens of olokizumab.

Aim. The study aimed to assess the economic effect of biological therapy with anti-interleukin (IL)-6 drugs: tocilizumab, olokizumab, and levilimab in patients with severe COVID-19 and cytokine storm.Materials and Methods. An assessment of the economic consequences of severe COVID-19 therapy was carried out using the cost of illness analysis in a model developed in Microsoft Excel 2016 (Microsoft, USA). The direct medical costs of providing care for COVID-19 were taken into account (ICU service, the cost of biological therapy, and the use of glucocorticosteroids (GC)). Data from a prospective, historical controlled CHIC study conducted in the Netherlands were used as a source of efficacy. A mathematical model has been developed for extrapolating the CHIC study results to clinical outcomes (transfer to mechanical ventilation, discharge from ICU, lethal outcome) and forecasting the costs of managing severe patients with COVID-19 in real clinical practice in the Russian Federation.Results. The reduction in the cost of therapy when the hypothesis of equal efficacy of tocilizumab, olokizumab, and levilimab is accepted by reducing the cost of drug therapy will be 1,251,698.99 rubles per 72 patients when comparing olokizumab with tocilizumab and 939,718.84 rubles per 72 patients when comparing olokizumab with levilimab.Conclusion. Anti-interleukin (IL)-6 drugs in combination with GC are an effective treatment option for moderate to severe patients with COVID-19 and cytokine storm symptoms. This group of drugs is indicated as the main one for the treatment of this condition.

Most subjects with the COVID-19 experience mild to moderate symptoms, but approximately 10% of cases suffer from severe course of disease. IL-6 inhibitors are actively used to neutralize and prevent the cytokine storm. Olokizumab is a humanized monoclonal antibody belonging to the G4/Kappa immunoglobulin isotype that selectively binds to human IL-6 and effectively neutralizes it. Aim.To evaluate the efficacy and safety of Artlegia (olokizumab) for the treatment of subjects with a disease caused by the SARS-COV-2 virus in a real-world clinical setting. Materials and methods.The analysis included data of 610 subjects aged 55.0812.68 years who received olokizumab at a single dose of 160 mg/mL 0.4 mL subcutaneously as a preemptive anti-inflammatory therapy. The comparison group included 511 subjects aged 55.2311.23 years who received standard therapy without IL-6 inhibitors. Control Endpoints: 1. Positive clinical changes on Day 7. 2. Changes in the CRP levels on Days 1, 2, and 7. 3. Duration of oxygen therapy. 4. Number of days in hospital. 5. Number of adverse events. 6. Disease outcome. Results.If a cytokine storm occurs, immune regulatory events will trigger the development of either a protective immune response or an exacerbated inflammatory response. The use of preemptive anti-inflammatory therapy has both a short-term and, most importantly, a long-term effect on the T and B parts of the immune process. These aspects definitely require further research and observation. Conclusion.The use of olokizumab to treat the new COVID-19 coronavirus disease has demonstrated a positive effect on clinical and laboratory parameters. Primarily, it affects the severity of clinical parameters by improving the general condition already on the first day of observation, and decreasing body temperature to normal values. The changes in the C-reactive protein levels show a significant effect of the IL-6 inhibitor on the systemic inflammatory response.