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Leishmanias is an anthropozoonosis caused by the Leishmania protozoa. The manifestation of the disease varies depending on the type of Leishmania and the immunestatus of the patient. Tumor Necrosis Factor (TNF)-αantagonists were introduced in the late 1990s and have had a marked impact on rheumatic diseases. Tumor necrosis factor plays an important role in the immune systems defense against intracellular infections and the use of TNF-αantagonists is linked with an increased frequency of infections. We here present a case of cutaneous leishmaniasis relapse following treatment with miltefosine and amphotericin B, in a patient undergoing treatment with a TNF-α antagonist.
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© 2015 Erik Otte, Mikael Christia nsen and Eskild Petersen. T his open access article is distrib uted under a Creative Com mons
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American Journal of Infectious Diseases
Case Reports
Relapsing Cutaneous Leishmaniasis in a Patient Treated with
Humira
1Erik Otte, 2Mikael Christiansen and 1,3Eskild Petersen
1Department of Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark
2Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
3De partment of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
Article history
Received: 03-12-2014
Revised: 02-01-2015
Accepted: 05-05-2015
Corresponding Author:
Eskild Petersen
Department of
Infectious Diseases and
Clinical Microbiology, Aarhus
University Hospital, Aarhus,
Denmark
Email: eskildp@dadlnet.dk
Abstract: Leishmanias is an anthropozoonosis caused by the Leishmania
protozoa. The manifestation of the disease varies depending on the type of
Leishmania and the immunestatus of the patient. Tumor Necrosis Factor
(TNF)-α antagonists were introduced in the late 1990s and have had a
marked impact on rheumatic diseases. Tumor necrosis factor plays an
important role in the immune systems defense against intracellular
infections and the use of TNF-α antagonists is linked with an increased
frequency of infections. We here present a case of cutaneous leishmaniasis
relapse following treatment with miltefosine and amphotericin B, in a
patient undergoing treatment with a TNF-α antagonist.
Keywords: Cutaneous Leishmaniasis, Humira, Adalimumab, TNF-α
Antagonist, Amphotericin B
Introduction
Leishmaniasis is an infection caused by the parasite
Leishmania, a protozoan zoonosis transmitted by
sandflies. Leishmaniasis has several clinical
presentations, including a cutaneous, mucosal and a
visceral form. Clinical presentation is, to a large extent,
determined by the Leishmania subtype of which more
than 20 are known. In Central and South America (New
World) Cutaneous Leishmaniasis (CL) is mainly caused
by L. mexicana and L. viannia complexes, with the
Lutzomyia sandfly as the primary vector. Old World
leishmaniasis (Europe, Africa and Asia) is transmitted by
the vector Phlebotomus and is mainly caused by the
subtypes L. major, L. tropica and L. aethiopica.
Worldwide cutaneous leishmaniasis is the most common
presentation of leishmania infection with an estimated
annual incidence of 0.7-1.2 million cases (Alvar et al.,
2012). CL is characterized by a painless dry noduli or
ulceration with indurated borders. The infection can be
latent and reactivated when a hosts immune system is
compromised. Globally an estimated 350 million people
are at risk and a northward spread has been reported with
cases of leishmaniasis presenting in northern Italy,
central Europe (Aspöck et al., 2008) and the Jura region
in France (Faber et al., 2012). Also within the last
decade an increasing number of travelers and military
personnel returning to Europe, with Leishmania
infections, have been reported (Hodiamont et al., 2014).
Ankylosing Spondylitis (AS), also known as Morbus
Bechterew, is a chronic inflammatory rheumatic disease
that primarily involves the sacroiliacal joints and the
spine. The first line treatment is NSAID’s and non-
pharmaceutical therapy such as exercise and
physiotherapy. Within the last decade anti TNF-α
therapy has emerged as a strong alternative and is now
recommended for patients with persistently high disease
activity despite conventional treatment (Braun et al.,
2011). Adalimumab (ADA) is a recombinant fully
human IgG1 monoclonal antibody which binds with
high affinity to soluble TNF-α and blocks its
interaction with cell surface TNF-α receptors. Large
randomized placebo-controlled trials with AS patients
have proven ADA highly efficient in reducing back-
pain, loss of function and inflammatory markers
(Van der Heijde et al., 2006). Here we report a case of
a patient with AS treated with ADA, who presented
with a case of relapsing CL after treatment with
miltefosine and amphotericin B.
Case Report
A 62-year old Caucasian man with a 17-year history
of AS, uveitis, psoriasis and Crohn’s disease, was
treated with Asacol, Salazopyrin. ADA was added to
the treatment in 2011 with a marked effect on AS
related symptoms. In May 2013, while holidaying in
Portugal, the patient presented with a cutaneous
ulceration on the dorsal side of his left antebrachii. No
systemic symptoms were present and initial treatment
Erik Otte et al. / American Jo urnal of Infect ious Diseases 2015, 11 (1): 7.10
DOI: 10.3844/ajidsp.2015.7.10
8
consisted of an oral antibiotic with no significant
response. Upon his return to Denmark in July, the
patient was seen at the Department of Dermatology.
Based on the clinical assumption of pyoderma
gangrenosum the patient received treatment with
corticosteroids. The lesion proved unresponsive to the
treatment and punch biopsies, of the affected area, were
performed (Fig. 1A). Histopathological findings
showed granuloma formation and CL was suggested as
a possible cause. Amplification of Leishmania genomic
sequences confirmed the diagnosis in August 2013. The
patient was referred to the Department of Infectious
Diseases, where treatment consisted of miltefosine 50
mg b.d. (twice daily) for 28 days. Post treatment,
clinical examination showed regression of the
cutaneous lesion, but not complete healing (Fig. 1B.)
Three months after the initial regression, the ulcer
recurred. New biopsies sent for PCR showed
Leishmania, leading to the conclusion of a treatment
failure. Liposomal amphotericin B (l-AmB) 200 mg IV
daily was given for 10 days in March 2014.
After the infusions the lesion partly healed, but
relapsed as treatment with l-AmB ended (Fig. 2A). It
was speculated that ADA treatment could be
responsible for the relapse of CL. ADA treatment was
therefore paused and a second course of l-AmB was
given. 16 doses of l-AmB 200 mg were administered
with 48 hours interval. Following this the patient was
seen at the Department of Infectious Diseases and it
was concluded that treatment, after pausing ADA, had
been successful (Fig. 2B). The pausing of ADA was
well tolerated for the duration of the CL treatment.
Fig. 1. Lesion before (A) and after miltefosin treatment (B)
Fig. 2. Lesion before (A) and after second l-AmB treatment (B)
Erik Otte et al. / American Jo urnal of Infect ious Diseases 2015, 11 (1): 7.10
DOI: 10.3844/ajidsp.2015.7.10
9
Discussion
In Southern Europe leishmaniasis is solely caused
by the subtype L. infantum and in Portugal domestic
dogs present a large zoonotic reservoir. L. infantum can
cause CL, although visceral leishmaniasis is the most
common presentation of the disease (Campino et al.,
2006). The protozoon is an obligate intracellular
parasite, infecting macrophages, which are essential in
the formation of granulomas. TNF-α antagonists are
potent inhibitors of cytokines that play an important
role in the formation of granulomas and the host’s
defense against intracellular infections such as
tuberculosis and legionellosis. Studies of mice have
shown that low levels of TNF-α and TNF-α antagonist
treatment corresponds with larger, hyperparasited
lesions less responsive to treatment (Titus et al., 1989;
Murray et al., 2000). Data for drug efficiency in
relation to treatment of CL is limited. Although
literature is limited, l-AmB in the given dose has been
shown to be effective in 97% of treated patients in one
smaller study (Solomon et al., 2013). L-AmB is as
polyene antibiotic with a specificity for macrophages
due to its liposomal form. It targets ergosterol and
causes death to the parasite by increased membrane
permeability. Previously cases of CL in patients
undergoing ADA treatment have been reported in
literature (Gomes et al., 2012; Franklin et al., 2009).
Gomes et al. (2012) reported a case of cutaneous
leishmaniasis which responded to Glucantime
treatment. In this case the authors found that there was
no reason to believe that an association was present as
the patient neither presented with disseminated or
relapsing Leishmania. ADA was paused for the
duration of the treatment. Franklin et al. (2009)
described the case of a latent leishmania infection
presumably activated by ADA treatment. The lesion
responded to l-AmB treatment.
Khan et al. (2010) described a case of
disseminated CL, in a patient treated with ADA for
psoriatic arthritis. The patient responded to treatment
with sodium stilbogluconate and l-AmB treatment, but
the patients underlying disease flared when ADA
treatment was paused and ADA treatment was
restarted under close monitoring. Zanger et al. (2012)
found that numbers of case reports linking leishmania
and anti TNF-α therapy were increasing. Looking at
previous cases they found evidence that suggested that
ertacenept treatment possibly should be favoured over
ADA and infliximab treatment, in patients at risk of
leishmania exposure.
Conclusion
We believe that repeated treatment failure of CL in
this case was explained by the use of TNF-α antagonists.
Our case proved unresponsive to treatment with
miltefosine and l-AmB. Only after withdrawal of
ADA did a second treatment course with l-AmB result
in healing. The use of TNF-α antagonists increases
globally. This in turn requires increased focus on
possible opportunistic infections and alterations of
treatment regimes in relation to these. The growing
consensus that ADA treatment should be paused for
the duration of CL treatment is underlined by this
case-report. In light of this case we find it
recommendable that pausing TNF-α antagonist treatment
should be considered in patients undergoing treatment
for CL and that patients, following treatment, should
be monitored closely, as small numbers of viable
parasites in lesions may result in reactivation of the
disease when ADA treatment is restarted. Furthermore it
might be considered altering the treatment in favor of
ertacenept in patients returning to, or living in, areas of
endemic leishmaniasis.
Conflicts of Interest
The authors declare that they have no conflicts of
interest.
Author’s Contributions
Erik Otte: Wrote the paper, performed the litterature
search.
Mikael Christiansen: Managed the humira
treatment, commented on the manuscript.
Eskild Petersen: Managed the leishmania treatment,
supervised writing of the manuscript, discussed the
publication with the patient.
Ethics
We obtained permission from the patient to publish
his data and the patient provided the phot's.
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