Unusual presentation of

tuberculosis in an
iniximab-treated patient
which is the correct TB screening
before starting a biologic?dth_1278 1..3
Alessia Gori, Caterina Fabroni, Francesca Prignano &
Torello Lotti
Department of Dermatological Sciences, University of Florence, Italy
ABSTRACT: Iniximab is an anti-TNFa chimeric monoclonal antibody, commonly used in the treat-
ment of moderate to severe psoriasis. TNFais a pro-inammatory cytokine which play a key role in host
defense from infections by intracellular bacteria, such as Listeria monocytogenes, Histoplasma Capsu-
latum and especially Mycobacterium Tuberculosis. Iniximab therapy increases the risk of tuberculosis
due mainly to the reactivation of latent TB infection (LTBI) and, therefore, it is mandatory to screen
patients for LTBI prior to starting a treatment with anti-TNFa agents. We report the case of a psoriatic
patient, who, despite a negative screening for infection by M. tuberculosis including both tuberculin
skin test (TST) and chest X-ray, developed after 4 months of iniximab treatment, a severe pulmonary,
lymphnodal and intestinal tuberculosis during iniximab treatment.
KEYWORDS: psoriasis, quantiferon assay, tuberculosis (TB), TB screening, tuberculin skin test, tumor
necrosis factor alpha (TNFa)
An increased risk of tuberculosis (TB), particularly
disseminated or extrapulmonary forms, has been
demonstrated in patients receiving antagonists of
tumor necrosis factor alpha (TNFa) (1). We report
on a case of tuberculosis in a psoriatic patient,
resulted negative to the standard TB screening
prior to initiate therapy with iniximab (an anti-
TNFa chimeric humane-murine monoclonal anti-
body), who has developed an active pulmonary,
lymphnodal, and intestinal disease during the
treatment.
A 37-year-old white man was referred to our
clinic for severe psoriasis who was previously
treated with oral retinoids and PUVA (psoralen
combined with UVA radiation) therapy, achieving
only a mild and transitory improvement. At the
time of the rst visit, he presented thick
erythemato-scaled lesions localized predomi-
nantly on limbs (FIG. 1), referring that psoriasis
heavily compromised the quality of his social and
professional life. Before starting a biologic therapy,
the patient performed a chemistry screen and TB
screening including tuberculin skin test (TST) and
chest X-ray. The laboratory tests were blood cell
count, total and HDL cholesterol, triglycerides,
liver function tests, erythrocyte sedimentation rate,
C-reactive protein, serum creatinin, and hepatitis
markers. TB and chemistry screen resulted
Address correspondence and reprint requests to: Alessia Gori,
MD, Department of Dermatological Sciences, University of
Florence, Lorenzo il Magnico 104, Florence, 50129, Italy, or
email: alessiagori@gmail.com.
S1
Dermatologic Therapy, Vol. 23, 2010, S1S3
Printed in the United States All rights reserved
2010 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY
ISSN 1396-0296
negative. Considering the patients clinical condi-
tion and dermatological history, we decided to
start a treatment with iniximab (Remicade,
Centocor Inc., Malvern, PA) at the dosage of
5 mg/kg with the standard infusion protocol.
Iniximab therapy resulted in almost total remis-
sion of skin manifestations after the induction
period (FIG. 1). The patient repeated control labo-
ratory tests before the fourth infusion, and there
was lymphocytosis (lymphocytes 53.9% against
neutrophylic granulocytes 35.1%) as the only
signicant data.
After 16 weeks of treatment, the patient devel-
oped a persistent fever with sweats and headache,
treated unsuccessfully with 875 mg of amoxicillin
plus 125 mg clavulanic acid three times daily for 7
days. So he was admitted to hospital and under-
went clinical examination and investigation,
among which a chest X-ray that showed a globular
thickening at the left pulmonary hilum. TST,
Quantiferon TB-Gold assay, direct microscopic
examination with Ziehl-Nielsen (ZN) stain, and
Mycobacterium tuberculosis culture from sputum
resulted negative. An antibiotic therapy with ceftri-
axon(1 g once a day) and azitromicin(500 mg once
a day) for 5 days was started; thus, the fever and the
headache disappeared. Computed tomography of
the chest showed a diffuse micronodular pattern of
the antero-lateral segment of the left lower pulmo-
nary lobe and multiple mediastinic lymphoadeno-
pathies, associated to a pleural and pericardial
effusion. A mediastinic lymphonode biopsy was
performed. Histopathology demonstrated a pat-
tern characterized by necrotic and colliquative
inammation and caseating necrotic gigantocellu-
lar granulomas compatible with tuberculosis. The
ZN stain, applied directly to bioptic material,
allowed the identication of many acid fast bacilli.
At the same time, sputum smear microscopy,
culture, and polymerase chain reaction analysis
for TB, performed on three separated occasions,
resulted positive for M. tuberculosis complex, con-
rming the clinical hypothesis of pulmonary and
lymphonodal tuberculosis. The physical examina-
tion showed also splenomegaly and ascites. After-
ward a paracentesis was performed, which
revealed normal cytological parameters, but direct
microscopic examination after the ZNstaining and
culture examination to detect the presence of
mycobacteria resulted positive. At computed
tomography of the abdomen, images showed
spread mesenteric lymphoadenopathy and the
microscopic examination of ZN stained stool
sample for the detection of mycobacteria resulted
positive. The nal diagnosis of pulmonary tubercu-
losis with mediastinic lymphoadenopathy, spread
mesenteric adenopathy, right pleural effusion,
pericardial effusion, and ascites was made. Antitu-
bercular treatment was started with rifampicin
(10 mg/kg/die: 600 mg), ethambutol (20 mg/kg/
die: 1200 mg), isoniazid (5 mg/kg/die: 300 mg),
and pirezinamid (500 mg three times a day) for 12
months, obtaining a clinical healing.
In the literature there are numerous reports
regarding anti-TNFa agents and the increased risk
of infections, particularly tuberculosis. In immu-
nocompetent people, infection with M. tuberculo-
sis often causes no symptoms because the persons
immune system acts to wall off the bacteria;
therefore, latent TB infection is presently much
more common than active TB infection. Given that
the most important risk connected with iniximab
therapy is due to the reactivation of latent TB-
inducing apoptosis of granulomatous cells through
the linkage of transmembrane TNFa, it is manda-
tory to screen patients for latent TB prior to initiat-
ing a treatment with biologics (2,3). Currently,
international guidelines recommend as screening
of latent tubercular infection to perform a TST and
a chest X-ray. TST yields a delayed hypersensitivity-
type response to puried protein derivatives of M.
tuberculosis. TSTs may yield false-negative results
in patients who are highly ill or immunocompro-
mised, as those receiving TNFa antagonists or
other immunosuppressive drugs, or false-positive
results in those immunized for TB or with past-
cleared infection caused by atypical mycobacteria
(4). Therefore, new TB tests are being developed
FIG. 1. Patients hands before (left) and after (right) iniximab therapy.
Gori et al.
S2
that offer the chance of less expensive, fast, and
more accurate TB testing. These use polymerase
chain reaction detection of bacterial DNAand anti-
body assays to detect the release of interferon
gamma in response to mycobacteria, increased in
the patients affected by latent M. tuberculosis infec-
tion. Since 2001 this complementary assay, the
interferon-gamma blood test Quantiferon-TB
(QFT), allows to determinate in vitro interferon-
gamma released by sensitized lymphocytes in
whole blood incubed for 1624 hours with puried
protein derivative, antigen of M. tuberculosis (5,6).
QFT results more specic and sensible than TST
because it distinguishes Mycobacterium Tubercu-
losis infection from atypical mycobacteriosis and
is associated with a lower percentage of false-
negatives in the patients with latent TB infection
(7). Unfortunately, in our case, both TST and QFT
resulted negative before starting iniximab therapy
and also during the active disease. Finally, only the
lymphonodal biopsy permitted the diagnosis of TB
infection in our case. The reason of this negative
QFT during active disease phase is not reported in
the literature. Our hypothesis is that the anti-TNFa
therapy could downregulate interferon-gamma
synthesis from inammatory cells. Because tuber-
cular screening tests may have false-negative
results, a detailed assessment of risk of tuberculosis
should be performed in every case, rethinking the
present, widely accepted screening procedure.
Disclosure
The authors have declared no conicts of interest.
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Unusual presentation of tuberculosis in an iniximab-treated patient
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