Clinical Immunology (2010) 135, 499–500
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Clinical Immunology
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LETTER TO THE EDITOR
CD4+ T-cells lymphocytosis and reduction of
neutrophils during treatment with adalimumab:
Challenge and dechallenge study
KEYWORDS
Adalimumab;
Adverse drug reaction;
Lymphocytosis;
CD4+ cells
To the Editor,
In this letter we document a case of CD4+ cells lympho-
cytosis with reduction in blood neutrophils during treatment
with adalimumab including dechallenge and rechallenge.
TNF-α targeting agents (infliximab, adalimumab, etanercept)
represent the first-line biologic therapy for the treatment of
different rheumatic diseases, such as rheumatoid arthritis,
psoriatic arthritis and ankylosing spondylitis [1]. Severe
hematologic complications are a rare adverse drug reaction
to anti-TNF-α treatment. Clinical trial showed cases of
aplastic anaemia [2] and pancytopenia potentially related
to the administration TNF-α blocking agents.
The patient is a 57-year-old woman with arterial
hypertension and osteoporosis, who developed rheumatoid
arthritis in 2005 manifest as bilateral arthritis of hands and
wrists. Despite treatment with DMARD's and steroids,
remission was not achieved. Thus, in September 2008,
adalimumab, a fully humanized anti-TNF-α monoclonal
antibody [3], was started at the dose of 40 mg subcuta-
neously every 2 weeks, together with methotrexate.
Before starting the patient had a normal leukocyte count
and differential (WBC 6700/mm3; neutrophils 4200/mm3;
lymphocytes 2100/mm3). After 8 weeks of treatment, her
blood count showed mild lymphocytosis (WBC 6250/mm3,
lymphocytes 3040/mm3) together with a reduction of
neutrophils compared to baseline values (neutrophils
2500/mm3). Red blood cells, hemoglobin and platelets
were normal. Immunophenotypic analysis showed an
expansion of total T lymphocytes (3132/mm3) mainly due
to an expansion of CD4+ lymphocytes (1972/mm3), with
normal values of CD8+, CD19+ and CD56+. No clinical signs
of infection were present and serological tests for hepatitis
1521-6616/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.clim.2010.02.004
B and C, human immunodeficiency virus, cytomegalovirus
and Epstein–Barr were negative. Also ANA, ENA and
neutrophil antibiodies were negative. Both adalimumab
and methotrexate were stopped, and leukocyte count
recovered after 6 weeks. Because of ongoing disease
activity, Adalimumab was restarted without methotrexate.
After 10 weeks the blood count again showed the pattern
of lymphocytosis (WBC 6530/mm3, lymphocytes 3600/mm3)
and concomitant reduction in neutrophils (neutrophils
1830/mm3) with immunophenotypic analysis showing T
cell lymphocytosis (3934/mm3) with expansion of −CD4+
cells (2619/mm3). Adalimumab was stopped and blood
count recovered in few weeks. The Naranjo probability
score result for causality was 8, thus confirming the
reaction as a probable adverse drug reaction to
adalimumab.
Here we have reported a case of reversible T-cell
lymphocytosis, mainly due to a non-malignant expansion of
CD4+ T-cells, accompanied by reduction in neutrophils, after
the administration of TNF-α targeting drug adalimumab.
Strongly supporting adalimumab in the genesis of these
abnormalities is the evidence that lymphocyte abnormalities
recovered after drug withdrawal and the lymphocytosis
reappeared when patient was rechallenged with adalimumab
on two occasions.
Among hematologic consequences of TNF-α therapeutic
blockade aplastic anaemia and pancytopenia have been
rarely reported and there is no sufficient evidence for a
direct role of TNF-α blocking agents administration in the
development of these complications.
Neutropenia represents the most commonly reported
possible hematologic complication of this class of drugs.
Ottaviani et al. [4] described a case of neutropenia
associated with adalimumab but similar cases have been
described with other drug of the same class, such as
infliximab and etanercept [5,6].
Evidence of lymphocytosis during treatment with bio-
logics is more limited. Theodoridou et al. [7] described a case
of large granular T-lymphocyte expansion and neutropenia
associated with the administration of adalimumab.
As a possible biologic basis for our case, there is the fact
that T cell development and recruitment are regulated by
different cytokines including TNF-α, which acts as a potent
mediator of cell death in cells expressing its receptor [8]. For
this reason TNF-α plays an important role in inflammation
and host anti-tumor responses. TNF-α also interacts with a
variety of other ligands such as CD30 and CD95, which are
500
expressed on different cell types including activated T cells
[9,10]. Consequently, blocking TNF-α would be expected to
cause a dysregulation of these interactions, resulting in a
non-malignant expansion of cells expressing TNF-α ligands,
including T cells. To our knowledge our case report is the first
reporting benign expansion of CD4+ T cells associated with a
TNF-α targetting agent. The clinical significance of this
abnormality needs be addressed in future studies.
References
[1] P.C. Taylor, M. Feldmann, Anti-TNF biologic agents: still the
therapy of choice for rheumatoid arthritis, Nat. Rev. Rheumatol.
5 (10) (2009) 578–582.
[2] ACR Hotline, FDA Advisory Committee Reviews Safety of TNF
Inhibitors, American College of Rheumatology, Atlanta (GA),
2001.
[3] HUMIRA® (adalimumab) product monograph, Abbott Laborato-
ries, North Chicago, IL, February 2005.
[4] S. Ottaviani, I. Cerf-Payrastre, F. Kemiche, E. Pertuiset,
Adalimumab-induced neutropenia in a patient with rheumatoid
arthritis, Joint Bone Spine 76 (3) (2009) 312–313.
[5] E. Montané, M. Sallés, A. Barriocanal, E. Riera, J. Costa, X.
Tena, Antitumor necrosis factor-induced neutropenia: a case
report with double positive rechallenges, Clin. Rheumatol. 26
(9) (2007) 1527–1529.
[6] I. Lahbabi, H. Adamski, S. Le Jean, V. Cannieux, E. Polard, J.
Chevrant-Breton, Neutropenia and thrombocytopenia in a
patient presenting psoriasis treated with etanercept, Ann.
Dermatol. Venereol. 135 (5) (2008) 409–410.
Letter to the Editor
[7] A. Theodoridou, C. Kartsios, E. Yiannaki, D. Markala, L. Settas,
Reversible T-large granular lymphocyte expansion and neutro-
penia associated with adalimumab therapy, Rheumatol. Int. 27
(2) (2006) 201–202.
[8] S. Gupta, S. Gollapudi, Molecular mechanisms of TNF-alpha-
induced apoptosis in naïve and memory T cell subsets,
Autoimmun. Rev. 5 (4) (2006) 264–268.
[9] C.M. Hill, J. Lunec, The TNF-ligand and receptor super-
families: controllers of immunity and the Trojan horses of
autoimmune disease, Mol. Aspects Med. 17 (5) (1996)
455–509.
[10] J. Clark, P. Vagenas, M. Panesar, A.P. Cope, What does tumour
necrosis factor excess do to the immune system long term, Ann.
Rheum. Dis. 64 (Suppl. 4) (2005) iv70–iv76.
Francesco Ursini*
Saverio Naty
Caterina Bruno
Marilena Calabria
Francesco Spagnolo
Rosa Daniela Grembiale
Rheumatology Research Unit,
Clinical and Experimental Medicine Department,
University of Catanzaro “Magna Graecia”,
University Campus “Salvatore Venuta”-
Viale Europa, Catanzaro, Italy
E-mail address: rheumatology@unicz.it (F. Ursini).
⁎Corresponding author. Fax: +39 09613647192.
4 February 2010