Bommelaer, G.

Buisson, A.

D’Incan, M.

Ferrier le Bouëdec, MC

Rouzaire, P.

Thévenot, J

Archive Ouverte en Sciences de l'Information et de la Communication

HAL Id: hal-02352024
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Submitted on 13 Nov 2019
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Rapid Desensitization to Adalimumab Is Associated
With Decreased Basophil Sensitivity
J Thévenot, Mc Ferrier Le Bouëdec, A. Buisson, G. Bommelaer, M. D’incan,
P. Rouzaire
To cite this version:
J Thévenot, Mc Ferrier Le Bouëdec, A. Buisson, G. Bommelaer, M. D’incan, et al.. Rapid De-
sensitization to Adalimumab Is Associated With Decreased Basophil Sensitivity. Journal of In-
vestigational Allergology and Clinical Immunology, ESMON Publicidad, 2019, 29 (2), pp.141-143.
￿10.18176/jiaci.0350￿. ￿hal-02352024￿
Title: Rapid desensitization to adalimumab is associated with a decrease of basophil sensitivity 1 
 2 
Short running title: Basophil activation test and rapid desensitization to adalimumab 3 
 4 
Manuscript word count: 1067 5 
Figure count: 1 6 
 7 
Authors and affiliations:  8 
Jonathan Thévenot, PhD1,2, Marie-Christine Ferrier le Bouëdec, MD3, Anthony Buisson, MD, PhD4, Gilles 9 
Bommelaer, MD, PhD4,  Michel D’Incan, MD, PhD3,5 and Paul Rouzaire, PhamD, PhD1,5,6 10 
 11 
1CHU de Clermont-Ferrand, Service d’Immunologie Biologique, Pôle de Biologie et d’anatomopathologie, 58 rue Montalembert, 69003 12 
Clermont-Ferrand, France 13 
2 current address: INRA / Agrocampus Ouest, UMR 1253, Science et Technologie du Lait et de l'Oeuf, 65 rue de St Brieuc, 35042 Rennes, 14 
France 15 
3CHU de Clermont-Ferrand, Service de Dermatologie, CHU Estaing, 1 Place Lucie et Raymond Aubrac, 69003 Clermont-Ferrand, France 16 
4CHU de Clermont-Ferrand, Service de Gastroentérologie, CHU Estaing, 1 Place Lucie et Raymond Aubrac, 69003 Clermont-Ferrand, France 17 
5 UMR 1240 INSERM/IMoST UCA 18 
6 current address: CHU de Clermont-Ferrand, Service d’Histocompatibilité, Pôle de Biologie et d’anatomopathologie, 58 rue Montalembert, 19 
69003 Clermont-Ferrand, France 20 
 21 
Corresponding author: Paul Rouzaire, PharmD, PhD, Service d’Histocompatibilité, Pôle de Biologie et 22 
d’anatomopathologie, CHU de Clermont-Ferrand, 58 rue Montalembert, 69003 Clermont-Ferrand, France. Email: 23 
porouzaire@chu-clermontferrand.fr. Phone: +334 73 751 983 24 
 25 
Conflict of interests: All the authors declare that tey have no relevant conflicts of interest in line with this 26 
work. 27 
 28 
Abstract: Rapid subcutaneous desensitization to adalimumab has been reported to be an effective management 29 
option. Monitoring this protocol using basophil activation test, we report here that desensitization is associated 30 
with a decrease of basophil sensitivity. 31 
 32 
Key words: adalimumab, rapid desensitization, basophil activation test, CDsens 33 
  34 
Adalimumab is a fully human recombinant monoclonal antibody against TNF-α, largely used in inflammatory 35 
diseases, such as Crohn disease or ulcerative colitis. Immediate hypersensitivity reactions to this molecule have 36 
been described, either local or systemic, ranging from pruritus to anaphylaxis (1). Rapid subcutaneous 37 
desensitization to adalimumab has been reported by several teams, and appears to be an effective management 38 
option, especially in patients without other obvious therapeutic options (2–5). Rapid drug desensitization protocols 39 
consist in administrating, in the patients who experienced hypersensitivity reactions, full therapeutic doses of 40 
eliciting drug, in an incremental manner, step by step (6). Despite no precise consensus exists today concerning 41 
the protocol to use, particularly for sub-cutaneous drugs, the sparse cases reported in literature validate the concept. 42 
Here, we report that successful desensitization to adalimumab of two patients is associated with a decrease of the 43 
basophil sensitivity, that we have monitored using basophil activation test (BAT). 44 
The patient #1 is a 30 years old woman, who presents a severe Crohn disease, diagnosed 12 years ago. She 45 
experienced severe urticarial lesions at the injection site within one hour of the first injection of adalimumab. This 46 
was a new course after a 6-year interruption of treatment (colectomy surgery, pregnancy). The patient #2 is a 38 47 
years old woman, suffering from a severe ulcerative colitis, diagnosed 10 years ago. She reported urticarial lesions 48 
at the injection site within one hour of the fifth injection of adalimumab. For both patients, prick tests to 49 
adalimumab were negative but intradermal test at the concentration of 1:1000 was positive at 20 min, suggesting 50 
an IgE sensitization. These two patients were addressed to the dermatology unit to benefit from rapid 51 
desensitization protocols to adalimumab. Given the lack of consensus on rapid drug desensitization, protocols have 52 
been established in line with the severity of inaugural reactions in these two patients. Patient #1 received for her 53 
first cure day a nine-step desensitization protocol, every 30 minutes reaching a cumulative dose of 54,3mg 54 
(respectively: 0,005mg, 0,05mg, 0,5mg, 1,25mg, 2,50mg, 5mg, 10mg, 15mg and 20mg). This protocol was 55 
repeated every week, decreasing the number of injections to reach only one injection (40 mg) at the visit #10. 56 
Patient #2 beneficiated from a nine-step protocol for the first day (0,005mg, 0,05mg, 0.5mg, 1.25mg, 2,5mg, 5mg, 57 
5mg, 10mg and 15mg) with a cumulative dose of 39.30 mg. The protocol was repeated every two weeks, 58 
decreasing there again the number of injections to one injection (40 mg), at the visit #12 with a good tolerance. 59 
We first report the performance of BAT in the assessment of allergic nature of the reaction (Fig. 1A), using the 60 
two most commonly used markers of activation/degranulation: CD203c and CD63. Before the beginning of the 61 
desensitization protocol, BAT to adalimumab were indeed strongly positive in both patients, according to the 62 
maximal percentage of activated basophil (i.e. CDmax, related to basophil reactivity). We validated the specificity 63 
of this in vitro reaction by testing four patients treated with adalimumab with a good tolerance. They all display 64 
negative BAT to adalimumab (Fig. 1A). Recently, another parameter of basophil activation test, the CDsens, was 65 
described to be correlated to basophil sensitivity (7,8). CDsens is defined as 1/LC50 x 100, where LC50 is the 66 
lowest concentration of allergen giving 50% of the maximum activation of basophils. We thus interested ourselves 67 
to investigate CDsens along the rapid desensitization protocol to adalimumab in the two patients. We thus repeated 68 
basophil activation testing three times (visits 1, 2 and 3 for the patient #1, i.e. before the protocol, at 3 weeks and 69 
6 weeks after the beginning; and visits 1, 3 and 5 for the patient #2, i.e. before the protocol, at 6 weeks and 10 70 
weeks after the beginning) (Fig. 1B). The first finding was, despite the increasing clinical tolerance to adalimumab, 71 
BAT remains strongly positive.  Indeed, CDmax remain constant, for both patients, using both marker (CD63 or 72 
CD203c). However, we observed a diminution of the CDsens parameter, reflecting a diminution of the sensitivity 73 
of the basophils, in both patients, with the two basophil activation/degranulation markers. To our knowledge, this 74 
is the first demonstration that rapid drug desensitization is associated with modifications on basophils, displaying 75 
a higher activation threshold along the injections.  76 
Pathophysiological mechanisms associated to rapid drug desensitization are not fully understood today. In vitro 77 
experiments and in vivo mouse models have shown that increasing doses of an antigen lead to prolonged 78 
hyporesponsiveness to triggering dose of the desensitizing antigen (6). Recently, BAT has been shown to be a 79 
potential biomarker for rapid drug desensitization, and Giavina-Bianchi et al. have demonstrated that BAT remains 80 
positive upon sequential injection of drug (9). Here we show that, despite the stability of CDmax, rapid drug 81 
desensitization is associated to a decrease of CDsens, demonstrating for the first time an impact in vivo of such 82 
protocols on the sensitivity of human basophils. These preliminary exciting data have now to be confirmed on 83 
larger studies, and will help to a better understanding of immunological mechanisms associated to the clinical 84 
success of rapid drug desensitization.  85 
References: 86 
1.  Singh S, Pardi DS. Update on anti-tumor necrosis factor agents in Crohn disease. Gastroenterol Clin North 87 
Am. 2014 Sep;43(3):457–78.  88 
2.  Bavbek S, Ataman Ş, Akıncı A, Castells M. Rapid subcutaneous desensitization for the management of local 89 
and systemic hypersensitivity reactions to etanercept and adalimumab in 12 patients. J Allergy Clin Immunol 90 
Pract. 2015 Aug;3(4):629–32.  91 
3.  Gutiérrez Fernández D, Foncubierta Fernández A, Anguita Carazo JL, Fernández Meléndez S, Fernández 92 
Anguita MJ, Medina Varo F. Adalimumab desensitization protocol in a patient with a generalized urticarial 93 
reaction and angioedema following adalimumab administration. J Investig Allergol Clin Immunol. 94 
2014;24(4):273–5.  95 
4.  Rodríguez-Jiménez B, Domínguez-Ortega J, González-Herrada C, Kindelan-Recarte C, Loribo-Bueno P, 96 
Garrido-Peño N. Successful adalimumab desensitization after generalized urticaria and rhinitis. J Investig 97 
Allergol Clin Immunol. 2009;19(3):246–7.  98 
5.  Quercia O, Emiliani F, Foschi FG, Stefanini GF. Adalimumab desensitization after anaphylactic reaction. 99 
Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 2011 Jun;106(6):547–8.  100 
6.  Castells Guitart MC. Rapid drug desensitization for hypersensitivity reactions to chemotherapy and 101 
monoclonal antibodies in the 21st century. J Investig Allergol Clin Immunol. 2014;24(2):72–9; quiz 2 p following 102 
79.  103 
7.  Santos AF, Du Toit G, Douiri A, Radulovic S, Stephens A, Turcanu V, et al. Distinct parameters of the basophil 104 
activation test reflect the severity and threshold of allergic reactions to peanut. J Allergy Clin Immunol. 2015 105 
Jan;135(1):179–86.  106 
8.  Chapuis A, Thevenot J, Coutant F, Messaoudi K, Michaud E, Pereira B, et al. Ara h 2 basophil activation 107 
test does not predict clinical reactivity to peanut. J Allergy Clin Immunol Pract. 2018 Feb 2;  108 
9.  Giavina-Bianchi P, Galvão VR, Picard M, Caiado J, Castells MC. Basophil Activation Test is a Relevant 109 
Biomarker of the Outcome of Rapid Desensitization in Platinum Compounds-Allergy. J Allergy Clin Immunol 110 
Pract. 2017 Jun;5(3):728–36.  111 
  112 
Figure legend: 113 
Fig. 1: Basophil activation test allows monitoring of rapid desensitization to adalimumab. A. Results of 114 
basophil activation test (BAT) to adalimumab, expressed in percentage of maximal activation (CDmax), either 115 
using CD63 (left) or CD203c (right), for the two patients (P#1 and P#2) and 4 controls tolerating adalimumab 116 
(C#1, C#2, C#3 and C#4). B. Results of BAT for the two patients (up and down), expressed in CD63 (left) and 117 
CD203c (right), along the rapid desensitization protocol (at V1, V2 and V3 for the patient #1 and V1, V3 and V5 118 
for the patient #2). CDsens is precised for each test. 119 
  120 
 121 
P#
1
P#
2
C
#1
C
#2
C
#3
C
#4
0
50
100
C
D
m
a
x
 (
C
D
6
3
) 
(%
)
A.
B.
50
m
g/
m
L
5m
g/
m
L
0,
5m
g/
m
L
0,
05
m
g/
m
L
0,
00
5m
g/
m
L
0
25
50
75
100
V3
V1
V2
CDsens= 2019,78
CDsens=   290,57
CDsens=   147,42
Adalimumab concentration
%
 o
f 
C
D
6
3
+
 b
a
s
o
p
h
il
s
Patient #1
50
m
g/
m
L
5m
g/
m
L
0,
5m
g/
m
L
0,
05
m
g/
m
L
0,
00
5m
g/
m
L
0
25
50
75
100
V1
V2
V3
CDsens= 2241,71
CDsens=   307,28
CDsens=   179,01
Adalimumab concentration
%
 o
f 
C
D
2
0
3
c
+
 b
a
s
o
p
h
ils
Patient #1
50
m
g/
m
L
5m
g/
m
L
0,
5m
g/
m
L
0,
05
m
g/
m
L
0,
00
5m
g/
m
L
0
25
50
75
100
V5
V1
V3
CDsens= 2505,28
CDsens= 1526,18
CDsens=   253,06
Adalimumab concentration
%
 o
f 
C
D
6
3
+
 b
a
s
o
p
h
ils
Patient #2
50
m
g/
m
L
5m
g/
m
L
0,
5m
g/
m
L
0,
05
m
g/
m
L
0,
00
5m
g/
m
L
0
25
50
75
100
V1
V3
V5
CDsens= 3454,65
CDsens=   379,15
CDsens=   277,90
Adalimumab concentration
%
 o
f 
C
D
2
0
3
c
+
 b
a
s
o
p
h
il
s
Patient #2
P#
1
P#
2
C
#1
C
#2
C
#3
C
#4
0
50
100
C
D
m
a
x
 (
C
D
2
0
3
c
) 
(%
)


English

Rapid Desensitization to Adalimumab Is Associated With Decreased Basophil Sensitivity

HAL Descartes

Ferrier Le Bouëdec, Mc

D’incan, M.

HAL Clermont Université

https://hal.archives-ouvertes.fr/hal-02352024/file/Thevenot%202019%20pour%20HLA.pdf

Rapid Desensitization to Adalimumab Is Associated With Decreased Basophil Sensitivity

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Archive Ouverte en Sciences de l'Information et de la Communication

HAL Descartes

HAL Clermont Université