Infectious Diseases

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/infd20

Blockade of interleukin seventeen (IL-17A) with

secukinumab in hospitalized COVID-19 patients –
the BISHOP study

Gustavo Gomes Resende, Ricardo da Cruz Lage, Samara Quadros Lobê,

Amanda Fonseca Medeiros, Alessandra Dias Costa e Silva, Antônio Tolentino
Nogueira Sá, Argenil José de Assis Oliveira, Denise Sousa, Henrique
Cerqueira Guimarães, Isabella Coelho Gomes, Renan Pedra Souza, Renato
Santana Aguiar, Roberto Tunala, Francisco Forestiero, Julio Silvio Souza
Bueno Filho & Mauro Martins Teixeira

To cite this article: Gustavo Gomes Resende, Ricardo da Cruz Lage, Samara Quadros Lobê,
Amanda Fonseca Medeiros, Alessandra Dias Costa e Silva, Antônio Tolentino Nogueira Sá, Argenil
José de Assis Oliveira, Denise Sousa, Henrique Cerqueira Guimarães, Isabella Coelho Gomes,
Renan Pedra Souza, Renato Santana Aguiar, Roberto Tunala, Francisco Forestiero, Julio Silvio
Souza Bueno Filho & Mauro Martins Teixeira (2022): Blockade of interleukin seventeen (IL-17A)
with secukinumab in hospitalized COVID-19 patients – the BISHOP study, Infectious Diseases,
DOI: 10.1080/23744235.2022.2066171

To link to this article: https://doi.org/10.1080/23744235.2022.2066171

Published online: 29 Apr 2022.

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INFECTIOUS DISEASES, https://doi.org/10.1080/23744235.2022.2066171
2022; VOL. 0,
NO. 0, 1–9

ORIGINAL ARTICLE

Blockade of interleukin seventeen (IL-17A) with secukinumab in hospitalized

COVID-19 patients – the BISHOP study

Gustavo Gomes Resendea , Ricardo da Cruz Lagea , Samara Quadros Lobe ^b ,

b b
Amanda Fonseca Medeiros , Alessandra Dias Costa e Silva , Anto ^nio Tolentino Nogueira Sab ,
Argenil Jose de Assis Oliveira b
, Denise Sousa , Henrique Cerqueira Guimar~aesb ,
b

Isabella Coelho Gomesb, Renan Pedra Souzac , Renato Santana Aguiarc , Roberto Tunalad ,
Francisco Forestierod , Julio Silvio Souza Bueno Filhoe and Mauro Martins Teixeiraf
a
Rheumatology Unit, Hospital das Clınicas - Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil; bHospital
Risoleta Tolentino Neves, Belo Horizonte, Brazil; cDept. of Genetics, Ecology and Evolution - UFMG, Belo Horizonte, Brazil;
d
Novartis, S~ao Paulo, Brazil; eDepartment of Statistics, Universidade Federal de Lavras (UFLA), Lavras, Brazil; fDepartment of
Biochemistry and Immunology UFMG, Belo Horizonte, Brazil

ABSTRACT
Background: Patients with severe COVID-19 seem to evolve with a compromised antiviral response and hyperinflamma-
tion. Neutrophils are critical players in COVID-19. IL-17A plays a major role in protection against extracellular pathogens
and neutrophil attraction/activation. We hypothesized that secukinumab, an anti-IL17A monoclonal antibody, could prevent
the deleterious hyperinflammation in COVID-19.
Methods: BISHOP was a randomized, open-label, single-centre, phase-II controlled trial. Fifty adult patients hospitalized
with PCR-positive Covid-19, were randomized 1:1 to receive 300 mg of secukinumab subcutaneously at day-0 plus standard
of care (group A) or standard of care alone (group B). A second dose of 300 mg of secukinumab could be administered on
day-7, according to staff judgement. The primary endpoint was ventilator-free days at day-28 (VFD-28). Secondary efficacy
and safety outcomes were also explored.
Results: An intention-to-treat analysis showed no difference in VFD-28: 23.7 (95%CI 19.6–27.8) in group A vs. 23.8
(19.9–27.6) in group B, p ¼ .62; There was also no difference in hospitalization time, intensive care unit demand and the
incidence of circulatory shock, acute kidney injury, fungal or bacterial co-infections. There was no difference in the inci-
dence of severe adverse events. Pulmonary thromboembolism occurred only in males and was less frequent in secukinu-
mab-treated patients (4.2% vs. 26.2% p ¼ .04). There was one death in each group. Upper airway viral clearance was also
similar in both groups.
Conclusion: The efficacy of secukinumab in the treatment of Covid19 was not demonstrated. Secukinumab decreased pul-
monary embolism in male patients. There was no difference between groups in adverse events and no unexpected events
were observed.

KEYWORDS ARTICLE HISTORY CONTACT

Covid-19 Received 29 November 2021 Gustavo Gomes Resende
secukinumab Revised 5 April 2022 gustavogomesresende@yahoo.com.br
IL-17 Accepted 8 April 2022
pulmonary thromboembolism
thromboinflammation

ß 2022 Society for Scandinavian Journal of Infectious Diseases

2 G. G. RESENDE ET AL.

Introduction Secukinumab is a human IgG1j monoclonal antibody

that binds to and neutralizes IL-17A. It is currently
The new coronavirus (SARS-CoV-2) pandemic, which
approved in many countries for the treatment of psoria-
started in late 2019, has spread with impressive speed
sis, ankylosing spondylitis, non-radiographic axial spon-
across the planet and has threatened all health systems
dyloarthritis and psoriatic arthritis. We hypothesised that
due to the considerable proportion of patients requiring
secukinumab could be used in patients with respiratory
inpatient treatment, including intensive care and mech-
failure due to COVID-19 and report here the results of a
anical ventilation [1]. The most severe patients, who pro-
phase-2 open-label randomized controlled trial to evalu-
gress to acute respiratory distress syndrome (ARDS),
ate the effects of secukinumab in hospitalized adult
seem to combine a poor antiviral response and a sys-
COVID-19 patients.
temic hyperinflammatory state [2–5]. Their laboratory
findings (liver dysfunction, hyperferritinaemia, dissemi-
nated intravascular coagulation, high levels of D-dimer, Methods
and C-reactive protein, along with cytopenias) and cyto- Study design and participants
kine responses resemble those of other hyperferritinae-
BISHOP (Blockade of Interleukin Seventeen in
mic syndromes [6], such as the macrophage activation
Hospitalized cOvid-19 Patients) is an investigator-initi-
syndrome (MAS), adult-onset Still’s disease (AOSD), sep-
ated, randomised, open-label, single-centre, phase-II con-
tic shock and catastrophic antiphospholipid syndrome
trolled (without placebo) trial. The study was performed
(CAPS) [7,8].
in Hospital Risoleta Tolentino Neves, referral centre for
It has been proposed that neutrophils are critical play-
treatment of COVID-19 in the northern region of Belo
ers in COVID-19 pathogenesis. Indeed, COVID-19 severity
Horizonte city in Brazil. Adult patients (age  18 years)
has been associated with neutrophilia, increased neutro-
admitted to the hospital were eligible for the study if
phil-to-lymphocyte ratio (NLR), and aberrant neutrophil
they had SARS-CoV-2 infection confirmed by RT-PCR of
activation [9]. Moreover, neutrophils infiltrate the lungs
nasopharyngeal swab and severe acute respiratory syn-
where diffuse alveolar damage and microvascular throm-
drome (SARS), according to the Brazilian Ministry of
bosis have been observed [10]. IL-17 is a cytokine contri-
Health criteria (dyspnoea/respiratory discomfort OR per-
buting to the pathogenesis of several immune-mediated
sistent chest pressure OR oxygen saturation less than
diseases, including spondyloarthritis and psoriasis [11,12].
95% in room air OR cyanosis of lips or face) [20].
IL-17 drives neutrophil accumulation in these diseases
Patients were included from September 1st to December
and can up-regulate expression of several cytokines,
29th, 2020.
including CXCL8, TGF-b, IL-1b, TNFa, and IL-6 [13–15] . In
The exclusion criteria were functional classes III and IV
the context of COVID-19, some studies have suggested
of congestive heart failure or chronic obstructive pul-
that IL-17 might contribute to the pathogenesis of severe
monary disease, stages 4 and 5 of chronic kidney disease
COVID-19 [16]. It has already been shown that Th17
(GFR <30 mL/min), diabetic ketoacidosis, known history
count and IL-17 levels were increased in critically ill of HIV/AIDS infection or chronic or acute HBV or HCV
COVID-19 patients when compared to healthy donors. In infection, unrestrained bacterial or fungal co-infections
addition, the ratio of Th17/Treg cells, RORct/FoxP3, and (defined by hemodynamic instability, prior 48 h of anti-
IL-17/IL-10 were considerably enhanced in patients who microbial covering, or at the discretion of the study’s
died, as compared to recovered cases [17]. Higher con- medical coordinator), active tuberculosis, history of
centrations of IL-17A in blood have been associated with malignancy in the last year, current use (or in the previ-
a more severe clinical course in patients with COVID-19 ous 15 days) of other immunosuppressants, baseline neu-
and an expansion of tissue-resident memory-like TH17 trophils count 1000/mm3, pregnancy or breastfeeding.
cells (TRM17 cells) has been observed in the lungs even
after viral clearance [18]. Furthermore, treatment with an
IL-17RA antibody decreased inflammation in the lungs of Randomisation and procedures
mice infected with SARS-CoV-2 pseudovirus expressing Enrolled patients were sequentially subjected to block
the ORF8 virus protein [19]. Although these findings randomisation (block size of 4) to receive 300 mg of
appear to suggest a role for IL-17 in the context of secukinumab subcutaneously at day-0 plus standard of
COVID-19, a direct demonstration of the relevance of IL- care (SoC), hereinafter called group A, or SoC alone
17 in the pathogenesis of the disease is lacking. (group B) in a 1:1 ratio (Figure 1). A second dose of
 INFECTIOUS DISEASES 3

102 patients recruited. infections (culture-confirmed); and the incidence of

52 screening failure acute renal failure (KDIGO III), circulatory shock or need
50 randomly assigned between SoC +
for vasopressors, pulmonary thromboembolism (PTE)
secukinumab (SEC) or SoC alone. and reactions at the injection site. The effects of secuki-
numab on viral clearance were explored by longitudinal
sampling and RT-PCR for SARS-CoV-2 in the upper air-
25 allocated to SoC+SEC. 25 allocated to SoC alone. way swab, collected on the inclusion day (D0) and every
25 received SEC. None received SEC.
three days until day 14. If a negative result was found,
1 consent withdrawn.
1 protocol deviation. the next collections were suspended. Data were col-
25 included in 28-day 25 included in 28-day
lected using the Research Electronic Data Capture
ITT analysis. ITT analysis. (REDCap) database (https://www.project-redcap.org).
Figure 1. Trial profile. SoC: standard of care.
Statistical analysis
300 mg of secukinumab could be administered at day 7,
according to the judgement of the attending medical An overall type-I error (2-sided) probability of 5% was
team and if all enrolment criteria still remained met. Of used. At the time of the study design, there was a scar-
note, secukinumab dose regimen in COVID-19 patients city of published data on studies evaluating the effects
has not been assessed previously. The standard of care of anti-inflammatory therapies in patients with COVID-
in Hospital Risoleta Tolentino Neves, available to all 19. A review and meta-analysis on the use of corticoste-
patients, regardless of their allocation, during the time roids in ARDS found a mean difference in VFD-28 of
this study was carried out, included antimicrobials (azith- 5.8 days (SD 7.8), favouring its use compared to placebo
romycin and a beta-lactam, at the time of admission [22]. The mean length of mechanical ventilation in critic-
and until bacterial infection could be excluded), cortico- ally ill patients with COVID-19 reported was 9.8 days (SD
steroids (dexamethasone, 6 mg daily, for 10 days), and 4.4), and the mean calculated VFD-28 was 9.4 (SD 6.7)
prophylactic anticoagulants (enoxaparin 40 mg q12hr, [23]. The minimum sample size to achieve 80% power
except if thromboembolism was diagnosed, in which to detect an increase of 5.5 days in the VFD-28 was 25
case full anticoagulation was performed). Other immu- patients per group.
nobiological agents, such as anti-IL-6R/anti-IL1b/anti- We used Fisher’s exact test independence hypothesis
TNF-a, were not allowed. Patients were monitored con- of proportions from two study groups in categorical
tinuously after hospital discharge by phone calls and data. For continuous numerical variables, the Student’s
messages made every three days by one of the study t-test was used to assess differences in population distri-
investigators until day 28 of study inclusion. In addition, butions. A per-protocol (PP) analysis was used for all
they received a number to call if there were issues. outcomes. Additionally, an intention-to-treat (ITT) ana-
lysis with covariable correction imputation method for
missing data was done only for the primary endpoint.
Outcomes
We used survival analysis to compare proportions of
The primary endpoint was ventilator-free days at day 28 achievement of score one on the WHO ordinal scale
(VFD-28). VFD-28 is defined as (28 - x), where x is the from each categorical variable. Logistic regression was
number of days spent receiving mechanical ventilation. used in nominal endpoints in which some marginal
This outcome focuses on the duration of need for mech- association was found to validate it. The R program ver-
anical ventilation while simultaneously taking mortality sion 4.1.2 (or-project.org4) and GraphPad Prism program
into consideration because it assigns a score of zero if (USA) version 8.4.3.686 were used for statistical analyses.
the patient dies before 28 days [21]. Secondary efficacy The study was approved by the National Research
and safety outcomes also included (all assessed within Ethics Commission – CONEP (approval number
the time frame of 28 days): mortality rate; length of hos- 4.100.115, on June 20th, 2020) and was registered at the
pitalisation; need and length of critical care in the ICU; Brazilian Registry of Clinical Trials – ReBEC (RBR-5vpyh4,
World Health Organization (WHO) Ordinal Scale for on June 6th, 2020). The informed consent form (ICF) was
Clinical Improvement; serious adverse events (any applied to all patients or their legal guardians for
undesirable event associated at least with prolongation patients unable to provide written consent due to their
of hospitalization), secondary bacterial and fungal medical condition.
4 G. G. RESENDE ET AL.

Table 1. Baseline characteristics of patients randomised to secukinumab þ standard of care (group A) or stand of care alone (group B).
Group A (SEC þ SoC) n ¼ 25 B (SoC alone) n ¼ 25 p value
Demographic characteristics
Sex (male), n (%) 10 (40) 16 (64) .16
Age, median (IQR) 54 (45–65) 54 (40-63) .37
Comorbidities, n (%)
Systemic arterial hypertension 13 (52) 11 (44) .78
Diabetes mellitus 8 (32) 9 (36) 1.00
Obesity and overweight 15 (60) 9 (36) .16
Cardiopathy 3 (12) 1 (4) .61
Pneumopathy 2 (8) 3 (12) 1.00
N of comorbidities/patient 1.6 1.2 .75
Clinical and laboratory measures, median (IQR)
Time from symptoms onset to randomisation (days) 10 (8–12) 9 (8-11) .62
Mean arterial pressure (mmHg) 97 (93–100) 94 (90-102) .18
Haemoglobin (g/dL) 12.7 (12.1–14.3) 13.4 (12.5–13.9) .22
White blood cells (109/L) 8.5 (7.6–9.8) 8.9 (7.3–11.6) .27
Neutrophils (109/L) 6.8 (5.9–8.3) 7.8 (5.8–9.3) .34
Lymphocytes (109/L) 1.3 (0.7–1.9) 1.2 (0.9–1.5) .68
Neutrophil/lymphocyte ratio 5.2 (3.6–10.5) 6.5 (4.5–9.1) .44
Platelets (109/L) 251 (195–297) 220 (171–301) .32
Creatinine (mg/dL) 0.70 (0.70–1.0) 0.75 (0.70–0,90) .76
Lactate dehydrogenase (U/L) 331 (296–451) 392 (324–499) .15
Ferritin (ng/mL) 659 (344–1296) 846 (428–1421) .54
C-reactive protein (mg/L) 43 (24–77) 63 (44–123) .11
Fibrinogen (mg/dL) 461 (436–559) 476 (442–527) .57
Troponin (ng/mL) 3.5 (1.8–8.9) 5.1 (3.3–14) .22
D-dimer (mcg/mL) 0.6 (0.3–1.3) 0.9 (0.4–2.3) .21
PaO2/FiO2 ratio 297 (216–384) 258 (174–339) .07
SOFA score 2.0 (1.0–3.0) 3.0 (1.0–3.0) .10
WHO scale 4 (4–4) 4 (4–4) .48
IQR: interquartile range; PaO2/FiO2 ratio: ratio of arterial oxygen partial pressure (in mmHg) to fractional inspired oxygen; SOFA score: Sequential Organ Failure
Assessment Score for sepsis; WHO scale: World Health Organisation Ordinal Scale for Clinical Improvement.

Results Table 2. Primary and secondary endpoints analyses comparing

secukinumab þ SoC (group A) to SoC alone (group B).
Fifty patients were enrolled. The two randomized groups A (SEC þ SoC) B (SoC alone)
were homogenous in parameters of age, sex, and Group n ¼ 25 n ¼ 23 p value
Primary endpoint
comorbidities (Table 1). Even though there appeared to VFD-28 (days), mean (SD) 23.7 (9.9) 23.8 (9.6) .62
be more systemic arterial hypertension, obesity/over- Secondary endpoints
Mechanical Ventilation, n (%) 5.0 (20) 5.0 (22) 1.00
weight, and cardiopathy in group A (treated patients) Hospital days, mean (SD) 9.3 (8.1) 11.0 (7.4) .34
and more male patients in group B (control patients), ICU, n (%) 7 (28) 9 (39) .54
ICU days, mean (SD) 4.0 (9.0) 3.2 (6.3) .55
none of these differences reached statistical significance. WHO scale  1, n (%) 12 (48) 6 (26) .14
The mean (SD) age at study entry was 55 (11) years-old WHO scale, mean (SD) 2.3 (2.1) 2.1 (1.5) .31
VFD-18: number of ventilator-free days after 28 days of follow-up; ICU: intensive
(YO) in group A and 52 (14) YO in group B. The mean care unit; WHO scale: World Health Organisation Ordinal Scale for Clinical
(SD) time since onset of symptoms to randomization Improvement.

was 9.9 (2.7) days in group A and 9.5 (3.0) in group B.

All included patients required supplemental oxygen
at baseline. of them did not fulfil SARS criteria anymore and the
During the trial, two patients were excluded, both third one was in septic shock.
from group B. One of them withdrew consent, alleging The primary endpoint was defined as the number of
intolerable discomfort with sequential blood and naso- ventilator-free days at day 28 (VFD-28). As seen in Table
pharyngeal swab collection. A second one was excluded 2, there was no difference in VFD-28 between groups
due to a protocol deviation (only after enrolment, the (23.7 days in group A and 23.8 days in group B, p ¼ 0.97).
patient was found to be receiving post-transplant A similar result was obtained in the ITT analysis.
immunosuppression). The analysis of secondary endpoints showed no sig-
Ten patients from group A were still hospitalised at nificant differences in all evaluated parameters.
day 7, and a second dose of 300 mg secukinumab was Although there was an apparent decrease in ICU admis-
administered to seven of them. The remaining three sions (28% vs. 39%) and hospitalisation length (9.3 vs.
patients did not receive the second dose, because two 11.0 days) in secukinumab-treated patients than in the
 INFECTIOUS DISEASES 5

Table 3. Incidence of adverse events of interest in secukinumab þ - in the control group. No allergic reactions or reactions
standard of care (group A) compared to standard of care alone at the injection site occurred in either study arm.
(group B).
Chronological analysis (from day-0 to day-14) of the
A (SEC þ SoC) B (SoC alone)
Group n ¼ 25 n ¼ 23 p value neutrophil/lymphocyte ratio (NLR), ferritin, and CRP lev-
Patients with SAE, n (%) 5 (20) 6 (26) .73 els during hospitalisation revealed a very similar evolu-
Any SAE, n (Incidence/100 patient-days) 16 (2.3) 11 (1.7) .56
Pulmonary thromboembolism, n (%) 1 (4) 6 (26) .04 tion of the inflammatory markers. NLR tended to
Secondary bacterial infection, n (%) 4 (16) 2 (8.7) .67 increase from days 10 to 14 in group A and decrease in
Secondary fungal infection, n (%) 1 (4) 0 1.00
Circulatory shock, n (%) 4 (16) 1 (4) .35 group B. Still, there were few hospitalised patients dur-
Acute kidney injury KDIGO III, n (%) 1 (4) 1 (4) 1.00 ing this period, and the differences were not statistically
Death, n (%) 1 (4) 1 (4) 1.00
SAE: serious adverse events; p < 0.05 ¼ statistically significant. significant (Figure 2).
The WHO Ordinal Scale for Clinical Improvement had
control group, these differences were not statistically dif- comparable evolution, from randomisation to day 28 in
ferent (Table 2). Similarly, there was an nominally longer both groups. The score in the WHO Ordinal Scale for
duration of mechanical ventilation (3.8 vs. 2.0 days) and Clinical Improvement at day 28 was not different
longer permanence in the ICU (4.0 vs. 3.2 days) in secuki- between groups (2.3 points in group A vs. 2.1 in group
numab-treated than control patients, but this was also B). There was a higher proportion of patients in group A
without statistical significance. (48%) than group B (26%), achieving a score of one on
The frequency of serious adverse events (SAE) was the scale throughout the 28 days of follow-up, although
generally comparable in both groups (20% vs. 26%; without significance (p ¼ .14). In the survival analysis
p ¼ .73) (Table 3). Secukinumab-treated individuals had a (Cox regression model), only baseline CRP (lower values)
higher rate of secondary bacterial infection (16% vs. 9%; were associated with higher cumulative hazard of
p ¼ .7) and circulatory shock (16% vs. 4%; p ¼ .3), albeit achieving score one on the WHO scale, as shown in
not significantly different. The frequency of pulmonary Figure 3.
thromboembolism (PTE), as confirmed by chest CT angi- Viral clearance, as defined by the change (2-DDCT) in
ography, was lower in the secukinumab-treated than in RNA viral load in the upper airway between day-0 and
the control group (4% vs. 26%; p ¼ .04). The incidence of day-7, was similar in both groups. After seven days,
PTE (per 100 patient-days) was 0.14 in group A and 0.93 there was viral clearance in 83% in group A and 77% in
in group B, with a relative risk reduction of 85% (Table group B, as shown in Figure 4.
3). PTE occurred only in males. Within this group with
PTE, younger men were more affected. The mean age Discussion
(SD) of the male patients was 42 (15) years-old in the To the best of our knowledge, this is the first rando-
subgroup with PTE and 56 (13) years in the subgroup mised clinical trial exploring the effects of secukinumab
without PTE (p ¼ .04). We used logistic regression ana- in COVID-19 patients. Our results show that secukinu-
lysis to evaluate whether PTE associated independently mab was well tolerated and not associated with a sig-
with the treatment with secukinumab. Because of the nificant increase of adverse events or secondary
robust association found with the male sex, no model infections. However, the anti-IL-17 antibody was not
that included sex showed any other variable (age, treat- effective in ameliorating the pulmonary failure observed
ment, baseline CRP, ferritin and D-dimer) that associated in severe acute respiratory syndrome COVID-19 patients.
with PTE. Only after multiple adjustments, in a model in Indeed, there was no decrease in the number of ventila-
which sex was excluded as an explanatory variable, a tor-free days at day 28 with secukinumab in addition to
weak association was seen with the interaction between the standard therapy used. Moreover, days in the hos-
age and treatment. In this model, secukinumab treat- pital, admission to ICU, and time to recovery (as
ment were marginally associated with a lower incidence assessed by the WHO score) were similar in
of PTE in younger patients (p ¼ .09). both groups.
There was one death and one patient who developed As seen in Table 2, there was no difference in the
acute kidney injury (KDIGO III) requiring haemodialysis in percentage of individuals intubated and the duration of
each group. There was only one fungal infection (vaginal intubation. Similarly, ICU admission and ICU stay were
candidiasis, treated with oral antifungal, without study similar between both groups. These results suggest that
interruption) in a secukinumab-treated patient and none the most severe forms of the disease are not altered in
6 G. G. RESENDE ET AL.

Figure 2. Chronological analysis of blood tests. CRP: C-reactive protein; NLR: neutrophil-lymphocyte ratio. Shadow areas represent the 95%
confidence interval.

Figure 3. Cumulative hazard of achieving score one at day 28 on the World Health Organisation Ordinal Scale for Clinical Improvement
evolution. A - comparison between who had baseline CRP lower than the mean (77 mg/L) and who had baseline CRP higher or equal to
mean. B – comparison between the groups of allocation in the study. Error lines (shadow areas) represent the 95% confidence inter-
val (95%CI).

any significant way by anti-IL-17 treatment. On the other

hand, there were parameters that, albeit not significant,
showed a potential for secukinumab in ameliorating the
less severe forms of the disease. Indeed, there was a
two-day difference in hospitalisation, mainly because
there was early amelioration of WHO scores in secukinu-
mab-treated patients.
Our study showed no difference between groups in
the incidence of adverse events, and no unexpected
events were observed in this small population (n ¼ 25 of
patients treated with secukinumab). These findings are
consistent with published data showing no increased
Figure 4. Viral clearance in upper airways from randomisation (D0) risk of COVID-19 infection or its complications in
to day 7 (D7). Error bars represent the 95% confidence interval of patients taking IL-17 inhibitors for immune-mediated
the mean change in RNA viral load. diseases [24–26]. There was a trend for more infections
 INFECTIOUS DISEASES 7

in secukinumab-treated individuals, but there was no started in September 2020, all patients were already tak-
statistical difference between the two groups. The ten- ing corticosteroids because of its benefits in oxygen-
dency to increase NLR as the disease progressed seen in dependent COVID-19 patients [38]. Possibly, this issue
group A (Figure 2) could reflect that difference since improved the challenge to show significant effects of an
neutrophil blood count started to rise on day-7 (data anti-inflammatory intervention on top of steroid use. In
not shown). fact, smaller studies with another anti-cytokine therapy
Of special interest, our study showed that the number (anti-IL-6R) have also reported no improvement in
of clinically relevant thromboembolic events was lower COVID-19 patients, while two larger trials clearly showed
in secukinumab-treated patients, although the logistic a benefit [39]. Furthermore, the optimal dose, route of
regression did not confirm that treatment was an inde- administration, and timing of secukinumab to ensure
pendent variable associated with this outcome. therapeutic tissue concentrations in COVID-19 are
Interestingly, only male subjects presented PTE during unknown. The dose regimen chosen in this study was
the study. This sex predominance may be due to mere the maximum weekly dose, currently approved for other
chance, especially considering the small sample of this indications. In addition, our chosen method to assess
study. But it may also be due to some sex-linked genetic
viral clearance (RNA viral load in the upper airway) is
differences since it has already been shown that the risk
not adequate to measure viral aggression in lower
of thromboembolism recurrence in men is higher than
respiratory tract, and also it cannot be translated as
in women [27].
viable viral particle.
It is estimated that 1% of patients tested for SARS-
In conclusion, secukinumab exhibited a satisfactory
CoV-2 develop pulmonary thromboembolism (PTE) [28].
safety profile in severe COVID-19 patients. The blockade
Clinically relevant PTE was estimated at 8% (95%CI,
of anti-IL-17A with secukinumab appears not to show a
4–11%) [29]. Notably, in critically ill patients, this preva-
clear benefit, compared to the standard of care, in the
lence is remarkably higher, with prevalences reported of
context of COVID-19 pulmonary failure. There was a
up to 76% in this population [30]. In our cohort, the
reduction of pulmonary thromboembolism in male
prevalence of PTE in the control group (26%) was close
patients and this find needs to be confirmed in larger
to that reported in the literature. Therefore, the substan-
tial reduction of pulmonary thromboembolism (PTE) clinical trials.
seen in secukinumab-treated patients was remarkable.
There is evidence that IL-17 may contribute to throm-
boinflammation under various circumstances. Upon Disclosure statement
stimulation, COVID-19 platelets released significantly GGR received personal payments for lectures from Abbvie,
larger amounts of IL-17, among other cytokines, com- Janssen, Lilly, Novartis and UCB; support for attending meetings
pared with control platelets [31]. IL-17A promotes and/or travel from Abbvie, Janssen, Lilly, Novartis and UCB; and
in vitro platelet aggregation and activation, neutrophil personal payments for participation on a data safety monitoring
extracellular trap (NET) release, and vein endothelial cell board or advisory board Abbvie, Janssen, Lilly and Novartis. RCL
activation. These effects were lost in platelets deficient received honoraria for presentations and speakers bureaus; and
support for attending meetings, including travel and hotel
for the IL-17 receptor (IL-17R) [32–34], resulting in less
expenses from Novartis. RT and FF were Novartis employees until
deep venous thrombosis (DVT) formation in two animal this submission. ADCS, AFM, ATNS, AJAO, DS, HCG, ICG, MMT,
models [35,36]. Besides, a series of thrombectomies SQL, RSA, JSSBF and RPS declare no competing interests.
observed that the coronary thrombus, superimposed on
ruptured atherosclerotic plaques, contains NETs coated
Funding
with IL-17 [37]. While this six-fold reduction of clinically
significant PTE in COVID-19 patients treated with secuki- Novartis Brazil supported this research providing expert input in
numab is of interest, larger studies are needed to con- the development of the project, drug supply, data management,
and monitoring. This project was also supported by CNPq (R.S.A.:
firm this protective effect of blocking IL-17.
312688/2017-2 and 439119/2018-9). MEC/CAPES 118 (14/
This study had some limitations. It was open-label 2020  23072.211119/2020-10), FINEP (0494/20 01.20.0026.00),
with a small sample size. The sample size was calculated UFMG-NB3, FINEP n 1139/20 (RSA) and The National Science and
based on the risk of intubation and death observed at Technology Programs (INCT Program project number 465425/
the beginning of the epidemic in Brazil. When inclusions 2014-3 funded by MCTI/CNPQ/CAPES/FAPS research call 16/2014).
8 G. G. RESENDE ET AL.

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