Leishmaniasis and tumor necrosis factor alpha antagonists in the Mediterranean basin. A switch in clinical expression

Abstract

BackgroundTumor necrosis factor alpha (TNF-α) blockers are recognized as a risk factor for reactivation of granulomatous infections. Leishmaniasis has been associated with the use of these drugs, although few cases have been reported.MethodologyWe performed a retrospective observational study including patients with confirmed leishmaniasis acquired in the Mediterranean basin that were under TNF-α blockers therapy at the moment of the diagnosis. Patients diagnosed in our hospital from 2008 to 2018 were included. Moreover, a systematic review of the literature was performed and cases fulfilling the inclusion criteria were also included.Principal findingsForty-nine patients were analyzed including nine cases from our series. Twenty-seven (55.1%) cases were male and median age was 55 years. Twenty-five (51%) patients were under infliximab treatment, 20 (40.8%) were receiving adalimumab, 2 (4.1%) etanercept, one (2%) golimumab and one (2%) a non-specified TNF-α blocker. Regarding clinical presentation, 28 (57.1%) presented as cutaneous leishmaniasis (CL), 16 (32.6%) as visceral leishmaniasis (VL) and 5 (10.2%) as mucocutaneous leishmaniasis (MCL). All VL and MCL patients were treated with systemic therapies. Among CL patients, 13 (46.4%) were treated with a systemic drug (11 received L-AmB, one intramuscular antimonials and one miltefosine) while 14 (50%) patients were given local treatment (13 received intralesional pentavalent antimonials, and one excisional surgery). TNF-α blockers were interrupted in 32 patients (65.3%). After treatment 5 patients (10.2%) relapsed. Four patients with a CL (3 initially treated with local therapy maintaining TNF-α blockers and one treated with miltefosine) and one patient with VL treated with L-AmB maintaining TNF-α blockers.ConclusionsThis data supports the assumption that the blockage of TNF-α modifies clinical expression of leishmaniasis in endemic population modulating the expression of the disease leading to atypical presentations. According to the cases reported, the best treatment strategy would be a systemic drug and the discontinuation of the TNF-α blockers therapy until clinical resolution.

Leishmaniasis in the United States: Emerging Issues in a Region of Low Endemicity

“…Several common themes appear to have emerged, including an association with all forms of leishmaniasis, a generally typical disease presentation, a prolonged interval period between TNF-α inhibitor initiation and symptomatic disease onset (median of 18 months in one series), and a relatively greater risk associated with monoclonal antibody constructs (e.g., adalimumab, infliximab) as compared with the pseudo-TNF receptor etanercept [ 128 , 129 ]. This latter phenomenon may in part be related to the ability of monoclonal antibodies to inhibit both soluble and transmembrane forms of TNF-α, whereas etanercept can only neutralize the soluble molecule, resulting in somewhat less potency and a concomitant lower risk of reactivation and dissemination [ 130 ].…”

“…Treatment guidance for TNF-blockade associated VL is limited to the experience cited in case series; good outcomes with relatively low recurrence rates have been attained with standard anti-leishmanial therapies coupled with reduction in or temporary cessation of immunosuppression, and over 90% of patients can achieve clinical cure with this approach [ 125 , 129 ]. Zanger et al reported leishmanial recurrence in two of seven rechallenged patients (one cutaneous and the other mucosal leishmaniasis), with no relapses of VL in the other five.…”

A Rare Infectious Complication of a Treatment with Biologics: Disseminated Cutaneous Leishmaniasis Associated with Adalimumab

“…In the era of biologics, physicians often witness the reactivation of latent infections, such as tuberculosis or leishmaniasis [1]. When it comes to leishmaniasis in relation to tumor necrosis factor alpha (TNF-α) inhibitors, one of the suggested pathogenetic mechanisms of infection is believed to be a TNF-α inhibitor-mediated downregulation of endothelial…”

“…Leishmaniasis is caused by an intracellular protozoon and is characterized by a broad spectrum of cutaneous, mucosal, and systemic presentations [1]. The clinical manifestations of leishmaniasis are determined by the subtype of the infectious agent and the immunocompetent profile of the patient [1].…”

“…The introduction of biologics is accompanied with impressive therapeutic outcomes, but also with an increase in the incidence of several infectious diseases [1]. We present the case of a patient who developed a disseminated cutaneous leishmaniasis infection during treatment with adalimumab.…”